Consumer medicine information

Lamivudine RBX Tablets

Lamivudine

BRAND INFORMATION

Brand name

Lamivudine RBX Tablets

Active ingredient

Lamivudine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lamivudine RBX Tablets.

What is in this leaflet

This leaflet answers some common questions about LAMIVUDINE RBX. It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

This leaflet was last updated on the date at the end of this leaflet. More recent information may be available. The latest Consumer Medicine Information is available from https://www.ebs.tga.gov.au/ and may contain important information about the medicine and its use of which you should be aware.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking LAMIVUDINE RBX against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What LAMIVUDINE RBX is used for

LAMIVUDINE RBX contains the medicine lamivudine which belongs to a group of medicines called antivirals.

LAMIVUDINE RBX is used together with other antivirals to slow down the progression of human immunodeficiency virus (HIV) infection, which can lead to Acquired Immune Deficiency Syndrome (AIDS) and other related illnesses (eg AIDS-related Complex or ARC).

LAMIVUDINE RBX does not cure AIDS or kill the HIV virus, but prevents further damage to the immune system by stopping production of new viruses.

LAMIVUDINE RBX does not reduce the risk of passing the infection to others. You will still be able to pass on the HIV virus by sexual activity or by contamination with infected blood. You should still use proper precautions.

While taking LAMIVUDINE RBX and/or any other therapy for HIV disease, you may continue to develop other infections and other complications of HIV infection. You should keep in regular contact with the doctor who is looking after you.

LAMIVUDINE RBX tablets are not addictive.

Your doctor may have prescribed LAMIVUDINE RBX for another reason.

Ask your doctor if you have any questions about why LAMIVUDINE RBX has been prescribed for you.

Before you take LAMIVUDINE RBX

When you must not take it

  • Do not take LAMIVUDINE RBX if you have ever had an allergic reaction to lamivudine or any of the ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.
  • Do not take LAMIVUDINE RBX if you are pregnant, trying to become pregnant or breast-feeding, unless your doctor says you should. Your doctor will discuss the risks and benefits of using LAMIVUDINE RBX if you are pregnant or breast-feeding.
  • Do not use LAMIVUDINE RBX to treat any other conditions unless your doctor tells you to.
  • Do not give LAMIVUDINE RBX tablets to anyone else, even though their symptoms may sound similar to yours.
  • Do not take LAMIVUDINE RBX after the expiry date (EXP) printed on the pack, or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal. If you're not sure whether you should be taking LAMIVUDINE RBX, talk to your doctor.

Before you start to take it

You must tell your doctor if:

  • you are allergic to foods, dyes, preservatives or any other medicines.
  • you have, or have ever had, liver problems, for example jaundice, hepatitis, virus affecting the liver, enlarged liver or liver scarring (cirrhosis) or if you have any risk factors for liver problems, e.g. excessive alcohol intake, illegal intravenous drug use with shared equipment, iron or copper storage disorders.
  • you have, or have ever had, problems with your kidney or pancreas.
  • you have diabetes.
  • you have any other illness, including those that you think are not related to HIV infection.

When you stop taking LAMIVUDINE RBX

If you have a long-standing viral infection of your liver (hepatitis B), it may flare up. This can cause serious illness particularly if your liver is already not working very well. If you have both HIV and hepatitis B, when you stop taking LAMIVUDINE RBX, your doctor is likely to arrange tests from time to time to check how well your liver is working and to measure virus levels.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may affect the way others work. Your doctor or pharmacist will be able to tell you what to do when taking LAMIVUDINE RBX with other medicines.

Lamivudine is not recommended to be used in combination with zalcitabine (used for the treatment of HIV infection).

HOW to take LAMIVUDINE RBX

Your doctor will tell you how many LAMIVUDINE RBX tablets to take and how often to take them. Do not take extra tablets or take the tablets more often than you have been told.

How much to take

For adults and adolescents 12 years and older, the usual dose is one 150 mg tablet twice a day or 300 mg once a day. Your doctor may prescribe a different dosage.

For younger children between 3 months to 12 years of age the dose of LAMIVUDINE RBX will depend on their weight in kilograms (kg). If you are giving LAMIVUDINE RBX to a child, follow your doctor's instructions.

How to take it

LAMIVUDINE RBX tablets should be swallowed whole with a glass of water. If you cannot swallow the tablet(s), you may crush and combine them with a small amount of food or drink and take the entire dose immediately.

How long to take it

Because your medicine helps to control your condition, but does not cure it, you will need to take the tablets every day. Do not stop taking your medicine without first talking to your doctor.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, then go back to taking it as you would normally.

Do not take a double dose to make up for the dose that you missed.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26), or go to the Emergency Department at your nearest hospital, if you think that you or anyone else may have taken too much LAMIVUDINE RBX. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention. Keep telephone numbers for these places handy.

If you are not sure what to do, contact your doctor or pharmacist.

While you are taking LAMIVUDINE RBX

Things you must do

Tell your doctor or pharmacist that you are taking LAMIVUDINE RBX if you are about to be started on any other medicines.

Tell your doctor if you become pregnant or are trying to become pregnant.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Things you must not do

Do not stop taking LAMIVUDINE RBX, or change the dose without first checking with your doctor.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not use LAMIVUDINE RBX to treat any other complaints unless your doctor says to.

Things to be careful of

Be careful driving or operating machinery until you know how LAMIVUDINE RBX affects you.

Side Effects

Tell your doctor as soon as possible if you don’t feel well while taking LAMIVUDINE RBX, even if the problems do not seem to be related to the medicine or are not listed in this leaflet.

Like all medicines, LAMIVUDINE RBX can cause some side effects. If they occur, they are most likely to be minor and temporary. However, some may be serious and need medical attention.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • Headache
  • Diarrhoea
  • Fatigue/tiredness
  • Abdominal discomfort and pain
  • Rash
  • Fever
  • Unusual feelings in any part of the body, such as numbness, burning, tingling or pins and needles
  • Increased bruising or bleeding
  • Joint or muscle pain

Changes in fat distribution have been reported in association with combination antiretroviral therapy, and may result in:

  • Loss of body fat from areas such as legs, arms and face
  • Increased fat appearing in areas such as abdomen (belly) and other internal organs, breasts and the back of the neck

Within the first few weeks of treatment with anti-HIV medicines, some people, particularly those that have been HIV-positive for some time, may develop inflammatory reactions (e.g. pain, redness, swelling, high temperature) which may resemble an infection and may be severe. It is thought that these reactions are caused by a recovery in the body's ability to fight infections previously suppressed by HIV. If you become concerned about any new symptoms or any changes in your health after starting HIV treatment, discuss with your doctor immediately.

Ask your doctor or pharmacist to answer any questions you may have.

If you have any of the following symptoms soon after starting to take LAMIVUDINE RBX, DO NOT TAKE ANY MORE LAMIVUDINE RBX and tell your doctor IMMEDIATELY or go to the accident and emergency department at your nearest hospital:

  • Lumps, rash or "hives" on your skin
  • Swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • Wheezing, chest pain or tightness
  • Fainting

These are very serious side effects. If you have them, you may have a serious allergic reaction. You may need urgent medical attention or hospitalisation. These side effects are very rare.

If you have any of the following symptoms soon after starting to take LAMIVUDINE RBX, DO NOT TAKE ANY MORE LAMIVUDINE RBX and tell your doctor IMMEDIATELY or go to the accident and emergency department at your nearest hospital:

  • Severe stomach pain or cramps
  • Nausea
  • Vomiting

These side effects may be due to a condition called pancreatitis.

If you are on medication for HIV and become very sick, with fast breathing, stop taking LAMIVUDINE RBX and consult your doctor immediately. You may have a condition known as "lactic acidosis". The fast breathing is due to high acid levels in the blood. Your liver may not be working properly and gets big and fatty. This can be life threatening. This illness occurs more often in women than men.

See your doctor if you feel generally unwell with loss of appetite, nausea, vomiting, itching, yellowness of the skin or eyes or dark coloured urine, or if the blood tests of your liver function are abnormal. It is likely you will have to stop taking LAMIVUDINE RBX.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Some people may get other side effects while taking LAMIVUDINE RBX. If you are concerned, talk to your doctor or pharmacist.

Ask your doctor or pharmacist if you don't understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking LAMIVUDINE RBX

Storage

Keep the tablets where children cannot reach them. A locked cupboard at least one-and-a-half metres above the ground is a good place to store them.

Keep LAMIVUDINE RBX in a cool, dry place where it stays below 25 degrees Celsius. Do not store the tablets, or any other medicine, in a bathroom or near a sink. Do not leave them in the car or on window sills. Heat and dampness can destroy some medicines.

Keep your LAMIVUDINE RBX tablets in the bottle with the cap tightly closed until you take them. If you take LAMIVUDINE RBX out of their pack they may not keep well.

Disposal

If your doctor tells you to stop taking LAMIVUDINE RBX, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets left over.

Product description

What LAMIVUDINE RBX looks like

LAMIVUDINE RBX 150 mg tablets are white, film-coated, modified diamond-shaped tablets, debossed with “RF & 96” on either side of the breakline on one side and a breakline on the other side. Available in bottles of 60 tablets.

LAMIVUDINE RBX 300 mg tablets are grey, film-coated, modified diamond-shaped tablets, debossed with “RF97” on one side and plain on the other side. Available in bottles of 30 tablets.

Ingredients

Active ingredient
LAMIVUDINE RBX tablets contain either 150 mg or 300 mg of lamivudine per tablet.

Inactive ingredients

  • Microcrystalline cellulose
  • Sodium starch glycollate type A
  • Magnesium stearate
  • Hypromellose
  • Titanium dioxide
  • Macrogol PEG 400
  • Polysorbate 80
  • Black iron oxide (E172) (only 300 mg tablets).

LAMIVUDINE RBX tablets do not contain gluten, lactose or sugar.

Sponsor

Ranbaxy Australia Pty Ltd.
9-13 Waterloo Road
Macquarie Park NSW 2113

Australian Registration Numbers

  • LAMIVUDINE RBX 150 mg
    - AUST R 172813
  • LAMIVUDINE RBX 300 mg
    - AUST R 172817

This leaflet was prepared in October 2013.

Further Information

This is not all the information that is available on LAMIVUDINE RBX. If you have any more questions or are not sure about anything, ask your doctor or pharmacist. They are the best people to provide individual advice for you. You may also be able to find out more information about your disease from books, for example in public libraries. Counselling is also available from your local AIDS council.

BRAND INFORMATION

Brand name

Lamivudine RBX Tablets

Active ingredient

Lamivudine

Schedule

S4

 

Name of the medicine

Lamivudine.

Excipients.

Microcrystalline cellulose, sodium starch glycollate type A and magnesium stearate, Opadry 13B28444 White (proprietary ingredient # 107104) (150 mg only), and Opadry 16B57534 Grey (proprietary ingredient # 107103) (300 mg only).

Description

Chemical name: (2R-cis)-4-amino-1-(2-hydroxymethyl- 1,3-oxathiolan-5-yl)-(1H)- pyrimidin-2-one. Molecular formula: C8H11N3O3S. MW: 229.26. CAS: 134678-17-4. Lamivudine is a white or almost white powder which is soluble in water.

Pharmacology

Mode of action.

Lamivudine is a potent, selective inhibitor of HIV-1 and HIV-2 replication in vitro. It is also active against zidovudine resistant clinical isolates of HIV.
In vitro, 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. Lamivudine therefore has, in vitro, a high therapeutic index.
Lamivudine is metabolised intracellularly to the 5'-triphosphate which has an intracellular half-life of 10.5-15.5 hours. Lamivudine 5'-triphosphate is a weak inhibitor of the RNA and DNA dependent activities of HIV reverse transcriptase; its main mode of action is as a chain terminator of HIV reverse transcription.
Lamivudine does not interfere with cellular deoxynucleotide metabolism and has little effect on mammalian cell and mitochondrial DNA content.
The relationships between in vitro susceptibility of HIV to lamivudine and the clinical response to therapy remain under investigation. In vitro sensitivity testing has not been standardised and results may vary according to methodological factors.
Reduced in vitro sensitivity to lamivudine has been reported for HIV isolates from patients who have received lamivudine therapy.
Lamivudine has been shown to be usually but not always synergistic with zidovudine, inhibiting the replication of HIV in cell culture. Synergistic antiviral activity has also been demonstrated in vitro with a combination of lamivudine and the protease inhibitor saquinavir (Ro 31-8959) and in triple combination with zidovudine and didanosine.
In vitro studies show that restored sensitivity to zidovudine may occur following serial passage of zidovudine resistant HIV-1 in increasing concentrations of lamivudine. Furthermore, in vivo, there is evidence showing that lamivudine plus zidovudine delays the emergence of zidovudine resistant isolates in individuals with no prior antiretroviral therapy.

Drug resistance.

Lamivudine resistant isolates of HIV-1 have been selected in vitro. The resistant isolates showed reduced susceptibility to lamivudine and genotypic analysis showed that the resistance was due to specific substitution mutations in the HIV-1 reverse transcriptase at codon 184 from methionine to either isoleucine or valine. HIV-1 strains resistant to both lamivudine and zidovudine have been isolated.
Susceptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harbouring zidovudine resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.

Cross resistance.

Cross resistance among certain reverse transcriptase inhibitors has been observed. Cross resistance between lamivudine and zidovudine has not been reported. In some patients treated with lamivudine alone or in combination with zidovudine, isolates have emerged with a mutation at codon 184, which confers resistance to lamivudine. In the presence of the 184 mutation, cross resistance to didanosine and zalcitabine has been seen in some patients; the clinical significance is unknown. In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple reverse transcriptase inhibitors, including lamivudine, have emerged.

Pharmacokinetics.

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 (tmax) to maximal serum concentrations (Cmax) is about an hour. At therapeutic dose levels, i.e. approximately 4 mg/kg/day (as 150 mg twice daily) Cmax is in the order of 1-1.9 microgram/mL.
When a capsule formulation of lamivudine was ingested with food, there was a significant reduction in Cmax (47%) and extension to Tmax (2.2 hours). Although absorption of lamivudine was delayed, the amount of drug absorbed is not reduced.
The 150 mg tablet is bioequivalent and dose proportional to the 300 mg tablet with respect to AUC, Cmax and tmax.
The active moiety, intracellular lamivudine triphosphate, has a prolonged terminal half-life in the cell (10.5 to 15.5 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 AUC24 and Cmax.
The mean intracellular lamivudine triphosphate C0,ss was reduced by 16% and the mean C24,ss was reduced by 19% in volunteers given lamivudine 300 mg once daily compared with lamivudine 150 mg bd. The clinical relevance of the lower Cmin is unknown.
A study compared the pharmacokinetics of lamivudine tablets 300 mg once daily and lamivudine tablets 150 mg twice daily in 60 healthy, fasted volunteers. Steady-state plasma lamivudine AUCs were comparable for the two dosage regimens (mean ratio 0.94, 90% CI: 0.92-0.97) whereas the Cmax was increased by 66% (mean ratio 90% CI: 1.57-1.74) and Ctrough was 53% lower (mean ratio 90% CI: 0.44-0.50) with the 300 mg once daily. The clinical significance of the lower trough levels in unknown.
Administration of crushed tablets with a small amount of semisolid 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 physiochemical and pharmacokinetic data, assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.

Distribution.

From intravenous studies, the mean volume of distribution is 1.3 L/kg and the mean terminal half-life of elimination is 5 to 7 hours.
Limited data shows lamivudine penetrates into the central nervous system and reaches the cerebrospinal fluid. 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.

Metabolism.

Coadministration of zidovudine and lamivudine in a study of twelve asymptomatic patients with HIV caused minimal changes in lamivudine levels. The availability (mean AUC) of zidovudine was increased by 13%, mean Cmax was increased by 28%, and mean t1/2 reduced by 11%. There was considerable individual variation and the changes were not statistically significant. The relevance of these changes to clinical efficacy and safety is not known.
The likelihood of adverse drug interactions with lamivudine is low due to limited metabolism and plasma protein binding and almost complete renal elimination of unchanged drug. An interaction with trimethoprim, a constituent of trimethoprim with sulphamethoxazole causes a 40% increase in lamivudine exposure at therapeutic doses.

Excretion.

The mean systemic clearance of lamivudine is approximately 0.32 L/kg/h, with predominantly renal clearance (> 70%) via active tubular secretion, but little (< 10%) hepatic metabolism.
A single dose pharmacokinetic study (n = 16) in HIV infected patients with normal renal function and with moderate (Clcr < 30 mL/min and > 10 mL/min) or end stage renal impairment (Clcr < 10 mL/min) showed there was a linear relationship between lamivudine clearance and renal function. A dosage adjustment is required in patients with creatinine clearance below 50 mL/min (see Dosage and Administration).
A single dose pharmacokinetic study (n = 24) in patients with moderate and severe hepatic impairment in comparison with healthy subjects showed no statistically significant differences for any of the mean pharmacokinetic parameters assessed. There was a trend towards reduced renal clearance in severely impaired subjects to an average of 76% (90% CI: 58% to 101%) relative to healthy control subjects.

Pharmacokinetics in children.

In general, lamivudine pharmacokinetics in paediatric patients are similar to adults. However, absolute bioavailability (approximately 55-65%) was reduced in paediatric patients below 12 years of age. In addition, systemic clearance values were greater in younger paediatric patients and decreased with age approaching adult values around 12 years of age. Recent findings indicate that exposure in children 2 to < 6 years of age may be reduced by about 30% compared with other age groups. Further data to support this conclusion are currently awaited. At present, the available data do not suggest that lamivudine is less efficacious in this age group.
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, for neonates a dose of 2 mg/kg should be considered. Glomerular filtration estimates suggests that to achieve similar adult and paediatric exposure, the recommended dose for children aged six weeks and older could be 4 mg/kg twice a day. However there is no data available in neonates older than one week old.

Clinical Trials

Clinical endpoint study.

Clinical endpoint data from a prospective study indicate that lamivudine in combination with zidovudine alone or in combination with zidovudine containing treatment regimens results in a significant reduction in the risk of disease progression and mortality.
NUCB3007 (CAESAR) was a multicenter, double blind, placebo controlled study comparing continued current therapy [zidovudine (AZT) alone (62% of patients) or zidovudine with didanosine (ddI) or zalcitabine (ddC) (38% of patients)] to the addition of lamivudine or lamivudine plus an investigational non-nucleoside reverse transcriptase inhibitor, randomised 1:2:1. A total of 1,840 HIV infected adults with 25 to 250 (median, 126) CD4 cells/mm3 at baseline were enrolled: median age was 36 years, 87% were male, 83% were nucleoside experienced, and 17% were therapy naïve. The median duration of treatment for each group was current therapy* 327 days, lamivudine plus current therapy* 360 days and lamivudine plus NNRTI plus current therapy 360 days. Results are summarised in Table 1.
The data showed there was a significant reduction in progression to the combined endpoint of a new AIDS event or death for patients who received lamivudine in combination with zidovudine containing regimens compared to patients maintained on zidovudine containing regimens alone (p < 0.0001). The hazard ratio (HR) was 0.427 (95% confidence interval 0.318-0.572), or a 57% reduction in risk. In addition, the data indicated a significant reduction in death, regardless of causality, in the combination lamivudine plus zidovudine containing regimens as compared to the zidovudine containing regimens alone (p = 0.0007); HR = 0.399 (95% CI 0.230-0.693) or a 60% reduction in risk.
ACTG320 was a randomised, double blind, placebo controlled study to compare indinavir, zidovudine (or stavudine) and lamivudine with the 2 drug regimen of zidovudine (or stavudine) and lamivudine in HIV infected patients with CD4 counts ≤ 200 cells/mm3. Patients had received ≥ 3 months prior zidovudine therapy and had no prior exposure to protease inhibitors. A total of 1156 patients were randomised. The median duration of follow-up was 38 weeks. During the study there were 96 new AIDS defining events or deaths, 63 (11%) in the zidovudine/ lamivudine arm and 33 (6%) in the zidovudine/ lamivudine/ indinavir arm (estimated hazard ratio 0.50). There were 13 (6%) deaths in the zidovudine/ lamivudine arm and 5 (2%) in the zidovudine/ lamivudine/ indinavir arm (hazard ratio 0.37). Both these results were statistically significant.

Surrogate endpoint studies in adults.

Clinical efficacy in adults was based on the results of four pivotal studies in patients with or without prior antiretroviral therapy. Study designs are summarised in Table 2. All were randomised, double blind, multicentre studies. The characteristics of the patients at baseline are given in Table 3.

After 24 weeks.

In zidovudine naïve patients the combination of lamivudine and zidovudine resulted in a highly significant (p < 0.001) increase in absolute CD4 cell count and reduction in log10 HIV RNA relative to zidovudine monotherapy (600 mg/day) or lamivudine monotherapy (600 mg/day). Similarly, in zidovudine experienced patients, the combination of lamivudine and zidovudine resulted in significantly greater improvements in CD4 cell count than either zidovudine monotherapy (600 mg/day) or a combination of zidovudine and zalcitabine (600 mg/day + 0.75 mg) and a significantly greater reduction in log10 HIV RNA than zidovudine monotherapy.
In the North American studies (NUCA3001 and NUCA3002) patients were allowed to remain in the study with blinding intact until the last patient had completed the 24 week assessment. Analysis of the subset of patients receiving treatment for at least 52 weeks established that the clinical benefits on CD4 cell count and viral load were maintained compared to zidovudine monotherapy over this period (p < 0.001). Results for CD4 count and log10 HIV RNA are given in Figures 1 and 2.

Once daily dosing.

EPV 20001 was a randomised, double blind, controlled, multicentre study to evaluate the efficacy and safety of lamivudine 300 mg once daily vs. lamivudine 150 mg bid, as a component of triple therapy, in antiretroviral naïve adults with HIV-1 infection.
The proportions of subjects with plasma HIV-1 RNA < 400 copies/mL for intention to treat population using missing = failure analysis are summarised in Table 4.
The data demonstrate that the proportion of patients with plasma HIV-1 RNA < 400 copies/mL at week 24 did not differ between treatment groups (od: 72%; bid: 72%). While the subjects in the od group had a baseline plasma HIV-1 RNA level 0.8 log10 copies/mL higher than those of the bid group (od: 5.1 log10 copies/mL; bid: 4.3 log10 copies/mL), the two groups were comparable with respect to on treatment plasma HIV-1 RNA response. Twenty nine (5%) of subjects had virological failure by week 24 but virus for resistance testing could only be isolated from 22 samples (11 subjects in each arm); the incidence of resistance was comparable in the treatment arms.
Median CD4+ cell count values and changes from baseline are summarised by treatment group in Table 5.
The data demonstrate that there were similar increases in median CD4+ cell counts observed between lamivudine treatment groups at week 24 (OD: 128 cells/mm3; BID: 123 cells/mm3).
The results for study EPV 20001 are reported to 24 weeks; this study is currently ongoing.
EPV40001 was a small, randomised, open label, controlled multicentre study in Thailand to evaluate the efficacy and safety of lamivudine once daily (OAD) versus lamivudine BID and abacavir (ABC) once daily versus ABC BID as components of a combination regimen including zidovudine (ZDV), lamivudine and ABC in antiretroviral naïve, HIV-1 infected adults. Subjects were randomised to receive ZDV/ lamivudine (BID)/ ABC (BID) (control group), ZDV/ lamivudine (OAD)/ ABC (BID) or ZDV/ lamivudine (BID)/ ABC (OAD).
The three groups showed comparable efficacy using AAUCMB (average area under curve minus baseline) for HIV-1 RNA at week 48, the primary efficacy parameter for establishing noninferiority with a confidence interval of 0.4 log10 copies/mL (-2.0 log10 copies/mL control group, -2.0 log10 copies/mL lamivudine OAD group, -1.9 log10 copies/mL ABC OAD group) in the intent to treat exposed population (ITTE).
Using a secondary parameter of efficacy, the proportions of subjects with plasma HIV-1 RNA < 400 copies/mL for the ITTE population in a missing = failure analysis are summarised in Table 6.
Although there was a small numerical difference in treatment response in favour of the control group, this difference was primarily driven by a slightly higher incidence of treatment discontinuations in the OAD arms for reasons other than virological failure. Fifteen (10%) subjects had virological failure associated with resistance mutations; the incidence was comparable in the treatment arms.
There were similar increases in median CD4+ cell counts observed in the three treatment groups at week 48 (control group: +216 cells/mm3; lamivudine OAD: +166 cells/mm3; ABC OAD: +152 cells/mm3.

Studies in children.

Pharmacokinetic studies in children have established that relatively higher doses are required (8 mg/kg/day) to achieve comparable clinical exposure to that obtained with the recommended dose in adults (see Pharmacokinetics; and Dosage and Administration).
An open label, dose escalation study (lamivudine monotherapy) was conducted in children aged 3 months to 17 years who had received no or minimal antiretroviral therapy (arm A) or had experienced toxicity or become refractory to prior antiretroviral therapy (arm B). At one centre compassionate treatment of patients with recurrent opportunistic infections was also allowed (arm C). Patients were dosed at 1, 2, 4, 8, 12 or 20 mg/kg/day in two divided doses for 24 weeks. Dose escalation/ reduction to 8 mg/kg/day was allowed after 24 weeks of treatment.
Lamivudine showed evidence of antiviral activity in both naïve (arm A) and experienced (arm B) patients but no consistent dose response effects. The combined results for all dose levels in both groups are given in Table 7. No efficacy data are available on patients in arm C.
The peak increase in CD4 count was 104 cells/mm3 at week 4 in arm A and 6 cells/mm3 in arm B. CD4 counts were maintained at or close to baseline values in both arms of the study to week 48. Serum HIV-1 RNA concentrations decreased during the same period and for the subset of patients with > 1000 copies/mL at baseline was significantly different to baseline in arm A at week 48 (-0.7 log10, p = 0.031), and in arm B at week 12 (-0.2 log10, p = 0.009), week 24 (-0.2 log10, p = 0.008) and week 48 (0.2 log10, p = 0.032).
ACTG300 was a multicentre randomised double blind study, in paediatric patients, that provided for comparison of lamivudine plus zidovudine to didanosine monotherapy. The median duration on study medication was 10.1 months for patients receiving lamivudine + zidovudine and 9.2 months for children receiving didanosine monotherapy. Table 8 provides details of the changes from baseline for the two treatment groups and Table 9 the number of patients reaching primary clinical endpoint (disease progression or death).
This study demonstrated a significant benefit of combination zidovudine/ lamivudine therapy over didanosine monotherapy by clinical and laboratory measures.
There are no studies of the safety and efficacy of lamivudine administered once daily in children.

Indications

Lamivudine RBX (lamivudine) in combination with other antiretroviral agents is indicated for the treatment of HIV infected adults and children.

Contraindications

The use of lamivudine is contraindicated in patients with known hypersensitivity to lamivudine or to any ingredient of the preparation.

Precautions

Use with caution in the following circumstances:

Pancreatitis in paediatric patients.

In paediatric patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis, lamivudine should be used with extreme caution and only if there is no satisfactory alternative therapy. Treatment with lamivudine should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur (see Adverse Effects).

Renal impairment.

In patients with moderate to severe renal impairment, the terminal plasma half-life of lamivudine exposure is increased due to decreased clearance. The dose should be adjusted (see Dosage and Administration).

Cirrhotic liver disease/ hepatitis B virus.

Clinical trial and marketed use of lamivudine, have shown that some patients with chronic hepatitis B virus (HBV) disease may experience clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease. If lamivudine is discontinued in a patient with HIV and HBV coinfection, periodic monitoring of both liver function tests and markers of HBV replication should be considered.

Fat redistribution.

Redistribution/ accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, elevated serum lipid and blood glucose levels have been observed either separately or together in some patients receiving combination antiretroviral therapy (see Adverse Effects).
Whilst all members of the PI and NRTI classes of medicinal products have been associated with one or more of these specific adverse events, linked to a general syndrome commonly referred to as lipodystrophy, data indicate that there are differences in the risk between individual members of the respective therapeutic classes.
In addition, the lipodystrophy syndrome has a multifactorial aetiology; with for example HIV disease status, older age and duration of antiretroviral treatment all playing important, possibly synergistic roles.
The long-term consequences of these events are currently unknown.
Clinical examination should include evaluation for physical signs of fat redistribution.
Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.

Lactic acidosis and severe hepatomegaly with steatosis.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues either alone or in combination, including lamivudine. A majority of these cases have been in women.
Clinical features which may be indicative of the development of lactic acidosis include generalised weakness, anorexia, and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnoea and tachypnoea).
Caution should be exercised when administering lamivudine to any patient, and particularly to those with known risk factors for liver disease. Treatment with lamivudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Immune reconstitution syndrome.

In HIV infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections 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 ART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Autoimmune disorders (such as Graves' disease, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however the time to onset is more variable, and can occur many months after initiation of treatment and sometimes can be an atypical presentation.

Carcinogenicity, mutagenicity.

When lamivudine was administered orally to separate groups of rodents at doses up to 2000 times (mice and male rats) and 3000 (female rats) mg/kg/day, there was no evidence of a carcinogenic effect due to lamivudine in the mouse study. In the rat study there was an increased incidence of endometrial tumours at the highest dose (approximately 70 times the estimated human exposure at the recommended therapeutic dose of one tablet twice daily, based on AUC). However, the relationship of this increase to treatment is uncertain.
Lamivudine was not mutagenic in Salmonella typhimurium or E. coli reverse mutation assays with and without metabolic activation but did induce mutations at the thymidine kinase locus of the mouse lymphoma L5178Y cells without metabolic activation and was clastogenic in human peripheral blood lymphocytes, with and without metabolic activation in vitro. In rats lamivudine did not cause chromosomal damage in bone marrow cells in vivo or cause DNA damage in primary hepatocytes at estimated exposures many times higher than those observed clinically.
Lamivudine should not represent a genotoxic hazard to patients undergoing treatment.

Effects on fertility.

No evidence of impaired fertility was seen in rats with exposures (based on Cmax) up to 70 times those observed at the clinical dosage.

Use in pregnancy.

(Category B3)
There is limited data available on the safety of lamivudine in human pregnancy. Studies in humans have confirmed that lamivudine crosses the placenta. Use in pregnancy should be considered only if the benefit outweighs the risk.
No evidence of teratogenicity was observed in rats and rabbits with exposure (based on Cmax) up to 40 and 36 times respectively those observed in humans at the clinical dosage. However, embryolethality was increased with consequent reduction in litter size in rabbits at exposures (based on both Cmax and AUC values) of less than those observed at the clinical dosage of 150 mg bd (approximately 4 mg/kg).
Lamivudine crossed the placenta in rats and rabbits. The significance of increased embryolethality seen in animal studies is uncertain in humans.
There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peripartum to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of developmental delay, seizures and other neurological disease. However, a causal relationship between these events and NRTI exposure in utero or peripartum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Use in lactation.

A study in lactating rats showed that the concentration of lamivudine in milk, was more than four times higher than that in maternal plasma. Following oral administration lamivudine was excreted in human breast milk at similar concentrations to those found in serum (1-8 microgram/mL). Since lamivudine and the virus pass into breast milk, it is recommended that mothers taking lamivudine do not breastfeed their infants.

Effects on the ability to drive and operate machinery.

There have been no studies to investigate the effect of lamivudine on driving performance or the ability to operate machinery. Further, a detrimental effect on such activities cannot be predicted from the pharmacology of the drug. Nevertheless, the clinical status of the patient and the adverse event profile of both lamivudine and zidovudine should be borne in mind when considering the patient's ability to drive or operate machinery.
Patients should be advised that current antiretroviral therapy, including lamivudine, has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.

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. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Interactions

The likelihood of interactions is low due to limited metabolism and plasma protein binding and almost complete renal elimination of unchanged drug. Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system, e.g. trimethoprim. Other drugs (e.g. ranitidine, cimetidine) are eliminated only in part by this mechanism and were shown not to interact with lamivudine.
Changes in zidovudine plasma levels when coadministered with lamivudine were not statistically significant. Zidovudine has no effect on the pharmacokinetics of lamivudine (see Pharmacokinetics).
Administration of trimethoprim, as trimethoprim/ sulfamethoxazole 160 mg/800 mg increased lamivudine exposure by about 40%. However, unless the patient already has renal impairment, no dosage adjustment of lamivudine is necessary. Lamivudine has no effect on the pharmacokinetics of trimethoprim/ sulfamethoxazole. Administration of lamivudine in patients with renal impairment should be assessed carefully. The effect of coadministration of lamivudine with higher doses of cotrimoxazole for the treatment of Pneumocystis carinii pneumonia and toxoplasmosis has not been studied.
In in vitro studies, ciprofloxacin, pentamidine and ganciclovir reduced the anti-HIV activity of lamivudine. The clinical significance of this is not known.
Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicinal products are used concurrently. Lamivudine is therefore not recommended to be used in combination with zalcitabine.

Adverse Effects

Table 10 lists all adverse events, occurring at an incidence of 5% or more, reported in controlled pivotal clinical trials in adults, irrespective of the investigator's assessment of the possible relationship to the study drug.
Common laboratory abnormalities observed during therapy are listed in Table 11.
Lamivudine appears to be well tolerated and most serious adverse events reported in clinical trials are not considered to be drug related. Adverse reactions from the 4 pivotal studies in adult patients receiving the recommended dose of lamivudine (150 mg bd) in combination with zidovudine 600 mg/day are included in Table 12 together with serious adverse reactions reported in large scale open studies.
With many of these adverse reactions it is unclear whether they are drug related or are a result of the underlying disease.
Cases of pancreatitis have occurred rarely in adult patients and more commonly in children. However it is not clear whether these cases were due to drug treatment or to their underlying HIV disease. Treatment with lamivudine should be stopped immediately if clinical signs or symptoms or laboratory abnormalities suggestive of pancreatitis occur.
In paediatric patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis, the combination of lamivudine with other antiretroviral therapies should be used with extreme caution and only if there is no satisfactory alternative therapy.
Pancreatitis, which has been fatal in some cases has been observed in paediatric patients receiving lamivudine alone or in combination with other antiretroviral agents. In an open label dose escalation study, 14 patients (14%) developed pancreatitis while receiving monotherapy with lamivudine. Three of these patients died of complications of pancreatitis. In a second open label study, 12 patients (18%) developed pancreatitis. In both these open label studies, the paediatric subjects had advanced, symptomatic HIV infection and many had received extensive prior therapy. In addition, many of the children had predisposing medical conditions or medications which could have contributed to pancreatitis. In study ACTG300 in therapy naïve subjects, pancreatitis was not observed in 236 patients randomised to lamivudine + zidovudine. Pancreatitis was observed in one patient in this study who received open label lamivudine in combination with zidovudine and ritonavir following discontinuation of didanosine monotherapy. Paraesthesia and peripheral neuropathies were reported in 15 patients (15%) in one open study and 6 patients (9%) in the other open study and in 2 patients (1%) in ACTG300.
Table 13 lists all the adverse events, occurring at an incidence of 5% or more, reported in study EPV 20001.
The data from the clinical trials have shown no significant difference in the frequency or severity of unwanted effects between administration of 150 mg twice daily and 300 mg once daily. There was however a higher incidence of hyperamylasaemia in the once daily regimen.
Adverse events and laboratory findings in study ACTG300 are provided in Tables 15 and 16.
Selected laboratory abnormalities experienced by therapy naïve (≤ 56 days of antiretroviral therapy) paediatric patients are listed in Table 16.

Postmarketing data.

The following events have been reported during therapy for HIV disease with lamivudine alone and in combination with other antiretroviral agents.

Musculoskeletal.

Arthralgia, muscle disorders including rarely rhabdomyolysis.

Skin.

Alopecia (rare).

Haematological.

Pure red cell aplasia.

Metabolism and nutrition disorders.

Hyperlactataemia (common).
Lactic acidosis (rare, see Precautions).
Redistribution/ accumulation of body fat (see Precautions). The incidence of this event is dependent on multiple factors including the particular antiretroviral drug combination.

Dosage and Administration

Food reduces the Cmax and extends the Tmax but the amount of drug absorbed is not reduced. The clinical significance of this is not known (see Pharmacokinetics).
Clinical studies indicate that lamivudine should be used in combination with other antiretroviral therapies. In controlled trials in adults, lamivudine was used in combination with zidovudine 200 mg tds (see Clinical Trials).
Since accurate dosing cannot be achieved with this formulation, dosing according to weight bands is recommended for scored tablets. This dosing regimen for paediatric patients weighing 14-30 kg is based primarily on pharmacokinetic modelling. Therefore monitoring of efficacy and safety is necessary in these patients. More accurate dosing can be achieved with oral solution of lamivudine (offered by other brands).
To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing. For patients who are unable to swallow tablets, the tablets may be crushed and 100% of the crushed tablets could be added to a small amount of semisolid food or liquid, all of which should be consumed immediately (see Pharmacokinetics). Alternatively, lamivudine is available as an oral solution by other brands.

Adults and adolescents weighing at least 30 kg.

The recommended dose of Lamivudine RBX is 150 mg twice daily. Alternatively, it may be administered as 300 mg once daily in patients who may benefit from a once daily regimen. (See Clinical Trials.)

Children less than three months of age.

The limited data available are insufficient to propose specific dosage recommendations (see Clinical Trials and Pharmacokinetics).

For children aged greater than three months and weighing less than 30 kg.

For children weighing between 21 kg to 30 kg.

The recommended oral dose of lamivudine (150 mg) is one-half tablet taken in the morning and one whole tablet taken in the evening.

Children weighing 14 to 21 kg.

The recommended oral dose of lamivudine (150 mg) is one half of a scored tablet taken twice daily.

Renal impairment.

Lamivudine plasma concentrations (AUC) are increased in patients with moderate to severe renal impairment due to decreased clearance. The dose should therefore be adjusted (see Tables 17, 18 and 19). Insufficient data are available to recommend a dosage of lamivudine in paediatric patients with renal impairment. A reduction in the dose and/or an increase in the dosing interval should be considered.
Intermittent dialysis is unlikely to require further dose modification from that defined by creatinine clearance.
Lamivudine RBX 150 mg and 300 mg tablets may not be suitable for all dosages and therefore other suitable available strengths and/or dosage forms of lamivudine should be used in such cases.

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.

Overdosage

Administration of lamivudine at very high dose levels in acute animal studies did not result in any organ toxicity. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdosage, although this has not been studied.
Treatment of overdosage should be symptomatic and consist of general supportive measures. Contact the Poisons Information Centre on 131 126 for advice on management of overdose.

Presentation

Tablets (modified diamond shaped, film coated), 150 mg (white, marked RF&96 on one side, scored on reverse): 60's; 300 mg (grey, marked RF97 on one side, plain on reverse): 30's (white, high density polyethylene (HDPE) bottle with plastic cap).

Storage

Store below 25°C in the original container.

Poison Schedule

S4.