Consumer medicine information

Zeffix Tablets

Lamivudine

BRAND INFORMATION

Brand name

Zeffix

Active ingredient

Lamivudine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zeffix Tablets.

SUMMARY CMI

ZEFFIX

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using ZEFFIX?

ZEFFIX contains the active ingredient lamivudine. ZEFFIX is used to treat patients 2 years of age or over with long term (chronic) viral infection of the liver caused by hepatitis B.

For more information, see Section 1. Why am I using ZEFFIX? in the full CMI.

2. What should I know before I use ZEFFIX?

Do not use if you have ever had an allergic reaction to lamivudine or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ZEFFIX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ZEFFIX and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use ZEFFIX?

  • The normal dose for adults and children aged 12 years or above is one 100 mg tablet once a day.
  • Swallow the tablet whole with a glass of water.

More instructions can be found in Section 4. How do I use ZEFFIX? in the full CMI.

5. What should I know while using ZEFFIX?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using ZEFFIX.
Things you should not do
  • Do not stop using this medicine or change the dose without first checking with your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how ZEFFIX affects you
  • ZEFFIX may cause dizziness and tiredness in some people
Looking after your medicine
  • Store ZEFFIX below 30°C in a cool dry place
  • Keep the medicine in the pack until it is time to use it

For more information, see Section 5. What should I know while using ZEFFIX? in the full CMI.

6. Are there any side effects?

Common side effects: headache, vomiting and diarrhoea, nausea, fatigue/ tiredness, abdominal discomfort and pain, coughing with phlegm not associated with cold and flu, dizziness, abnormal liver function tests, muscle disorder (including muscle pain and cramps).

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

ZEFFIX

Active ingredient(s): lamivudine

Consumer Medicine Information (CMI)

This leaflet provides important information about using ZEFFIX. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ZEFFIX.

Where to find information in this leaflet:

1. Why am I using ZEFFIX?
2. What should I know before I use ZEFFIX?
3. What if I am taking other medicines?
4. How do I use ZEFFIX?
5. What should I know while using ZEFFIX?
6. Are there any side effects?
7. Product details

1. Why am I using ZEFFIX?

ZEFFIX contains the active ingredient lamivudine. ZEFFIX belongs to a group of medicines called antivirals.

ZEFFIX is used to treat patients 2 years of age or over with long term (chronic) viral infection of the liver caused by hepatitis B.

Hepatitis B is a virus which damages the liver. Treatment with ZEFFIX can reduce the amount of hepatitis B virus in your body. This should lead to less liver damage.

ZEFFIX has not been shown to reduce the risk of passing hepatitis B to others. You will still be able to pass on the hepatitis virus by sexual contact or through your blood. You should use appropriate precautions.

Your doctor may have prescribed ZEFFIX for another reason.

ZEFFIX is not addictive.

If you are already taking this medicine lamivudine for HIV infection (3TC®, Combivir®), your doctor will continue to treat you with the higher dose for that treatment.

2. What should I know before I use ZEFFIX?

Warnings

Do not use ZEFFIX if:

  • you are allergic to lamivudine, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have any other medical conditions
  • you have, or have ever had, kidney problems
  • you have or have ever had problems with your pancreas.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. The safety of ZEFFIX has not been established in human pregnancy. Use in pregnancy should be considered only if the benefit outweighs the risk.

Talk to your doctor if you are breastfeeding or intend to breastfeed. The safety of ZEFFIX has not been established in breast fed infants. ZEFFIX should only be used if the expected benefit justifies the potential risk to the baby.

3. What if I am taking other medicines?

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

Some medicines may interfere with ZEFFIX and affect how it works. These include:

  • zalcitabine, used to treat HIV infection (sometimes called the AIDS virus).
  • medicines (usually liquids) containing sorbitol and other sugar alcohols (such as xylitol, mannitol, lactitol or maltitol).
  • other medicines containing lamivudine, used to treat HIV infection (sometimes called the AIDS virus).
  • emtricitabine used to treat HIV infection or hepatitis B infection
  • cladribine, used to treat hairy cell leukaemia.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ZEFFIX.

4. How do I use ZEFFIX?

How much to take

  • The normal dose for adults and children aged 12 years or above is one 100 mg tablet once a day.
  • Your doctor may prescribe a different dosage, for example if you have kidney problems.
  • Follow the instructions provided and use ZEFFIX until your doctor tells you to stop.

When to take / use ZEFFIX

  • Your doctor or pharmacist will tell you when to take ZEFFIX each day.

In order for ZEFFIX tablets to be effective, you must take ZEFFIX tablets every day for as long as your doctor says you should take them.

How to take ZEFFIX

  • Swallow the tablet whole with a glass of water
  • ZEFFIX can be taken with or without food

If you forget to use ZEFFIX

ZEFFIX should be used regularly at the same time each day.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

If you use too much ZEFFIX

If you think that you have used too much ZEFFIX, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using ZEFFIX?

Things you should do

Call your doctor straight away if you:

  • Become pregnant or intend to become pregnant
  • Have not taken ZEFFIX as intended

Remind any doctor, dentist or pharmacist you visit that you are using ZEFFIX.

Things you should not do

  • Do not stop using this medicine suddenly or change the dose without first checking with your doctor. If you stop taking ZEFFIX your hepatitis may get worse.

This can cause serious illness particularly if your liver is already not working very well. If you do have to stop taking ZEFFIX your doctor is likely to arrange tests over the following four months to check how well your liver is working.

Each patient responds to the treatment differently. Your doctor will check you by taking regular blood samples. The results will help decide when you should stop taking ZEFFIX.

  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Do not use ZEFFIX to treat any other complaints unless your doctor says to.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ZEFFIX affects you.

ZEFFIX may cause dizziness and tiredness in some people.

Looking after your medicine

  • Store below 30°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Headache.
  • Vomiting and diarrhoea.
  • Nausea.
  • Fatigue/tiredness.
  • Abdominal discomfort and pain.
  • Coughing, with phlegm, not associated with a cold or flu.
  • Dizziness.
  • Abnormal Liver Function tests.
  • Muscle disorders, (including muscle pain and cramps).
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Wheezing, swelling of the lips/mouth, difficulty in breathing, hayfever, lumpy rash (hives) or fainting. These could be symptoms of an allergic reaction.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What ZEFFIX contains

Active ingredient
(main ingredient)		Lamivudine
Other ingredients
(inactive ingredients)		Microcrystalline cellulose
Magnesium stearate
Titanium dioxide
Hypromellose
Sodium starch glycollate
Polyethylene glycol
Polysorbate 80
Macrogol 400
Iron oxide yellow CI 77192
Iron oxide red CI 77491
Potential allergensn/a

Do not take this medicine if you are allergic to any of these ingredients.

ZEFFIX tablets do not contain gluten or lactose.

What ZEFFIX looks like

ZEFFIX tablets are butterscotch coloured, film-coated, capsule shaped, biconvex tablets engraved "LV" on one side and "100" on the other.

ZEFFIX tablets are supplied in foil blisters and are in a carton containing 28 tablets.

(AUST R 66828).

Who distributes ZEFFIX

Arrow Pharma Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121
Australia.

This leaflet was prepared in September 2023.

Published by MIMS October 2023

BRAND INFORMATION

Brand name

Zeffix

Active ingredient

Lamivudine

Schedule

S4

 

1 Name of Medicine

Lamivudine.

2 Qualitative and Quantitative Composition

Lamivudine is a white to off-white crystalline solid which is highly soluble in water.
Zeffix tablets contain 100 mg of lamivudine.
Zeffix oral solution contains 5 mg/mL lamivudine.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets.

Zeffix tablets are butterscotch coloured, film coated, capsule shaped, biconvex and engraved "LV" on one side and "100" on the other side.

Oral solution.

Zeffix oral solution contains 240 mL of Zeffix solution, for oral use only, and is in a carton. The pack includes a clear polypropylene oral dosing syringe and polyethylene syringe-adapter.

4 Clinical Particulars

4.1 Therapeutic Indications

Zeffix (lamivudine) is indicated for the treatment of children (2 years and above), adolescent and adult patients with chronic hepatitis B and evidence of hepatitis B virus (HBV) replication.
This indication is based on changes in serological and histological markers in clinical studies of up to 2 years duration in adult patients with compensated liver disease and serological data up to 18 months in children and adolescents. Children and adolescents also require evidence of active hepatic inflammation (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The safety and efficacy of Zeffix (lamivudine) have not been established in patients with decompensated liver disease in placebo controlled studies. However, Zeffix (lamivudine) has been shown to reduce HBV DNA levels prior to and post liver transplantation.

4.2 Dose and Method of Administration

Adults and adolescents 12* years and older.

The recommended dosage of Zeffix is 100 mg once daily.

Children from two to eleven years*.

The recommended dose is 3 mg/kg once daily up to a maximum of 100 mg daily.
* The effectiveness of treatment beyond 1 year in children aged from 2 - 17 years and the optimum duration of treatment for this group has not been established (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Children less than two years.

There are insufficient data available to propose specific dosage recommendations in this age group.
Zeffix oral solution is available for use in children and for those patients for whom the tablets are inappropriate.
Food reduces the Cmax and extends the Tmax but the amount of drug absorbed is not reduced. These changes to the pharmacokinetic parameters are not statistically or clinically significant (see Section 5.2 Pharmacokinetic Properties).
Discontinuation of Zeffix may be considered in immunocompetent patients when HBeAg and/or HBsAg seroconversion occurs. Discontinuation may also be considered when loss of efficacy occurs, as indicated by recurrent signs of hepatitis. There are limited data regarding the maintenance of seroconversion long term after stopping treatment with Zeffix.
Patient compliance should be monitored while on Zeffix therapy. If Zeffix is discontinued, patients should be periodically monitored for evidence of recurrent hepatitis (see Section 4.4 Special Warnings and Precautions for Use).

Renal insufficiency.

Lamivudine serum concentrations are increased in patients with moderate to severe renal impairment due to decreased renal clearance. The dosage should therefore be reduced for patients with a creatinine clearance of < 50 mL/minute (see Table 1 for adults and Table 2 for children 2 - 11 years of age). When doses less than 100 mg are required Zeffix oral solution should be used. The same percentage reduction in dose applies for children with renal impairment (see Table 2).
Data available in patients undergoing intermittent haemodialysis (4 hrs dialysis 2-3 times weekly), indicate that following the initial dosage reduction of Zeffix to correct for the patient's creatinine clearance, no further dosage adjustments are required while undergoing dialysis.

Hepatic insufficiency.

Data obtained in patients with hepatic impairment, including those with end-stage liver disease awaiting transplant, show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these data, no dose adjustment is necessary in patients with hepatic impairment unless accompanied by renal impairment.

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Initiation of lamivudine treatment should only be considered when the use of an alternative antiviral agent with a higher genetic barrier to resistance is not available or appropriate.
During initiation and maintenance of treatment patients should be monitored regularly by a physician experienced in the management of chronic hepatitis B. Optimum duration of therapy has not been established.
During treatment with patients should be monitored regularly. Serum ALT and HBV DNA levels should be monitored at 3 month intervals and in HBeAg positive patients HBeAg should be assessed every 6 months.
There are limited data on the use of lamivudine in patients receiving concurrent immunosuppressive regimens, including cancer chemotherapy, and therefore close monitoring of this group is required.
The efficacy of lamivudine has not been established in patients not responding to alpha-interferon therapy.
Patients should be advised that therapy of chronic hepatitis B, with Zeffix has not been proven to reduce the risk of transmission of hepatitis B virus to others through sexual contact or blood contamination and therefore, appropriate precautions should still be taken.

Pancreatitis and neuropathy/severe hepatomegaly with steatosis.

In patients with HIV infection, cases of pancreatitis and peripheral neuropathy (or paraesthesia) have been reported although no relationship to treatment with lamivudine (3TC) has been clearly established. In patients with chronic hepatitis B there was no observed difference in the incidence of these events between placebo and lamivudine 100 mg daily treated patients.

Lactic acidosis and severe hepatomegaly.

Cases of lactic acidosis, usually associated with severe hepatomegaly and hepatic steatosis, including fatal cases have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including lamivudine in the treatment of patients with HIV. A majority of these cases have been in women. Female sex, obesity and prolonged exposure nucleoside may be risk factors. Most of these reports have described patients receiving nucleoside analogues for the treatment of HIV infection.
There have been occasional reports of these adverse events in hepatitis B patients with decompensated liver disease, however there is no evidence that these events were related to treatment with lamivudine.
Particular caution should be exercised when administering Zeffix to any patient with known risk factors for liver disease (other than hepatitis B); however, cases have also been reported in patients with no known risk factors. Treatment with Zeffix should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Cirrhotic liver disease/hepatitis B virus.

Severe acute exacerbations of hepatitis have been reported in patients who have discontinued anti-hepatitis B therapy, including therapy with Zeffix. Hepatic function should be monitored closely in patients who discontinue anti-hepatitis B therapy. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Exacerbations on treatment.

Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients as serum HBV DNA levels decline. In patients with compensated liver disease, these increases in serum ALT were generally not accompanied by an increase in serum bilirubin concentrations or signs of hepatic decompensation.
HBV viral subpopulations (YMDD variant HBV) with reduced susceptibility to lamivudine have been identified during extended therapy. In a minority of cases this variant can lead to recurrent hepatitis, primarily detected by serum ALT elevations and re-emergence of HBV DNA. In patients who have YMDD mutant HBV, a switch to or addition of an alternative agent without cross resistance to lamivudine based on therapeutic guidelines should be considered (see Section 5.1). In controlled trials, when patients developed YMDD mutant HBV, they had a rise in HBV DNA and ALT from previous on-treatment levels. Progression of hepatitis B has been reported in some patients with YMDD mutant HBV. The long term clinical significance of these variants is yet to be fully established.

Exacerbations after treatment discontinuation.

Acute exacerbation of hepatitis has been observed in patients who have discontinued hepatitis B therapy and is usually detected by serum ALT elevations and re-emergence of HBV DNA. In the controlled Phase III trials with no-active-treatment follow-up, the incidence of post-treatment ALT elevations (more than 3 times baseline) was higher in lamivudine-treated patients compared with those receiving placebo. However, the proportion of patients who had post-treatment elevations associated with bilirubin elevations was low and similar in both treatment arms. For lamivudine-treated patients, the majority of post-treatment ALT elevations occurred between 8 and 12 weeks post-treatment.
Fatalities are very rare and the causal relationship to discontinuation of lamivudine treatment is unknown.
If lamivudine is discontinued, patients should be periodically monitored both clinically and by assessment of serum liver function tests (ALT and bilirubin levels), for at least four months for evidence of recurrent hepatitis; patients should then be followed as clinically indicated. For patients who develop evidence of recurrent hepatitis post-treatment, there are insufficient data on re-initiation of lamivudine treatment.

Exacerbations in patients with decompensated cirrhosis.

Transplantation recipients and patients with advanced liver disease are at greater risk from active viral replication. Due to marginal liver function in these patients, hepatitis reactivation at discontinuation of lamivudine or loss of efficacy during treatment may induce severe and even fatal decompensation. It is recommended that these patients are monitored for parameters associated with hepatitis B, for liver and renal function, and for antiviral response during treatment (at least every month). Laboratory parameters to be monitored should include (as a minimum) serum ALT, bilirubin, albumin, blood urea nitrogen, creatinine, and virological status: HBV antigen/antibody, and serum HBV DNA concentrations when possible. If treatment is discontinued for any reason, it is recommended that these patients are monitored for at least 6 months post cessation of treatment. Patients experiencing signs of hepatic insufficiency during or post-treatment should be monitored frequently, as appropriate.
For patients who develop evidence of recurrent hepatitis post-treatment, there are insufficient data on the benefits of re-initiation of lamivudine treatment.

Co-infection with HIV.

Some chronic hepatitis B patients may be coinfected with HIV. The possibility of such coinfection should be considered prior to initiating lamivudine therapy.
There are no adequate clinical data on the treatment with lamivudine of patients co-infected with HIV and Hepatitis B virus. For the treatment of patients who are coinfected with HIV and are currently receiving or are planning to receive an antiretroviral treatment regimen including lamivudine, the dose of lamivudine usually prescribed for HIV infection should be maintained. Zeffix (lamivudine 100 mg) once daily is not an appropriate dose or dose frequency for use in the treatment of patients with HIV infection. Co-infected patients requiring lamivudine therapy for HIV should be treated with the dose, dose frequency and appropriate use as set out in the product information for lamivudine 150 mg tablets (3TC) and lamivudine/zidovudine combination tablets (Combivir). For HIV co-infected patients not requiring anti-retroviral therapy, there is a risk of HIV mutation when using lamivudine alone for treating chronic hepatitis B.
Several serious adverse events have been reported with use of lamivudine in HIV infected patients. Reports of anaphylaxis, rhabdomyolysis and peripheral neuropathy have been rare (< 1 in 1000).

Hematologic.

Lamivudine use at higher doses in HIV disease has resulted in very rare occurrences of pure red cell aplasia. To date no definitive occurrences have been seen in hepatitis B patients at the recommended dose.

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. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlipasemia). Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). The neurological disorders might be transient or permanent. Any child exposed in utero to nucleoside and nucleotide analogues, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in cases which have relevant signs or symptoms.

Delta hepatitis or hepatitis C.

There are no clinical data on the efficacy of lamivudine 100 mg daily in patients co-infected with Hepatitis B virus and Delta virus. There is no information available on maternal-foetal transmission of hepatitis B virus in pregnant women receiving treatment with lamivudine 100 mg. The standard recommended procedures for hepatitis B virus immunisation in infants should be followed.
Patients should be advised that therapy with lamivudine 100 mg has not been proven to reduce the risk of transmission of hepatitis B virus to others and therefore, appropriate precautions should still be taken.

Diabetes (oral solution only).

Diabetic patients should be advised that each dose of oral solution (100 mg = 20 mL) contains 4 g of sucrose.

Animal toxicity.

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 reduction in liver weights. Reduction of erythrocytes and neutrophil counts were identified as the effects most likely to be of clinical relevance. These events were seen infrequently in clinical studies.

Use in renal impairment.

In patients with moderate to severe renal impairment, serum lamivudine concentrations (AUC) are increased due to decreased renal clearance, therefore the dose should be reduced for patients with a creatinine clearance of < 50 mL/minute (see Section 4.2 Dose and Method of Administration).

Immunosuppressive treatments.

Data are limited on the use of lamivudine in HBeAg negative (pre-core mutant) patients and in those receiving concurrent immunosuppressive regimes, including cancer chemotherapy. Lamivudine should be used with caution in these patients.

Clinical resistance.

In HBeAg positive or negative patients, the development of YMDD (tyrosine-methionine-aspartate-aspartate) mutant HBV may result in a diminished therapeutic response to lamivudine, indicated by a rise in HBV DNA and ALT from previous on-treatment levels. In order to reduce the risk of resistance in patients receiving lamivudine monotherapy, a switch to or addition of an alternative agent without cross-resistance to lamivudine should be considered if serum HBV DNA remains detectable at or beyond 24 weeks of treatment.

Use in the elderly.

Clinical studies of lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In elderly patients, normal ageing with accompanying renal decline has no clinically significant effect on lamivudine exposure, except in patients with creatinine clearance of < 50 ml/min. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, because lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments should be made accordingly (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Paediatric use.

Lamivudine has been administered to children (2 years and above) and adolescents with compensated chronic hepatitis B. However, due to limitations of the data, the administration of lamivudine to this patient population is not currently recommended (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The likelihood of metabolic 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.
Drugs shown to be predominately excreted either via the active organic anionic pathway, or by glomerular filtration are unlikely to yield clinically significant interactions with lamivudine.

Effect of other agents on the pharmacokinetics of lamivudine.

Lamivudine is a substrate of multidrug and toxin extrusion protein 1 (MATE1), MATE2-K and organic cation transporter 2 (OCT2) in vitro. Trimethoprim (an inhibitor of these drug transporters) when given in combination with sulphamethoxazole, has been shown to increase lamivudine plasma concentrations.
Lamivudine is a substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minor role in the clearance of lamivudine, drug interactions due to inhibition of OCT1 are unlikely to be of clinical significance.
Lamivudine is an in vitro substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP), however due to its high bioavailability it is unlikely that these transporters play a significant role in the absorption of lamivudine. Co-administration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.

Effect of lamivudine on the pharmacokinetics of other agents.

In vitro, lamivudine demonstrates no or weak inhibition of the drug transporters organic anion transporter 1B1 (OATP1B1), OATP1B3, BCRP or Pgp, MATE1, MATE2-K or OCT3. Lamivudine is therefore not expected to affect the plasma concentrations of drugs that are substrates of these drug transporters.
Lamivudine is an inhibitor of OCT1 and OCT2 in vitro, however lamivudine has low potential to affect the plasma concentrations of OCT1 and OCT2 substrates at therapeutic drug exposures.

Trimethoprim/sulphamethoxazole 160 mg/800 mg.

Administration of trimethoprim, as trimethoprim/sulfamethoxazole 160 mg/800 mg, causes an increase of about 40% in lamivudine plasma levels. However, unless the patient 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.

Zidovudine.

A modest increase in Cmax (28%) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) was not significantly altered. Zidovudine had no effect on the pharmacokinetics of lamivudine (see Section 5.2 Pharmacokinetic Properties).

Alpha-interferon.

Lamivudine has no pharmacokinetic interaction with alpha-interferon when the two drugs are concurrently administered.

Immunosuppressant drugs.

There were no observed clinically significant adverse interactions in patients taking Zeffix concurrently with commonly used immunosuppressant drugs (e.g. cyclosporin A). However, formal interaction studies have not been performed.

Zalcitabine.

Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicinal products are used concurrently. Zeffix is therefore not recommended to be used in combination with zalcitabine.

Emtricitabine.

Due to similarities, Zeffix should not be administered concomitantly with other cytidine analogues, such as emtricitabine. Lamivudine may inhibit the intracellular phosphorylation of emtricitabine when the two medicinal products are used concurrently. Lamivudine is not recommended for use in combination with emtricitabine.

Cladribine.

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).

Sorbitol.

Co-administration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose (Adult HIV daily dose) of lamivudine oral solution resulted in dose-dependent decreases in lamivudine exposure in adults. When possible, avoid chronic co-administration of Zeffix with medicinal products containing sorbitol or other osmotic acting poly-alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol, maltitol). Consider more frequent monitoring of HBV viral load when chronic co-administration cannot be avoided.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No evidence of impaired fertility was seen in rats administered lamivudine at oral doses up to 2000 mg/kg BID, resulting in a maximum systemic exposure (based on Cmax) of at least 59 times those observed at the clinical dosage.
This reproductive study in rats has shown no effect on male or female fertility.
(Category B3)
There are limited data available on the safety of lamivudine in human pregnancy. Studies in humans have confirmed that lamivudine crosses the placenta. Lamivudine concentrations in infant serum at birth were similar to those in maternal and cord serum at delivery.
Lamivudine crosses the placenta in rats and rabbits. No evidence of teratogenicity was observed in rats and rabbits at oral doses up to 2000 and 500 mg/kg BID, respectively, resulting in systemic exposures of at least 51 and 45 times (based on Cmax), respectively, of those observed at the clinical dosage. However, embryonic loss was increased, with consequent reduction in litter size, in rabbits at oral doses of 20 mg/kg BID and above, resulting in systemic exposures (based on both Cmax and AUC) comparable to those observed at the clinical dosage. No embryonic loss occurred in rats at systemic exposures of at least 51 times the clinical exposure (Cmax).
The safety of lamivudine has not been established in human pregnancy. Use in pregnancy should be considered only if the benefit outweighs the risk. Although the results of animal studies are not always predictive of human response, the findings in the rabbit suggest a potential risk of early embryonic loss. Consequently, Zeffix administration is not recommended during the first three months of pregnancy.
For patients 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 (see Section 4.4 Special Warnings and Precautions for Use).
Based on the limited data, it has not been established whether lamivudine can prevent the maternal-fetal transmission of hepatitis B virus in pregnant women receiving treatment with lamivudine. The standard recommended procedures for hepatitis B virus immunization in infants should be followed.
 Following oral administration lamivudine was excreted in human breast milk at similar concentrations to those found in serum (range 1-8 microgram/mL). The safety of lamivudine has not been established in breastfed infants. No effects were observed in neonatal rats which received lamivudine via maternal milk and supplemented with oral (gavage) dosing, resulting in systemic exposures (Cmax) of 16 to 19 times those observed at the clinical dosage.
Lamivudine should only be used in a nursing mother if the expected benefit justifies the potential risk to the infant. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from lamivudine therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

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 Special Warnings and Precautions for Use).

4.7 Effects on Ability to Drive and Use Machines

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 lamivudine should be borne in mind when considering the patient's ability to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial information.

Adults.

In clinical studies of patients with chronic hepatitis B, lamivudine 100 mg was well tolerated. The incidence of adverse events and laboratory abnormalities (with the exception of elevations of ALT and CPK, see below) were similar between placebo and lamivudine 100 mg treated patients. The most common adverse events reported were malaise and fatigue, respiratory tract infections, headache, abdominal discomfort and pain, nausea, vomiting and diarrhoea. The clinical adverse events occurring at an incidence of 1% or greater in controlled clinical trials and considered to be possibly, probably or almost certainly related to lamivudine are shown in Table 3. A dash represents an incidence of less than 1%.

Children and adolescents.

In clinical studies of paediatric and adolescent patients with chronic hepatitis B, lamivudine 100 mg was well tolerated. The incidence of adverse events was similar between placebo and lamivudine 100 mg treated patients and is consistent with those seen in the adult patient population. The most common adverse events reported were abdominal discomfort and pain and headache. The clinical adverse events occurring at an incidence of 3% or greater in controlled clinical trials and considered to be possibly, probably or almost certainly related to lamivudine are shown in Table 4.
Adverse reactions are listed below by system organ class and frequency. Frequency categories are only assigned to those adverse reactions considered to be at least possibly causally related to lamivudine. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000) and very rare (< 1/10,000).
The frequency categories assigned to the adverse reactions below are estimates: for most events, suitable data for calculating incidence are not available. Very common and common adverse drug reaction frequency categories were determined from clinical trial data and the background incidence of placebo groups was not taken into account. Adverse drug reactions identified through postmarketing surveillance were categorised as rare or very rare.

Hepatobiliary disorders.

Very common: elevations of ALT.
Elevations in ALT were more common post-treatment in patients treated with Zeffix than placebo. In controlled trials in patients with compensated liver disease, however, there was no appreciable difference post treatment in clinically severe ALT elevations associated with bilirubin elevations and/or signs of hepatic insufficiency, between Zeffix and placebo treated patients. The relationship of these recurrent hepatitis events to Zeffix treatment or to the previous underlying disease is uncertain (see Section 4.4 Special Warnings and Precautions for Use). Exacerbations of hepatitis, primarily detected by serum ALT elevations, have been reported 'on-treatment' and following lamivudine withdrawal. Most events have been self-limited, however fatalities have been observed very rarely.

Musculoskeletal and connective tissue disorders.

Common: elevations of CPK, cramps.

Metabolism.

Very rare: lactic acidosis.

Immune system disorders.

Rare: angioedema.

Skin and subcutaneous tissue disorders.

Common: rash, pruritus.

Postmarketing data.

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of Zeffix.

Blood and lymphatic system disorders.

Unknown/very rare: thrombocytopenia, anaemia, neutropenia, pure red cell aplasia, lymphadenopathy, splenomegaly.

Musculoskeletal and connective tissue disorders.

Common: muscle disorders, including myalgia and cramps.
Unknown/very rare: rhabdomyolysis, arthralgia.

Metabolism and nutrition disorders.

Hyperlactataemia, hyperglycemia, lactic acidosis (see Section 4.4 Special Warnings and Precautions for Use), redistribution/accumulation of body fat. The incidence of this event is dependent on multiple factors including the particular antiretroviral drug combination.

Nervous system disorders.

Headache, paraesthesia, peripheral neuropathy.

Gastrointestinal disorders.

Diarrhea, nausea, pancreatitis, rises in serum amylase, upper abdominal pain, vomiting.

Skin and subcutaneous tissue disorders.

Alopecia.

General disorders and administration site conditions.

Fatigue, fever, malaise.

Respiratory.

Abnormal breath sounds/wheezing.

Other special populations.

In patients with HIV infection, cases of pancreatitis and peripheral neuropathy (or paresthesia) have been reported. In patients with chronic hepatitis B there was no observed difference in incidence of these events between placebo and lamivudine treated patients.
In patients with HIV infection, cases of pancreatitis and peripheral neuropathy (or paresthesia) have been reported, although no relationship to treatment with lamivudine has been clearly established. In patients with chronic hepatitis B there was no observed difference in incidence of these events between placebo and lamivudine treated patients.
Cases of lactic acidosis, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of combination nucleoside analogue therapy in patients with HIV. There have been occasional reports of these adverse events in hepatitis B patients with decompensated liver disease, however the relation to treatment with lamivudine is unclear.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Administration of lamivudine at very high dose levels in acute animal studies did not result in any organ toxicity. Limited data are available on the consequences of ingestion of acute overdoses in humans. No fatalities occurred, and the patients recovered. No specific signs or symptoms have been identified following such overdose.
If 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Lamivudine is an antiviral agent which is highly active against hepatitis B virus in virus-transfected human hepatoma cell lines and in experimentally infected animals.
Lamivudine is metabolised by both hepatitis B virus-transfected and non-transfected hepatoma cells to the triphosphate (TP) derivative which is the active form of the parent compound. The intracellular half-life of the triphosphate in hepatoma cells is 17 - 19 hours in vitro. Lamivudine-TP acts as a substrate for the HBV viral polymerase. It is considered that the formation of further viral DNA is blocked by incorporation of lamivudine-TP into the chain and subsequent chain termination.
Lamivudine-TP does not interfere with cellular deoxynucleotide metabolism. It is also a weak inhibitor of mammalian DNA polymerases alpha and beta. Furthermore, lamivudine-TP has little effect on mammalian cell DNA content.
In assays relating to potential drug effects on mitochondrial structure and DNA content and function, lamivudine lacked appreciable toxic effects. It has a very low potential to decrease mitochondrial DNA content, is not permanently incorporated into mitochondrial DNA, and does not act as an inhibitor of mitochondrial DNA polymerase gamma.

Clinical trials.

Adults.

The safety and efficacy of lamivudine were evaluated in five controlled studies. One of the studies (NUCB3014) was conducted in HBeAg negative/HBV DNA positive patients.
NUCA3010 was a randomised, double-blind comparison in 143 patients in the USA of lamivudine 100 mg once daily versus placebo for 52 weeks followed by a 16 week no treatment period in treatment naïve patients. The primary endpoint was improvement in liver histology. After 52 weeks of treatment a significantly greater number of patients who received lamivudine demonstrated an improvement in necro-inflammatory score compared to placebo (53% lamivudine vs. 24% placebo; p < 0.001). HBeAg seroconversion occurred significantly more frequently in lamivudine patients (17%) than in placebo treated patients (6%) (p < 0.05). Significantly more lamivudine treated patients demonstrated a sustained HBV DNA response (defined as negative HBV DNA on two consecutive occasions without two consecutive positive values to end week 52) compared to placebo (44% vs. 16% respectively; p < 0.001). Similarly, a significantly greater number of lamivudine treated patients (41%) demonstrated a sustained normalisation of ALT (defined as two consecutive ALT values < ULN maintained to week 52) compared to placebo (7%; p < 0.001).
NUCB3009 was a randomised, double-blind comparison of lamivudine 25 mg daily versus lamivudine 100 mg daily versus placebo for 52 weeks in 358 Asian patients. The primary endpoint was improvement in liver histology. After 52 weeks of treatment a significantly greater number of patients who received lamivudine 100 mg demonstrated an improvement in necro-inflammatory score compared to placebo (56% lamivudine vs. 25% placebo; p < 0.001). HBeAg seroconversion occurred significantly more frequently in lamivudine 100 mg patients (16%) than in placebo treated patients (4%) (p < 0.05). Significantly more lamivudine 100 mg treated patients demonstrated a sustained HBV DNA response compared to placebo (57% vs. 3% respectively; p < 0.001). Similarly, a significantly greater number of lamivudine 100 mg treated patients (72%) demonstrated a sustained normalisation of ALT compared to placebo (24%; p < 0.001).
NUCB3010 was a randomised, partially blind comparison in 230 predominantly Caucasian patients of lamivudine 100 mg once daily for 52 weeks versus placebo once daily for 8 weeks followed by placebo once daily plus interferon alpha monotherapy (10 MU subcutaneously three times weekly) for 16 weeks versus lamivudine 100 mg once daily for 8 weeks followed by lamivudine 100 mg once daily plus interferon alpha monotherapy (10 MU subcutaneously three times weekly) for 16 weeks. The primary endpoint was HBeAg seroconversion with concomitant clearance of HBV DNA. There was no statistically significant difference in the rates of HBeAg seroconversion demonstrated by the three treatment groups (18% lamivudine, 19% interferon-alpha, 29% lamivudine plus interferon alpha). A greater proportion of patients in the lamivudine treated group demonstrated a sustained ALT normalisation than in the interferon-alpha alone group (40% vs. 17% respectively; p < 0.01) but there was no difference between lamivudine and the combination group. The safety profile of lamivudine 100 mg daily alone was superior to the alpha interferon containing treatment regimens.
NUCB3018 was a randomised, double-blind, placebo controlled follow-on study of NUCB3009. The primary endpoint was sustained suppression of HBV DNA. Fifty-two percent of patients receiving lamivudine for two years achieved a sustained suppression in HBV DNA through to week 104 compared to 5% of patients who received lamivudine for one year followed by placebo (p < 0.001). Sustained ALT response was evident in 50% of patients after 104 weeks lamivudine compared to 8% in patients randomised to placebo after the first 52 weeks of lamivudine (p < 0.001). HBeAg seroconversion was observed in 27% (25/93) of patients.
NUCB3014 was a randomised, double-blind comparison of lamivudine 100 mg once daily for 52 weeks versus placebo for 26 weeks (non-responders were withdrawn at week 26) in 125 predominantly Caucasian patients with HBeAg negative/HBV DNA positive chronic hepatitis B. The primary endpoint was combined clearance of HBV DNA and ALT normalisation. Sustained suppression of HBV DNA at 52 weeks occurred significantly more often in the lamivudine group (71%) than in the placebo group (15%) (p < 0.001) demonstrating that lamivudine is effective at suppressing HBV replication in patients infected with pre-core mutant HBV. Sustained normalisation of serum ALT occurred in a significantly greater proportion of lamivudine treated patients (67%) compared to placebo (5%) (p < 0.001).
In the analysis of NUCB3009 and NUCA3010 progression of fibrosis occurred in more patients receiving placebo compared to patients receiving lamivudine 100 mg (NUCB3009: 15% vs. 3%, p = 0.009; NUCA3010: 27% vs. 6%, p = 0.004). However, given the slow progression of fibrosis, the long-term clinical significance of these results is not known.
In patients who have not HBeAg seroconverted during treatment, discontinuation of Zeffix results in a return of HBV replication with both HBV DNA and serum aminotransferases returning towards pretreatment levels within 2-6 months.
In small uncontrolled studies in patients with decompensated liver disease due to chronic hepatitis B, lamivudine 100 mg daily has been administered prior to, during and post liver transplantation, to suppress existing or recurrent HBV. In some of these patients, lamivudine 100 mg daily demonstrated HBV suppression and normalisation of serum aminotransferase.
HBV viral sub-populations with reduced susceptibility to lamivudine in vitro have been identified. In the sensitive polymerase chain reaction (PCR) assay YMDD variant HBV was detected in a minority of chronic hepatitis B patients who experience a return of detectable serum HBV DNA levels whilst on lamivudine 100 mg daily treatment. YMDD variant HBV was detected in a minority of chronic hepatitis B patients without decompensated liver disease treated with lamivudine 100 mg once daily for 52 weeks (16-32%). The incidence of YMDD variant HBV detected by PCR increases with duration of treatment (42% at 2 years) and may be influenced by the immune status of the patient. A higher proportion of immunosuppressed patients had detectable YMDD variant HBV during treatment of hepatitis B recurrence following liver transplantation.
Despite the emergence of YMDD mutant HBV, patients treated for one year had significantly lower serum HBV DNA and ALT levels and improved liver histology compared to patients on placebo. After 2 years of Zeffix treatment, patients with YMDD mutant HBV maintained lower serum HBV DNA and ALT levels than their pre-treatment values. The adverse event profile is similar for patients with or without YMDD mutant HBV.
Following the development of YMDD mutant HBV, the withdrawal of lamivudine 100 mg daily was followed by a re-emergence of wild-type HBV which is sensitive to lamivudine 100 mg (see Section 4.4 Special Warnings and Precautions for Use). Therefore, despite the development of YMDD mutants, continuation of lamivudine 100 mg therapy will suppress residual wild-type HBV and may provide continued benefit in these patients. YMDD mutant HBV appears to be less replication competent in vitro and in vivo and therefore may be less virulent than wild-type HBV.

Children and adolescents.

In a randomised, double blind, placebo controlled study of 286 patients aged 2 to 17 years with chronic hepatitis B who were HBsAg positive for at least 6 months, HBeAg positive, with detectable HBV DNA, ALT ≥ 1.3 x ULN and liver biopsy evidence of inflammation. Patients were randomised (2:1) to receive 52 weeks of lamivudine 3 mg/kg once daily to a maximum of 100 mg once daily or placebo.
Patients treated with lamivudine for one year had a significantly better complete virological response (loss of HBeAg and HBV DNA) compared with patients receiving placebo (23% [44/191] vs. 13% [12/95] p = 0.037). Normalisation of serum ALT was more frequent in patients treated with lamivudine compared with placebo (55% [100/183] vs. 13% [11/88] p < 0.001). In a stratified follow-on study for 6 months, complete virological response was maintained in 83% [33/40] of patients who had responded after one year of treatment with lamivudine and then stopped therapy.
Lamivudine treated patients who did not respond after one year continued treatment for a further 6 months resulting in an additional 10% (12/123) of patients achieving complete virological response and a cumulative complete virological response of 28% (45/163) over 18 months. The complete virological response rate in the last 6 months of treatment was consistent with the placebo response rate, a benefit from continuing treatment in children beyond 52 weeks has not been established.
The incidence of YMDD variant HBV was 18% (30/166) at week 52 and up to 45% (53/118) in patients treated continuously for 18 months. No HBeAg seroconversion was observed in patients with YMDD variant HBV.

5.2 Pharmacokinetic Properties

Absorption.

Lamivudine is well absorbed from the gut, 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. 100 mg once daily, Cmax is in the order of 1-1.5 microgram/mL and trough levels were 0.015 - 0.020 microgram/mL.
The 100 mg tablet was administered orally to 16 healthy subjects on two occasions, once in the fasted state and once with food (standard meal: 967 kcal; 67 grams fat, 33 grams protein, 58 grams carbohydrate). There was no significant difference in systemic exposure (AUCinf) in the fed and fasted states. A reduction in Cmax (about 10%) and delay in Tmax (0.25 hrs) with the ingestion of a high fat meal were not statistically or clinically significant.

Distribution.

From intravenous studies, the mean volume of distribution is 1.3 L/kg. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding to albumin.
Limited data show relatively low penetration of lamivudine into the central nervous system. The mean ratio CSF/serum lamivudine concentration 2 to 4 hours after oral administration was approximately 0.12.

Metabolism.

Lamivudine is predominately cleared by renal excretion of unchanged drug. The likelihood of metabolic drug interactions with lamivudine is low due to limited metabolism and plasma protein binding and almost complete renal clearance. An interaction with trimethoprim, a constituent of cotrimoxazole (trimethoprim with sulphamethoxazole) causes a 40% increase in lamivudine exposure at therapeutic doses.

Excretion.

The mean systemic clearance of lamivudine is approximately 0.3 L/h/kg. The observed half-life of elimination is 5 to 7 hours. The majority of lamivudine is excreted unchanged in the urine via glomerular filtration and active secretion (organic cationic transport system). Renal clearance accounts for about 70% of lamivudine elimination.

Special populations.

Lamivudine pharmacokinetics were evaluated in a 28-day dose-ranging study in 53 paediatric patients with chronic hepatitis B. Patients aged 2 to 12 years were randomised to receive lamivudine 0.35 mg/kg twice daily, 3 mg/kg once daily, 1.5 mg/kg twice daily, or 4 mg/kg twice daily. Patients aged 13 to 17 years received lamivudine 100 mg once daily. Lamivudine was rapidly absorbed (Tmax 0.5 to 1 hour). In general, both Cmax and exposure (AUC) showed dose proportionality in the dose range studied. Weight-correct oral clearance was highest at age 2 and declined from 2 to 12 years, where values were similar to those seen in adults. A dose of 3 mg/kg given once daily produced a steady-state lamivudine AUC (mean 5953 nanogram.hour/mL ± 1562 SD) similar to that associated with a dose of 100 mg/day in adults.
Studies in patients with renal impairment show there is a linear relationship between lamivudine clearance and renal function. Dose reduction in patients with a creatinine clearance of < 50 mL/min is necessary (see Section 4.2 Dose and Method of Administration).
A study in non-HIV and non-HBV infected hepatically impaired patients (n = 16) showed lamivudine is well tolerated in this patient group with no changes in laboratory parameters or the adverse event profile of lamivudine. The pharmacokinetics of lamivudine are unaffected by hepatic impairment. Limited data in patients undergoing liver transplantation (n = 14), show that impairment of hepatic function does not impact significantly on the pharmacokinetics of lamivudine unless accompanied by renal dysfunction.
In elderly patients (n = 6) the pharmacokinetic profile of lamivudine suggests that normal ageing with accompanying renal decline has no clinically significant effect on lamivudine exposure, except in patients with creatinine clearance of < 50 mL/min (see Section 4.2 Dose and Method of Administration).
Following oral administration, lamivudine pharmacokinetics in late pregnancy were similar to nonpregnant adults.

5.3 Preclinical Safety Data

Genotoxicity.

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, an oral dose of lamivudine 2000 mg/kg did not cause chromosomal aberrations in bone marrow cells, nor unscheduled DNA synthesis in primary hepatocytes in vivo. Three consecutive daily oral doses of lamivudine 2000 mg/kg in rats, resulting in a systemic exposure (based on Cmax) of at least 56 times the clinical exposure, did not induce micronuclei in bone marrow in vivo.
Lamivudine was not genotoxic in vivo at doses that gave plasma concentrations around 60-70 times higher than the anticipated clinical plasma levels. As the in vitro mutagenic activity of lamivudine could not be confirmed by in vivo tests, it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing treatment.

Carcinogenicity.

When lamivudine was administered orally to separate groups of rodents at doses of up to 2000 (mice and male rats) or 3000 (female rats) mg/kg/day, there was no evidence of a carcinogenic effect in the mouse study, nor in male rats (at 37 and 133 times the estimated human exposure, based on AUC, respectively). In female rats, no increase in tumours was observed at the intermediate dose of 1000 mg/kg/day, which resulted in a systemic exposure based on AUC 78 times the estimated human exposure. However, there was an increase in endometrial tumours in female rats at the highest dose (9% tumour incidence) compared with controls (4% incidence). The high dose in female rats resulted in a systemic exposure 220 times the estimated human exposure based on AUC. The relationship of the increase in tumours to treatment is uncertain.

6 Pharmaceutical Particulars

6.1 List of Excipients

Zeffix tablets contain microcrystalline cellulose, sodium starch glycollate, magnesium stearate, hypromellose (464), titanium dioxide (171), macrogol, polysorbate 80 (433), yellow iron oxide CI77192 and red iron oxide CI77491.
Zeffix oral solution contains sucrose, methyl hydroxybenzoate, propyl hydroxybenzoate, citric acid, propylene glycol, sodium citrate dihydrate, strawberry 57883 AP0551 (PI 2480), banana flavour 59256 AP0551 (PI 2481), and purified water.
See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Tablets.

Store below 30°C.

Oral solution.

Store below 25°C.

6.5 Nature and Contents of Container

Tablets.

Zeffix tablets are supplied in blister packs (AI/AI material) containing 28 tablets or 84 tablets*.
* Pack size not currently marketed.

Oral solution.

Zeffix oral solution is supplied in an opaque white HDPE bottle, with a child-resistant cap.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Chemically, lamivudine is the free base of (2R-cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one, and has the following structural formula:
The molecular formula of lamivudine is C8H11N3O3S and it has a relative molecular mass of 229.3.

CAS number.

CAS registry number: 134678-17-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes