Consumer medicine information

Lamivudine 150 mg + Zidovudine 300 mg Alphapharm

Lamivudine; Zidovudine

BRAND INFORMATION

Brand name

Lamivudine 150 mg + Zidovudine 300 mg Alphapharm

Active ingredient

Lamivudine; Zidovudine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lamivudine 150 mg + Zidovudine 300 mg Alphapharm.

What is in this leaflet

Please read this leaflet carefully before you start LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm. This leaflet answers some common questions about LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm against the benefits they expect it will have on you.

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

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

What LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm is used for

LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm contains lamivudine and zidovudine which belongs to a group of medicines called antiretrovirals.

Please note that lamivudine is available as a stand alone tablet (as LAMIVUDINE Alphapharm lamivudine 150mg & 300mg tablets).

Lamivudine with zidovudine is used alone or with other antiretrovirals, to slow down the progressing 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 with zidovudine does not cure AIDS or HIV infection, but slows production of human immunodeficiency virus. In this way it stops ongoing damage to the body's immune system, which fights infection.

Lamivudine with zidovudine does not reduce the risk of passing HIV infection to others. You will still be able to pass on the HIV virus by sexual activity or by passing on blood or bodily secretions which carry the HIV virus. You should still use proper precautions.

While taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm 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. The long-term risks and benefits of taking lamivudine / zidovudine combination tablets are not known.

Your doctor may have prescribed LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm for another reason. Ask your doctor if you have any questions about why it has been prescribed for you.

LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm is not addictive.

Before you take LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm

When you must not take them

Do not take LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm if you have an allergy to:

  • any medicine containing lamivudine
  • any medicine containing zidovudine or
  • any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may be mild or severe. They usually include some or all of the following: wheezing, swelling of the lips/mouth, difficulty in breathing, hay fever, lumpy rash ("hives") or fainting.
  • Do not take LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm if you are pregnant or breastfeeding, unless your doctor says you should.
    Your doctor should discuss with you the risks and benefits of using LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm if you are pregnant or breast feeding.
  • Do not take LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm if you have.
    - Kidney disease
    - Liver disease
    - Reduced red blood cell count (anaemia),
    - Reduced white blood cell count (neutropenia).

If you have certain conditions, you doctor may advise that you take a lower dose of lamivudine and/or zidovudine, the active ingredients in LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm.

Lamivudine and zidovudine are available as separate dosage forms. Ask your doctor if you are not sure whether you should take LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm.

  • Do not take LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm after the expiry date (EXP) printed on the pack.
    If you take them after the expiry date has passed, it may not work as well.
  • Do not take LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm if the packaging is torn or shows signs of tampering.

If you're not sure whether you should be taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm talk to your doctor.

Before you start to take them

You must tell your doctor if:

  • you are allergic to any other medicines, foods, preservatives or dyes.
  • You are taking or have taken any other medicines.
  • You have, or have ever had, hepatitis B infection.
  • You have, or ever had, liver problems.

When you stop taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm

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 your LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm, 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 or pharmacist if you are taking any other medicines, including any that you get without a prescription from a pharmacy, supermarket or health food shop.

If you take ribavirin and LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm together it may cause or worsen anaemia. Please contact your doctor if you notice symptoms of anaemia (such as tiredness and shortness of breath). Your doctor will advise you whether you should stop taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm.

There is little information about the way other medicines might affect the way LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm works, or how LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm affects other medicines. Particular care is needed when taking the painkiller, paracetamol.

Your doctor or pharmacist will be able to tell you what to do when taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm with other medicines.

Tell your doctor if you are taking any of the medicines below:

  • Ribavirin, paracetamol
  • Phenytoin, oxazepam, lorazepam.
  • Aspirin, codeine, morphine, methadone, rifampicin, indometacin, ketoprofen, naproxen, cimetidine, clofibrate, probenecid.
  • Pentamidine, pyrimethamine, dapsone, atovaquone, amphotericin B (amphotericin), flucytosine, ganciclovir, interferon, trimethoprim, sulfamethoxazole, clarithromycin.
  • Vincristine, vinblastine and doxorubicin.
  • Aciclovir, inosine pranobex, adriamycin, ciprofloxacin
  • Stavudine, zalcitabine or emtricibine
  • Sorbitol-containing medicines (usually liquids) used regularly.
    LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm should not be taken with stavudine or zalcitabine

Use in children

LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm is not recommended for use in children under 12 years of age. Because it is a fixed dose combination tablet it cannot be adjusted according to the size and weight of the patient.

How to take LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm

Your doctor will tell you have many LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm to take and how often to take them. You will also find this information on the label or your medicine.

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

The usual dosage of LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm is one tablet twice a day.

How to take them

Swallow the LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm whole with a full glass of water. Do not divide.

When to take them

Your doctor or pharmacist will be able to tell you when you should take your LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm tablets.

How long to take them

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 them

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 you missed.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm. 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 using LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm.

There is little information about the way other medicines might affect the way that LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm works. You must tell your doctor or pharmacist that you are taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm before you start taking medicines you buy from a pharmacy, health food shop or supermarket. This is especially important regarding medicines which might have an effect on the kidneys, liver, red or white blood cells or other body cells.

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 150mg + ZIDOVUDINE 300mg Alphapharm or change the dosage without checking with your doctor.

Do not give LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm to anyone else, even if they have the same condition as you.

Do not take LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm to treat any other complaints unless your doctor tells you to.

Do not give this medicine to children under 12 years of age. Because it is a fixed dose combination tablet it cannot be adjusted according to the size and weight of the patient.

Things to be careful of

Be careful driving or operating machinery until you know how LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm affects you. LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm taken alone generally do not cause any problems with your ability to drive a car or operate machinery. However, as with many other medicines, LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm may cause headache and tiredness in some people.

Side effects

Check with your doctor or pharmacist as soon as possible if you do not feel well while you are taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm , even if you think that the problems are not connected with the medicine or are not listed in this leaflet.

Like all medicines, LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm 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.

The most serious side effects include:

  • Reduced red blood cell count (anaemia).
  • Reduced white blood cell count (neutropenia).

The frequency and severity of anaemia and neutropenia are greater in patients with advanced HIV disease, or in patients who start taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm in the later stages of HIV disease.

While you are taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm , it is very important that your doctor keeps a close check on your health and takes blood samples to monitor levels of red and white blood cells. If you develop anaemia or neutropenia, your doctor may reduce or stop the dose of LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm , or recommend standard treatment for these conditions. As your doctor any questions which you may have.

It is not known whether many of these side effects are due to taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm or taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm while taking other medicines. Some of these symptoms may occur as part of HIV infection, AIDS and AIDS-related Complex.

The side effects listed below have been reported:

  • Body odour, sweating, chills, swelling of lips and/or tongue, flu-like symptoms, fever, increased sensitivity to pain, back pain, enlarged glands, chest pain, weakness, weight loss, generally feeling unwell, breast enlargement in male patients.
  • Widening of blood vessels, possibly leading to low blood pressure or feeling faint.
  • Constipation, difficulty in swallowing, gas from stomach or bowel, diarrhoea, bleeding gums or nose, blood in stools, mouth ulcers, heartburn, vomiting, loss or reduction in appetite, nausea.
  • Abdominal discomfort or pain.
  • Muscle aches or pains, muscle shaking or spasm or twitching, muscle disease.
  • Enlarged fatty liver, abnormal results of blood tests of liver function, inflammation of the pancreas.
  • Confusion, depression, nervousness, fainting, loss of mental clarity, dizziness, seizures, severe headache, sleeplessness, fatigue/tiredness.
  • Cough, sore throat, hay fever, sinus problems, hoarseness, change to perception of taste.
  • Acne, itchiness, skin rash, changes in nail, skin or mouth colour.
  • Vision problems, hearing loss, sensitivity to light.
  • Passing too much urine, pain, difficulty or increased frequency of passing urine.
  • Reduction in all blood cells.
  • Increased bruising or bleeding.
  • Blood chemistry changes, with excess acidity of the blood.
  • Unusual feelings in any part of the body, such as numbness, burning, tingling or pins and needles.
  • Hair loss.

Changes in fat distribution have been reported in association with combination antiretroviral therapy. These may include:

  • 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 development inflammatory reactions (eg, 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 of the new symptoms, or any changes in your health after starting HIV treatment, please discuss with your doctor immediately.

Ask your doctor or pharmacist to answer any questions you may have. If you experience any of these side effects, and they concern you, see your doctor or pharmacist.

If you think you are having an allergic reaction to LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm , TELL YOUR DOCTOR IMMEDIATELY or go to the nearest Accident and Emergency department at your nearest hospital. Symptoms usually include some or all of the following:

  • Wheezing
  • Swelling of the lips/mouth
  • Difficulty in breathing
  • Hay fever
  • Lumpy rash ("hives")
  • Fainting

If you have any of the following symptoms soon after starting to take your medicine, DO NOT TAKE ANY MORE LAMIVUDINE 150MG + ZIDOVUDINE 300MG ALPHAPHARM and tell your doctor IMMEDIATELY or go to the nearest 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 150mg + ZIDOVUDINE 300mg Alphapharm 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 a 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 150mg + ZIDOVUDINE 300mg Alphapharm.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

Side effects may depend on whether you take LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm alone, or also have taken other antiretroviral medication(s). Less is known about possible side effects of taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm with other antiretrovirals.

Tell your doctor if you notice any else that is making you feel unwell, even if it is on this list.

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 using LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm

Storage

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

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not store LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep your tablets in the bottle until it is time to take them. If you take the tablets out of the bottle they may not keep well.

Disposal

If your doctor tells you to stop taking LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm or the expiry date has passed, ask your pharmacist what to do with any tablets left over.

Product description

What it looks like

LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm is a white to off-white, capsule shaped, biconvex film coated tablet, debossed with "M" on left of the scoreline and "103" on right, on one side and scored on the other side.

LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm is supplied in 60 tablet bottles.

Ingredients

LAMIVUDINE 150 mg + ZIDOVUDINE 300 mg Alphapharm contains 150 mg of lamivudine and 300 mg of zidovudine as the active ingredient.

It also contains the following inactive ingredients:

  • Microcrystalline cellulose.
  • Sodium starch glycollate type A.
  • Magnesium stearate.
  • Colloidal anhydrous silica.
  • Propylene glycol (film coating).
  • Opadry Complete Film Coating System 03H58736 White (Proprietary Ingredient Number 106640).

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

LAMIVUDINE 150 mg + ZIDOVUDINE 300 mg Alphapharm is supplied in Australia by:

Alphapharm Pty Limited
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian registration numbers:

LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm bottle:

AUST R 167477

This leaflet was prepared in August 2019.

LAMIVUDINE 150mg + ZIDOVUDINE 300mg Alphapharm_cmi\Aug19/00

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Lamivudine 150 mg + Zidovudine 300 mg Alphapharm

Active ingredient

Lamivudine; Zidovudine

Schedule

S4

 

1 Name of Medicine

Lamivudine and zidovudine.

6.7 Physicochemical Properties

Lamivudine.

Chemical name: (2R-cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one.
Molecular formula: C8H11N3O6S.
Molecular weight: 229.26.

Zidovudine.

Chemical name: 1-(3-Azido-2,3-dideoxy-β-d-erythro-pentofuranosyl)-5-methylpyrimidine-2,4(1H,3H)-dione. Formerly called azidothymine (AZT) or 3'-azido-3'-deoxythymidine.
Molecular formula: C10H13N5O4.
Molecular weight: 267.24.
Lamivudine is a white to off-white crystalline solid which is highly soluble in water. Zidovudine is a white to yellowish odourless powder which is sparingly soluble in water and soluble in alcohol.

Chemical structure.


CAS number.

Lamivudine.

CAS Registry no.: 134678-17-4.

Zidovudine.

CAS Registry no.: 30516-87-1.

2 Qualitative and Quantitative Composition

Lamivudine with zidovudine tablets are a fixed combination product containing lamivudine 150 mg and zidovudine 300 mg.
The product information for lamivudine tablets contain additional information specific for lamivudine.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Lamivudine 150 mg + Zidovudine 300 mg Alphapharm lamivudine 150 mg and zidovudine 300 mg tablets: White to off-white capsule shaped, bi-convex film coated tablet, debossed with "M" on left of the scoreline and "103" on right, on one side and scored on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Zidovudine is an inhibitor of the in vitro replication of some retroviruses including HIV, whereas lamivudine is a potent, selective inhibitor of HIV-1 and HIV-2 replication in vitro. Lamivudine has been shown to be usually synergistic with zidovudine at inhibiting the replication of HIV in cell culture. Both drugs are metabolised sequentially by intracellular kinases to their 5'-triphosphate (TP) derivatives. Lamivudine 5'-triphosphate and triphosphate are substrates for and competitive inhibitors of HIV reverse transcriptase. However, their main antiviral activity is through incorporation of the monophosphate form (MP) form into the viral DNA chain, resulting in chain termination. Lamivudine and zidovudine triphosphates show significantly less affinity for host cell DNA polymerases.
The relationships between in vitro susceptibility of HIV to lamivudine and zidovudine 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.
Individually, lamivudine and zidovudine therapy has resulted in HIV clinical isolates which show reduced sensitivity in vitro to the nucleoside analogue to which they have been exposed. However in vitro studies also indicate that zidovudine resistant virus isolates may become sensitive again to zidovudine when they simultaneously acquire resistance to lamivudine. Furthermore in vivo there is clinical evidence that lamivudine plus zidovudine delays the emergence of zidovudine resistance in antiretroviral naive patients.

Clinical trials.

Pregnancy.

The Antiretroviral Pregnancy Registry (APR) has received reports of over 11,000 exposures to lamivudine during pregnancy resulting in live birth. These consist of over 4,500 exposures during the first trimester, over 7,200 exposures during the second/third trimester and included 143 and 207 birth defects respectively. The prevalence (95% CI) of defects in the first trimester was 3.1% (2.6, 3.7%) and in the second/third trimester, 2.9% (2.5, 3.3%). The APR has received reports of over 13,000 exposures to zidovudine during pregnancy resulting in live birth. These consist of over 4,100 exposures during the first trimester, over 9,300 exposures during the second/third trimester and included 133 and 264 birth defects respectively. The prevalence (95% CI) of defects in the first trimester was 3.2% (2.7, 3.8%) and in the second/third trimester, 2.8% (2.5, 3.2%). These proportions are not significantly higher than those reported in the two population based surveillance systems (2.72 per 100 live births and 4.17 per 100 live births respectively). The Antiretroviral Pregnancy Registry does not show an increased risk of major birth defects for lamivudine or zidovudine compared to the background rate.

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 naive. 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 11.
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.

The approved indication for the lamivudine and zidovudine combination tablet is based on analyses of several surrogate endpoints in clinical studies of the combination of lamivudine 150 mg twice daily and zidovudine 200 mg three times daily. The subjects of these studies were patients with or without prior antiretroviral therapy.
Study designs are summarised in Table 12. All were randomised, double blind, multicentre studies. The characteristics of the patients at baseline are given in Table 13.
There are no results of clinical studies of the combination of lamivudine 150 mg with zidovudine 300 mg taken twice daily. The approval of the use of zidovudine 300 mg twice daily in lamivudine and zidovudine combination tablet is based on extrapolation from clinical studies in which several other dosage regimens have been used.

After 24 weeks.

In zidovudine naive 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. A meta-analysis of the 4 pivotal trials showed that lamivudine in combination with zidovudine slowed the progression of HIV disease compared to controls (all other treatment arms).
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.

5.2 Pharmacokinetic Properties

Absorption.

Lamivudine and zidovudine are well absorbed from the gut. The bioavailability of oral lamivudine in adults is normally between 80-85% and for zidovudine 60-70%.
A bioequivalence study in healthy volunteers compared the combination lamivudine 150 mg + zidovudine 300 mg tablet with the lamivudine 150 mg tablets and zidovudine 300 mg tablets taken together.
In fasted subjects, the combination lamivudine 150 mg + zidovudine 300 mg tablet was shown to be bioequivalent to lamivudine 150 mg and zidovudine 300 mg administered together as separate tablets. Following the combination lamivudine 150 mg + zidovudine 300 mg tablet administration, the Cmax (95% confidence interval) for lamivudine was 1.5 microgram/mL (1.3-1.8) and for zidovudine was 1.8 microgram/mL (1.5-2.2). The median tmax (range) was 0.75 hours (0.50-2.00) and 0.50 hours (0.25-2.00) for lamivudine and zidovudine, respectively. The extent (AUC) of lamivudine and zidovudine absorption, and estimates of half-life following administration of lamivudine 150 mg + zidovudine 300 mg tablet with food were similar when compared to fasted subjects.
The rate of absorption, however, was reduced for both drugs. For lamivudine, mean Cmax was 85% of that in the fasted state while median tmax increased from 0.75 to 1.5 hours. For zidovudine, the mean Cmax was 55% of that in the fasted state while the median tmax was increased from 0.5 to 1.0 hours. The clinical significance of the effect of food on the absorption of lamivudine 150 mg + zidovudine 300 mg tablet is not known.
A bioequivalence study was conducted comparing the generic lamivudine 150 mg/ zidovudine 300 mg tablets with the originator lamivudine 150 mg/ zidovudine 300 mg tablets. The generic and originator mean Cmax for lamivudine was 1650 nanogram/mL and 1666 nanogram/mL respectively, and the generic and originator mean Cmax for zidovudine was 2229 nanogram/mL and 2209 nanogram/mL respectively. The Cmax point estimate for lamivudine was 0.9767 with the 90% confidence interval between 0.9031 and 1.0562, and the Cmax point estimate for zidovudine was 0.9881 with the 90% confidence interval was between 0.8403 and 1.1618. The mean AUC point estimate for lamivudine was 1.0112 with the 90% confidence interval between 0.9683 and 1.0559, and the mean AUC point estimate for zidovudine was 0.9885, the 90% confidence interval was between 0.9487 and 1.0300. The tmax for both the generic and originator tablets was 1.1 hours for the lamivudine component and 0.5 hours for the zidovudine component.

Distribution.

From intravenous studies, the mean volume of distribution of lamivudine is 1.3 L/kg. Plasma protein binding is limited. Zidovudine plasma protein binding is 34% to 38%.
Limited data show relatively low penetration of lamivudine into the central nervous system. When individually administered the mean ratio cerebrospinal fluid/ serum concentration for lamivudine and zidovudine 2 to 4 hours after dosing was approximately 0.12 and 0.5 respectively.

Metabolism.

The likelihood of adverse drug interactions with lamivudine is low due to limited metabolism (< 10% hepatic) and plasma protein binding and almost complete renal elimination. An interaction with trimethoprim, a constituent of trimethoprim with sulfamethoxazole causes a 40% increase in lamivudine exposure following administration of one trimethoprim 160 mg/ sulfamethoxazole 800 mg tablet once daily for 5 days. The effects of higher doses of trimethoprim on lamivudine plasma levels have not been investigated.
Zidovudine is rapidly metabolised during first pass to 3'-azido-3'-deoxy-5'-O-β-D-glucopyranuronosylthymidine (GAZT) which has an apparent elimination half-life of 1 hour (range 0.61 to 1.73 hours). Following oral administration, urinary recoveries of zidovudine and GAZT accounted for 14 and 74% of the dose, respectively, and the total urinary recovery averaged 90% (range 63 to 95%), indicating a high degree of absorption.
Limited data has identified 3'-amino-3'deoxythymidine (AMT) as a metabolite of zidovudine following intravenous and oral dosing. A small in vitro study showed that AMT reduced the growth of haemopoietic progenitor cells; the clinical significance of this finding is unknown.

Excretion.

Mean terminal half-life of elimination of lamivudine is 5 to 7 hours and mean systemic clearance is approximately 0.32 L/h/kg, with predominantly renal clearance (> 70%) via active tubular secretion, but little (< 10%) hepatic metabolism.
Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction. Dose reduction is required for patients with creatinine clearance < 50 mL/min (see Section 4.2 Dose and Method of Administration).
The mean terminal half-life of elimination of zidovudine is approximately one hour. Renal clearance of zidovudine is estimated to be 0.34 L/h/kg, indicating glomerular filtration and active tubular secretion by the kidneys. Zidovudine concentrations are increased in patients with advanced renal failure.
Limited data indicate that zidovudine crosses the placenta and is found in amniotic fluid and foetal blood. Zidovudine has also been detected in semen. Lamivudine crosses the placenta in rats and rabbits.

Pharmacokinetics in special patient groups.

There are limited data on the pharmacokinetics of zidovudine in patients with renal or hepatic impairment. Dosage adjustment of zidovudine is required in patients with advanced renal failure and severe hepatic impairment. There are also limited data on the pharmacokinetics of zidovudine in pregnant women. No specific data are available on the pharmacokinetics of zidovudine in the elderly.
A single dose pharmacokinetic study of lamivudine (n = 16) in HIV infected patients with normal renal function and with moderate (creatinine clearance < 30 mL/min and > 10 mL/min) or end stage renal impairment (creatinine clearance < 10 mL/min) showed there was a linear relationship between lamivudine clearance and renal function.
Since dosage adjustments of lamivudine are required in patients with impaired renal function and for zidovudine in patients with advanced renal failure or severe hepatic impairment the use of a fixed dose combination tablet such as lamivudine 150 mg + zidovudine 300 mg tablet is not recommended in these patients (see Section 4.4 Special Warnings and Precautions for Use).
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 the physiochemical and pharmacokinetic characteristics of the active ingredients and the in vitro dissolution behaviour of lamivudine zidovudine tablets in water, assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.

Pharmacokinetics in children.

In children over the age of 5-6 months, the pharmacokinetic profile of zidovudine is similar to that in adults. Zidovudine is well absorbed from the gut and at all dose levels studied in adults and children, the bioavailability was between 60-74% with a mean of 65%. Cssmax levels were 4.45 microM (1.19 microgram/mL) following a dose of 120 mg zidovudine (in solution)/m2 body surface area and 7.7 microM (2.06 microgram/mL) at 180 mg/m2 body surface area. Dosages of 180 mg/m2 four times daily in children produced similar systemic exposure (24 hour AUC 40.0 hr.microM or 10.7 hr.microgram/mL) as doses of 200 mg six times daily in adults (40.7 hr.microM or 10.9 hr.microgram/mL).
In six HIV infected children from 2 to 13 years of age, zidovudine plasma pharmacokinetics were evaluated while subjects were receiving 120 mg/m2 zidovudine three times daily and again after switching to 180 mg/m2 twice daily. Systemic exposures (daily AUC and Cmax) in plasma from the twice daily regimen appeared equivalent to those from the same total daily dose given in three divided doses [Bergshoeff, 2004].
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. Due to these differences, the recommended dose for lamivudine in children (from three months to 12 years; approximately 6 kg to 40 kg) is 8 mg/kg/day. This dose will achieve an average AUC0-12 ranging from approximately 3,800 to 5,800 nanogram.h/mL. 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.

5.3 Preclinical Safety Data

No mutagenicity or carcinogenicity studies have been carried out using a combination of lamivudine and zidovudine.

Genotoxicity.

With zidovudine no evidence of mutagenicity (with or without metabolic activation) was observed in the Salmonella mutagenicity assay. In a mutagenicity assay conducted in L5178Y/TK+/- mouse lymphoma cells, zidovudine was weakly mutagenic in the presence and absence of metabolic activation. In an in vitro cytogenetic study performed in cultured human lymphocytes, zidovudine induced dose related structural chromosomal abnormalities. Zidovudine was clastogenic in in vivo micronucleus tests in rats and mice. Zidovudine gave positive results in an in vitro mammalian cell transformation assay.
Lamivudine was not active in a microbial mutagenicity screen but did induce mutations at the thymidine kinase locus of mouse lymphoma L5178Y cells without metabolic activation. Lamivudine was clastogenic in human peripheral blood lymphocytes in vitro, with or without metabolic activation. In rats, lamivudine did not cause chromosomal damage in bone marrow cells in vivo or cause DNA damage in primary hepatocytes.

Carcinogenicity.

Zidovudine was administered orally to separate groups of mice and rats at doses up to 40 and 300 mg/kg/day, respectively. In mice, seven late appearing (after 19 months) vaginal neoplasms (5 nonmetastasising squamous cell carcinomas, one squamous cell papilloma, and one squamous polyp) occurred in animals given the highest dose. One late appearing squamous cell papilloma occurred in the vagina of a middle dose animal. No vaginal tumours were found at the lowest dose. In rats, two late appearing (after 20 months), nonmetastasising vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumours occurred at the low or middle dose in rats. No other drug related tumours were observed in either sex of either species. At doses that produced tumours in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 4 times (mouse) and 27 times (rat) the estimated human exposure at the recommended therapeutic dose of one tablet twice daily.
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.

4 Clinical Particulars

4.1 Therapeutic Indications

Lamivudine and zidovudine combination tablet is indicated for use alone or in combination with other antiretroviral therapies in the treatment of HIV infection.

4.3 Contraindications

Lamivudine and zidovudine combination tablet is contraindicated in patients with known hypersensitivity to lamivudine, zidovudine or to any ingredient of the preparation.
As zidovudine is contraindicated in patients with abnormally low neutrophil counts (< 0.75 x 109/L), or abnormally low haemoglobin levels (< 7.5 g/dL or 4.65 mmol/L), lamivudine and zidovudine combination tablets is contraindicated in these patients (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Patients receiving lamivudine and zidovudine combination tablets or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV infection.
Patients should be advised that current antiretroviral therapy, including lamivudine and zidovudine combination tablet, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.
The full safety and efficacy profiles of the active ingredients in lamivudine and zidovudine combination tablet have not been completely defined, particularly in regard to prolonged use.
It is recommended that separate preparations of lamivudine and zidovudine should be administered in cases where dosage adjustment is necessary (see Section 4.2 Dose and Method of Administration). Physicians should refer to the individual product information for these drugs.

Haematological effects.

Therapy with zidovudine preparations is commonly associated with haematologic toxicity including granulocytopenia and severe anaemia requiring transfusions particularly in patients with advanced HIV disease (see Section 4.8 Adverse Effects (Undesirable Effects)).
There have been reports of pancytopenia associated with the use of zidovudine, which was reversible in most instances after discontinuance of the drug.
Because anaemia, neutropenia and leucopenia (usually secondary to neutropenia) can be expected to occur in patients with advanced symptomatic HIV disease receiving zidovudine, haematological parameters should be carefully monitored in patients receiving lamivudine and zidovudine combination tablet (see Section 4.3 Contraindications). These haematological effects are not usually observed before four to six weeks of therapy. For patients with advanced symptomatic HIV disease, it is generally recommended that blood tests are performed at least every two weeks for the first three months of therapy and at least monthly thereafter.
In patients with early HIV disease haematological adverse reactions are infrequent. Depending on the overall condition of the patient blood tests may be performed less often, for example every one to three months. Decreases in the haemoglobin level of more than 25% from baseline and falls in the neutrophil count of more than 50% from baseline may require more frequent monitoring.
Additionally, dosage adjustment of zidovudine may be required if severe anaemia or myelosuppression occurs during treatment with lamivudine and zidovudine combination tablets, or in patients with pre-existing bone marrow compromise e.g. haemoglobin < 9 g/dL or granulocyte count < 1000 cells/mm3 (see Section 4.2 Dose and Method of Administration). As dosage adjustment of lamivudine and zidovudine combination tablets is not possible, separate preparations of zidovudine and lamivudine should be used. Physicians should refer to the individual product information for these drugs.

Hypersensitivity.

Sensitisation reactions, including anaphylaxis in one patient, have been reported in individuals receiving zidovudine therapy. Patients experiencing a rash should undergo medical evaluation.

Pancreatitis.

Cases of pancreatitis have occurred rarely in patients treated with lamivudine and zidovudine. However it is not clear whether these cases were due to drug treatment or to the underlying HIV disease. Treatment with lamivudine and zidovudine combination tablets should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.

Lipoatrophy.

Treatment with zidovudine has been associated with loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs and buttocks, may be only partially reversible and improvement may take several months when switching to a zidovudine-free regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine and other zidovudine containing products (Retrovir and Trizivir), and if feasible therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy development.

Serum lipids and blood glucose.

Serum lipid and blood glucose levels may increase during antiretroviral therapy. Disease control and life style changes may also be contributing factors. 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 and zidovudine. 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 and zidovudine combination tablets to any patient, and particularly to those with known risk factors for liver disease. Treatment with lamivudine and zidovudine combination tablets should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis with or without hepatitis (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.

Patients coinfected with hepatitis C virus.

Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. Therefore, the co-administration of ribavirin and zidovudine is not advised and consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This is particularly important in patients with a known history of zidovudine induced anaemia.

Use of paracetamol and other medicines.

Zidovudine recipients who used paracetamol during the controlled trial in advanced HIV disease had an increased incidence of granulocytopenia which appeared to be correlated with the duration of paracetamol use.
If the lamivudine and zidovudine combination tablet is coadministered with other drugs metabolised by glucuronidation, careful thought should be given to the possibilities of interactions with zidovudine, because the toxicity of either drug may be potentiated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients should be cautioned about the concomitant use of self administered medications (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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.

Other precautions.

Alternative dose forms should be used for patients weighing less than 30 kg (see Section 4.2 Dose and Method of Administration).

Use in hepatic impairment or disease.

Lamivudine and zidovudine combination tablets should be used with caution in patients with HIV and chronic hepatitis B virus infection as 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.
The use of lamivudine and zidovudine combination tablets in patients with hepatic impairment is discussed (see Section 4.2 Dose and Method of Administration).

Use in renal impairment.

In patients with moderate to severe renal impairment, the terminal plasma half-life of lamivudine exposure is increased due to decreased clearance. Dosage adjustment in these patients is better controlled using individual zidovudine and lamivudine preparations as the dose frequency of lamivudine may need to be reduced (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

The dosing guidelines for the use of lamivudine and zidovudine combination fixed dose tablet in children in the bodyweight range 14-30 kg are based on 360-480 mg/m2/day for zidovudine and 8 mg/kg/day for lamivudine given as 2 or 3 divided doses in the clinical trials involving children. The extrapolation to weight based regime results in only approximate rather than accurate dosing. More accurate dosing can be achieved with use of separate oral solutions of zidovudine and lamivudine.
For children weighing less than 30 kg, Alphapharm lamivudine 150 mg and zidovudine 300 mg fixed dose combination unscored tablets are not recommended for use since correct dosage reduction with them is not possible. Appropriate oral solutions or scored tablet presentations must be used in these children.
For children < 3 months of age, sufficient data are not available to make specific dosing recommendations (see Section 4.2 Dose and Method of Administration).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

As lamivudine and zidovudine combination tablets contain lamivudine and zidovudine, any interactions that have been identified with these agents individually may occur with the combination tablets. The likelihood of interactions with lamivudine is low due to limited metabolism and plasma protein binding and almost complete renal clearance. Similarly zidovudine has limited protein binding but is eliminated primarily by hepatic conjugation to an inactive glucuronidated metabolite.

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, breast cancer resistance protein (BCRP) or P-glycoprotein (Pgp), multidrug and toxin extrusion protein 1 (MATE1), MATE2-K or organic cation transporter 3 (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 with IC50 values of 17 and 33 microM, respectively, however lamivudine has low potential to affect the plasma concentrations of OCT1 and OCT2 substrates at therapeutic drug exposures (up to 300 mg).

Effect of other agents on the pharmacokinetics of lamivudine.

Lamivudine is a substrate of MATE1, MATE2-K and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations, however this interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.
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 a substrate of Pgp and BCRP, however due to its high bioavailability it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore co-administration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.
As experience of drug interactions with lamivudine and zidovudine combination tablet is limited, care should be taken when combining with other drug regimens. The interactions listed below should not be considered exhaustive but are representative of the classes of drug where caution should be exercised.

Interactions relevant to lamivudine.

The possibility of interaction with other drugs administered concurrently with the lamivudine and zidovudine combination tablet should be considered, particularly when the main route of elimination is active renal secretion especially via the cationic system, e.g. trimethoprim.

Sorbitol.

Co-administration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose of lamivudine oral solution resulted in dose-dependent decreases of 14% (9-20%), 32% (28-37%), and 36% (32-41%) in lamivudine exposure (AUC) and 28% (20-34%), 52% (47-57%), and 55% (50-59%) in the Cmax of lamivudine in adults. When possible, avoid chronic co-administration of sorbitol-containing medicines with lamivudine. Consider more frequent monitoring of HIV-1 viral load when chronic co-administration cannot be avoided.

Trimethoprim.

Administration of trimethoprim, as trimethoprim/ sulfamethoxazole 160 mg/800 mg, causes an increase in lamivudine plasma levels. However, unless the patient already has renal impairment, no dosage adjustment of lamivudine is necessary. The effects of higher doses of trimethoprim on lamivudine plasma levels have not been investigated. Lamivudine has no effect on the pharmacokinetics of trimethoprim/sulfamethoxazole. Administration of lamivudine in patients with renal impairment should be assessed carefully.
In in vitro studies, ciprofloxacin, pentamidine and ganciclovir reduced the anti-HIV activity of lamivudine. The clinical significance of this is not known.

Other medicines.

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 and zidovudine combination tablet is therefore not recommended to be used in combination with zalcitabine.
Lamivudine may inhibit the intracellular phosphorylation of emtricitabine when the two medicinal products are used concurrently. Additionally, the mechanism of viral resistance for both lamivudine and emtricitabine is mediated via mutation of the same viral reverse transcriptase gene (M184V) and therefore the therapeutic efficacy of these drugs in combination therapy may be limited. Lamivudine is not recommended for use in combination with emtricitabine or emtricitabine-containing fixed-dose combinations.

Interactions relevant to zidovudine.

Changes in zidovudine plasma levels when coadministered with lamivudine were not statistically significant. Zidovudine has no effect on the pharmacokinetics of lamivudine (see Section 5.2 Pharmacokinetic Properties).

Atovaquone.

Zidovudine does not appear to affect the pharmacokinetics of atovaquone. However, pharmacokinetic data have shown that atovaquone appears to decrease the rate of metabolism of zidovudine to its glucuronide metabolite (steady-state AUC of zidovudine was increased by 33% and peak plasma concentration of the glucuronide was decreased by 19%). At zidovudine dosages of 500 or 600 mg/day it would seem unlikely that a three week, concomitant course of atovaquone for the treatment of acute PCP would result in an increased incidence of adverse reactions attributable to higher plasma concentrations of zidovudine. Extra care should be taken in monitoring patients receiving prolonged atovaquone therapy.

Clarithromycin.

Clarithromycin tablets reduce the absorption of zidovudine. This can be avoided by separating the administration of zidovudine and clarithromycin by at least two hours.

Stavudine.

Zidovudine may inhibit the intracellular phosphorylation of stavudine when the two medicinal products are used concurrently. Stavudine is therefore not recommended to be used in combination with lamivudine and zidovudine combination tablets.

Paracetamol.

Paracetamol use during treatment with zidovudine in a placebo controlled trial was associated with an increased incidence of neutropenia especially following chronic therapy. However, the available pharmacokinetic data indicate that paracetamol does not increase plasma levels of zidovudine nor of its glucuronide metabolite.

Phenytoin.

Phenytoin blood levels have been reported to be low in some patients receiving zidovudine, while in one case a high level was documented. These observations suggest that phenytoin levels should be carefully monitored in patients receiving lamivudine and zidovudine combination tablets and phenytoin since many patients with advanced HIV infections have CNS conditions which may predispose to seizure activity.

Rifampicin.

Limited data suggests that co-administration of zidovudine and rifampicin decreases AUC of zidovudine.

Other medicines.

Coadministration of zidovudine with drugs that are nephrotoxic, cytotoxic, or which interfere with RBC/WBC number or function (e.g. pyrimethamine, sulfamethoxazole and trimethoprim, doxorubicin, dapsone, systemic pentamidine, ganciclovir, amphotericin B (amphotericin), flucytosine, vincristine, vinblastine, adriamycin, or interferon) may increase the risk of adverse reactions to zidovudine. If concomitant therapy with lamivudine and zidovudine combination tablets and any of these drugs is necessary then extra care should be taken in monitoring renal function and haematological parameters and, if required, the dosage of one or more agents should be reduced.
Probenecid may reduce renal excretion of zidovudine and in addition, like some other drugs (e.g. codeine, methadone, morphine, inosine pranobex, paracetamol, aspirin, or indometacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone) may alter the metabolism of zidovudine by competitively inhibiting glucuronidation or directly inhibiting hepatic microsomal metabolism (see Section 4.4 Special Warnings and Precautions for Use). Careful thought should be given to the possibilities of drug interactions before using such drugs, particularly for chronic therapy, in combination with lamivudine and zidovudine combination tablets.
Some experimental nucleoside analogues affecting DNA replication antagonise the in vitro antiviral activity of zidovudine against HIV and thus, concomitant use of such drugs should be avoided.
The nucleoside analogue ribavirin antagonises the in vitro antiviral activity of zidovudine and so concomitant use of lamivudine and zidovudine combination tablets with this drug should be avoided.
Some drugs such as trimethoprim and sulfamethoxazole, aerosolised pentamidine, pyrimethamine, and aciclovir may be necessary for the management or prevention of opportunistic infections. In the controlled trial in patients with advanced HIV disease, increased toxicity was not detected with limited exposure to these drugs. However, there is one published report of neurotoxicity (profound lethargy) associated with concomitant use of zidovudine and aciclovir (see Interactions relevant to lamivudine).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Neither orally administered zidovudine (225 mg/kg BID) nor lamivudine (up to 70 times anticipated clinical exposure based on Cmax) have shown evidence of impairment of fertility in male and female rats. There are no data on their affect on human female fertility. In men zidovudine has not been shown to affect sperm count, morphology or motility.
(Category B3)
Lamivudine and zidovudine have been evaluated in the Antiretroviral Pregnancy Registry (APR) in over 11,000, and 13,000 women respectively during pregnancy and postpartum. Available human data from the APR do not show an increased risk of major birth defects for lamivudine or zidovudine compared to the background rate (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The safe use of lamivudine and zidovudine in human pregnancy has not been established in adequate and well-controlled trials investigating congenital abnormalities. Therefore administration of lamivudine and zidovudine in pregnancy should be considered only if the expected benefit outweighs the possible risk to the foetus.
Lamivudine and zidovudine have been shown to cross the placenta in humans (see Section 5.2 Pharmacokinetic Properties). The use of zidovudine in pregnant women, with subsequent treatment of the newborn infants, has been shown to reduce the rate of maternal foetal transmission of HIV.
Lamivudine and zidovudine have been associated with findings in animal reproductive studies. Pregnant women considering using lamivudine-zidovudine during pregnancy should be made aware of these findings. There are limited data regarding the use of zidovudine in human pregnancy. It is not known whether zidovudine can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity.
In reproductive studies in animals, oral doses of both lamivudine and zidovudine were shown to cross the placenta. Lamivudine caused an increase in early embryonic deaths in the rabbit at exposures (based on Cmax and AUC) less than the maximum anticipated clinical exposure. Oral zidovudine caused an increase in foetal resorptions in the rat (75 mg/kg BID) and rabbit (250 mg/kg BID). Lamivudine was not teratogenic in rats and rabbits with exposure (based on Cmax) up to 40 and 36 times respectively those observed in humans at the clinical dosage. At maternally toxic doses, zidovudine (3000 mg/kg/day) given to rats during organogenesis resulted in an increased incidence of malformations. No evidence of foetal abnormalities were observed at lower doses.
Vaginal tumours have been seen in rodents following 19-month daily oral dosing with zidovudine at exposures (based on AUC) more than 4 times (mouse) and more than 27 times (rat) the estimated clinical exposure (see Section 5.3 Preclinical Safety Data). The relevance of these findings to either infected or uninfected infants exposed to zidovudine is unknown. However, pregnant women considering using lamivudine and zidovudine combination tablets during pregnancy should be made aware of these findings.
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 peri-partum 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 peri-partum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Health experts recommend that where possible HIV infected women do not breast feed their infants in order to avoid transmission of HIV. In settings where formula feeding is not feasible, local official lactation and treatment guidelines should be followed when considering breast feeding during antiretroviral therapy.
Following oral administration of lamivudine or zidovudine to lactating rats, the respective drug was excreted in the milk. In a study following repeat oral dose of either 150 mg lamivudine twice daily (given in combination with 300 mg zidovudine twice daily) or 300 mg lamivudine twice daily, lamivudine was excreted in human breast milk (0.5 to 8.2 microgram/mL) at similar concentrations to those found in maternal serum, while after administration of a single dose of 200 mg zidovudine to HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum. In other studies following repeat oral administration of 150 mg lamivudine (given either in combination with 300 mg zidovudine or as lamivudine and zidovudine combination tablets) and 300 mg zidovudine twice daily (given either as a single entity or as lamivudine and zidovudine combination tablets) the breast milk: maternal plasma ratio ranged between 0.4 and 3.2 for zidovudine, and 0.6 and 3.3 for lamivudine. Lamivudine median infant serum concentrations ranged between 18 and 28 nanogram/mL and were not detectable in one of the studies (assay sensitivity 7 nanogram/mL). Zidovudine median infant serum concentration was 24 nanogram/mL in one study and was below assay limit of qualification (30 nanogram/mL) in another study. Intracellular zidovudine and lamivudine triphosphate (active metabolites of zidovudine and lamivudine) levels in breastfed infants were not measured therefore the clinical relevance of the serum concentrations of the parent compound measured is unknown.

4.8 Adverse Effects (Undesirable Effects)

Adverse events have been reported during therapy for HIV disease with lamivudine and zidovudine, administered separately or in combination. With many it is unclear whether they are related to lamivudine, zidovudine, or to the wide range of drugs used in the management of HIV disease or are as a result of the underlying disease process.
Information regarding the safety of the lamivudine and zidovudine combination tablet, zidovudine or lamivudine in combination with other antiretroviral drugs is limited. Physicians should refer to the complete product information for the respective antiretroviral therapy for a description of the known associated adverse reactions.
As the combination tablets contain lamivudine and zidovudine, the type and severity of adverse reactions associated with each of the compounds may be expected. There is no evidence of added toxicity following concurrent administration of the two compounds.

Adverse reactions with the lamivudine and zidovudine combination tablet.

Clinical trial data.

In a clinical study in twenty four healthy volunteers the following adverse reactions possibly or probably related to lamivudine and zidovudine combination tablets (or lamivudine 150 mg with zidovudine 300 mg taken separately) were recorded: headache (4 subjects), nausea (4), disturbances of vision (1), phlebitis (1).

Postmarketing data.

There is little experience with lamivudine and zidovudine combination tablets currently.

Adverse reactions to combinations of lamivudine and zidovudine.

Clinical trial data.

Table 2 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 3.
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 4 together with serious adverse reactions reported in large scale open studies.
Cases of pancreatitis have occurred rarely in adult patients and more commonly in children. 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.

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 (lamivudine and zidovudine); aplastic anaemia (zidovudine).

Metabolism and nutrition disorders.

Hyperlactataemia (common).
Lactic acidosis (rare, see Section 4.4 Special Warnings and Precautions for Use).

Adverse reactions with zidovudine monotherapy.

The frequency and severity of adverse events associated with the use of zidovudine are greater in patients with more advanced infection at the time of initiation of therapy. Tables 5, 6 and 7 summarise the relative incidence of haematologic adverse events observed in the placebo controlled clinical studies by severity of HIV disease present at the start of treatment.
The most serious adverse reactions include anaemia (which may require transfusions), neutropenia and leucopenia. These occur more frequently at higher dosages (1200-1500 mg/day) and in patients with advanced HIV disease (especially when there is poor bone marrow reserve prior to treatment), particularly in patients with CD4 cell counts less than 100 cells/mm3. Dosage reduction or cessation of therapy may become necessary (see Section 4.2 Dose and Method of Administration). The anaemia appeared to be the result of impaired erythrocyte maturation as evidenced by increasing macrocytosis (MCV) while on drug.
The incidence of neutropenia was also increased in those patients whose neutrophil counts, haemoglobin levels and serum vitamin B12 levels were low at the start of zidovudine therapy, and in those patients taking paracetamol concurrently (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Some of the HIV infected individuals participating in these clinical trials had baseline symptoms and signs of HIV disease and/or experienced adverse events at some time during study. It was often difficult to distinguish adverse events possibly associated with zidovudine administration from underlying signs of HIV disease or intercurrent illnesses. The possibility of such events being drug related, however, cannot be excluded. The following table summarises clinical adverse events or symptoms which occurred in at least 5% of all patients with advanced HIV disease treated with zidovudine in the original placebo controlled study. Of the items listed in Table 8, only severe headache, nausea, insomnia and myalgia were reported at a significantly greater rate in zidovudine recipients.
Clinical adverse events which occurred in less than 5% of all patients treated with zidovudine in the advanced HIV study are listed below. Since many of these adverse events were seen in placebo treated patients as well as zidovudine recipients, their possible relationship to the drug is unknown.

Body as a whole.

Body odour, chills, oedema of the lip, flu syndrome, hyperalgesia, back pain, lymphadenopathy, chest pain.

Cardiovascular.

Vasodilation.

Gastrointestinal.

Constipation, dysphagia, oedema of the tongue, eructation, flatulence, bleeding gums, rectal haemorrhage, mouth ulcer.

Hepatic.

Changes in liver function tests including increases in AST levels.

Musculoskeletal.

Arthralgia, muscle spasm, tremor, twitch, myopathy.

Nervous.

Anxiety, confusion, depression, emotional lability, nervousness, syncope, loss of mental acuity, vertigo, seizures.

Respiratory.

Cough, epistaxis, pharyngitis, rhinitis, sinusitis, hoarseness.

Skin.

Acne, pruritus, urticaria, nail pigmentation.

Special senses.

Amblyopia, hearing loss, photophobia.

Urogenital.

Dysuria, polyuria, urinary frequency, urinary hesitancy.

Metabolism and nutrition disorders.

Treatment with zidovudine has been associated with loss of subcutaneous fat (see Section 4.4 Special Warnings and Precautions for Use).
Subsequent to the initial trial, sensitisation reactions, including anaphylaxis in one patient, have been reported in individuals receiving zidovudine therapy.
All unexpected events and expected events of a severe or life threatening nature were monitored in the placebo controlled studies in early HIV disease and asymptomatic HIV infection. Data concerning the occurrence of additional signs or symptoms were also collected. No distinction was made in reporting events between those possibly associated with the administration of the study medication and those due to the underlying disease. Tables 9 and 10 summarise all those events reported at a statistically significant greater incidence for zidovudine recipients in these studies:
The following events have also been reported in patients treated with zidovudine. The relationship between these events and the use of zidovudine is difficult to evaluate, particularly in the medically complicated situations which characterise advanced HIV disease. If the severity of the symptoms warrants it, a reduction or suspension of zidovudine therapy may assist in the assessment and management of these conditions: cardiomyopathy; pancytopenia with marrow hypoplasia and isolated thrombocytopenia; lactic acidosis in the absence of hypoxaemia; liver disorders such as severe hepatomegaly with steatosis, raised blood levels of liver enzymes and bilirubin; pancreatitis; skin and oral mucosa pigmentation; hyperlactataemia; gynaecomastia.

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.

4.2 Dose and Method of Administration

Lamivudine with zidovudine combination tablets may be administered with or without food. Food reduces the Cmax and extends the Tmax of lamivudine but the amount of drug absorbed is not reduced. The clinical significance of this is not known (see Section 5.2 Pharmacokinetic Properties).
To ensure administration of the entire recommended dose, the tablet(s) should be swallowed whole and not divided or crushed. If the patient is unable to swallow whole 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 Section 5.2 Pharmacokinetic Properties).
For situations where discontinuation of therapy with one of the active constituents of lamivudine and zidovudine combination tablets, or dose reduction is necessary, separate preparations of lamivudine tablets and zidovudine tablets are available.
The dosing regimens for paediatric patients weighing 14-30 kg is based primarily on pharmacokinetic modelling and supported by data from clinical studies using the individual components lamivudine and zidovudine. A pharmacokinetic overexposure of zidovudine can occur; therefore close safety monitoring is warranted in these patients.
Alphapharm lamivudine and zidovudine combination tablets should not be used for adults or children weighing less than 30 kg, since the tablets cannot be split to enable appropriate dosage reduction according to the weight of the child. For these patients and for patients who are unable to swallow tablets oral solutions of lamivudine and zidovudine are available.
For children < 3 months of age, sufficient data are not available to make specific dosing recommendations (see Section 4.4 Special Warnings and Precautions for Use).

Adults and adolescents weighing at least 30 kg.

The recommended dose of lamivudine and zidovudine combination tablets is one tablet twice daily, giving a total daily dose of 600 mg zidovudine and 300 mg lamivudine.

Children weighing between 21 kg and 30 kg.

Use alternative dose forms of lamivudine and zidovudine.

Children weighing from 14 kg to 21 kg.

Use alternative dose forms of lamivudine and zidovudine.
For children weighing less than 14 kg, lamivudine and zidovudine should be taken as separate formulations according to the prescribed dosing for these products.

Monitoring of patients.

Haematologic toxicities appear to be related to pretreatment bone marrow reserve and to dose and duration of therapy. In patients with poor bone marrow reserve, particularly in patients with advanced symptomatic HIV disease, frequent monitoring of haematologic indices is recommended to detect serious anaemia or granulocytopenia (see Section 4.4 Special Warnings and Precautions for Use). In patients who experience haematologic toxicity, reduction in haemoglobin may occur as early as 2 to 4 weeks, and granulocytopenia usually occurs after 6 to 8 weeks.

Dose adjustment.

Significant anaemia (haemoglobin of < 7.5 g/dL or reduction of > 25% of baseline) and/or significant granulocytopenia (granulocyte count of < 750 cells/mm3 or reduction of > 50% from baseline) require a dose interruption until evidence of marrow recovery is observed (see Section 4.4 Special Warnings and Precautions for Use). For less severe anaemia or granulocytopenia, a reduction in daily dose may be adequate. In patients who develop significant anaemia, dose modification does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose modification, gradual increases in dose may be appropriate depending on haematologic indices and patient tolerance. As dosage adjustment of lamivudine and zidovudine combination tablets is not possible, separate preparations of zidovudine and lamivudine should be used. Physicians should refer to the complete prescribing information for these drugs.

Dosage in the elderly.

No specific data are available; however, special care is advised in this age group due to age associated changes such as the decrease in renal function and alterations in haematological parameters.

Dosage adjustment in renal insufficiency.

Lamivudine and zidovudine concentrations are increased in patients with renal impairment due to decreased clearance. Therefore as dosage adjustment of these may be necessary, it is recommended that separate preparations of lamivudine and zidovudine be administered to patients with reduced renal function (creatinine clearance ≤ 50 mL/min) (see Section 4.4 Special Warnings and Precautions for Use).
Compared to healthy subjects, patients with advanced renal failure have a 50% higher maximum plasma concentration of zidovudine. Systemic exposure (measured as area under the zidovudine concentration time curve) is increased 100%; the half-life is not significantly altered. In renal failure there is substantial accumulation of the major glucuronide metabolite compared to healthy volunteers but this does not appear to cause toxicity (see Table 1).
Haemodialysis and peritoneal dialysis have no significant effect on zidovudine elimination. In a small number of patients haemodialysis would appear to be more efficient in eliminating the glucuronide metabolite than peritoneal dialysis. Intermittent dialysis is unlikely to require further dose modification from that defined by creatinine clearance.

Dosage adjustment in hepatic insufficiency.

Limited data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients with hepatic impairment because of decreased glucuronidation. Dosage adjustments may be necessary but precise recommendations cannot be made at present. If monitoring of plasma zidovudine levels is not feasible, physicians will need to pay particular attention to signs of intolerance and increase the interval between doses as appropriate. It is recommended that separate preparations of zidovudine and lamivudine be administered to patients with severe hepatic impairment (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 or zidovudine 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.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
There is no experience of overdosage with the lamivudine and zidovudine combination tablet. However, there is limited data available on the consequences of ingestion of acute overdoses of either lamivudine or zidovudine in humans. No fatalities occurred, and all patients recovered. No specific signs or symptoms have been identified following such overdosage.

Treatment.

Patients should be observed closely for evidence of toxicity (see Section 4.8 Adverse Effects (Undesirable Effects)) and given the necessary supportive therapy.
Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdosage, although this has not been studied. Haemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine. The primary metabolite, GAZT, appears to be more efficiently removed by haemodialysis than peritoneal dialysis. For more details, physicians should refer to the individual product information for these preparations.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablets also contain microcrystalline cellulose, sodium starch glycollate type A, magnesium stearate, colloidal anhydrous silica and the film coating contains propylene glycol with Opadry Complete Film Coating System 03H58736 White (Proprietary Ingredient Number: 106640).

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

Store below 30°C.

6.5 Nature and Contents of Container

PVC/PVDC/Al blister packs* and HDPE bottles of 60 tablets.
*Not marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes