Consumer medicine information

Combivir [8227]

Lamivudine; Zidovudine

BRAND INFORMATION

Brand name

Combivir Tablets

Active ingredient

Lamivudine; Zidovudine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Combivir [8227].

What is in this leaflet

Please read this leaflet carefully before you start taking COMBIVIR tablets.

This leaflet answers some common questions about COMBIVIR. 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 COMBIVIR tablets against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine.

You may need to read it again.

What COMBIVIR tablets are used for

COMBIVIR contains both lamivudine and zidovudine which belong to a group of medicines called antiretrovirals.

Please note that these medicines are also available separately: lamivudine alone is 3TC, (tablets and oral solution) and zidovudine alone is RETROVIR (capsules and syrup).

COMBIVIR is used, alone or with other antiretrovirals, to slow down the progression of human immunodeficiency virus (HIV) infection, which can lead to Acquired Immune Deficiency Syndrome (AIDS) and other related illnesses (e.g. AIDS-related Complex or ARC).

COMBIVIR 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.

COMBIVIR does not reduce your 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 continue to take all appropriate precautions.

While taking COMBIVIR 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 your doctor.

The long-term risks and benefits of taking COMBIVIR are not known.

Your doctor may have prescribed COMBIVIR for another reason. Ask your doctor if you have any questions about why COMBIVIR has been prescribed for you.

COMBIVIR is not addictive.

Before you take COMBIVIR tablets

When you must not take them

  • Do not take COMBIVIR tablets if you have ever had an allergic reaction to either lamivudine (trade name 3TC) or zidovudine (trade name RETROVIR), 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 COMBIVIR tablets if you are pregnant, trying to become pregnant or breastfeeding, unless your doctor says you should.
    Your doctor should discuss with you the risks and benefits of using COMBIVIR tablets if you are pregnant or breastfeeding.
  • Do not take COMBIVIR if you have
    - kidney disease
    - liver disease
    - reduced red blood cell count (anaemia),
    - reduced white blood cell count (neutropenia).

    If you have certain health conditions, your doctor may advise that you take a lower dose of lamivudine and/or zidovudine, the active ingredients in COMBIVIR tablets. Lamivudine is available separately as 3TC tablets and oral solution, and zidovudine is available as RETROVIR capsules and syrup. Ask your doctor if you are not sure whether you should take COMBIVIR.
  • Do not take COMBIVIR tablets after the expiry date (EXP) printed on the pack.
    If you take them after the expiry date has passed, they may not work as well.
  • Do not take COMBIVIR tablets if the packaging is torn or shows signs of tampering.

If you're not sure whether you should be taking COMBIVIR tablets, talk to your doctor.

Before you start to take them

You must tell your doctor if:

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

When you stop taking COMBIVIR Tablets

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 COMBIVIR tablets, 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 your pharmacy, supermarket or health food shop.

If you take ribavirin and COMBIVIR together it may cause or worsen anaemia. 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 COMBIVIR.

There is little information about the way other medicines might affect the way that COMBIVIR works, or how COMBIVIR 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 COMBIVIR 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, indomethacin, ketoprofen, naproxen, cimetidine, clofibrate, probenecid.
  • Pentamidine, pyrimethamine, dapsone, atovaquone, amphotericin, flucytosine, ganciclovir, trimethoprim, sulfamethoxazole, interferon, clarithromycin.
  • Vincristine, vinblastine and doxorubicin
  • Aciclovir, inosine pranobex, adriamycin, ciprofloxacin
  • Stavudine, zalcitabine or emtricibine
  • Sorbitol-containing medicines (usually liquids) used regularly

COMBIVIR should not be taken with stavudine or zalcitabine

Use in children

COMBIVIR 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 COMBIVIR tablets

Your doctor will tell you how many COMBIVIR tablets to take and how often to take them. You will also find this information on the label of 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 COMBIVIR tablets is one tablet, twice a day.

How to take them

Your COMBIVIR tablets should be swallowed with a drink of water. Do not halve the tablet.

When to take them

Your doctor or pharmacist will be able to tell you when you should take your COMBIVIR 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 that you missed.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre. (In Australia telephone 131126. In New Zealand telephone 0800 764766 or 0800 POISON), or go to accident and emergency at your nearest hospital, if you think you or anyone else may have taken too many COMBIVIR tablets. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Keep these telephone numbers handy.

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

While you are taking COMBIVIR tablets

Things you must do

Tell your doctor or pharmacist that you are taking COMBIVIR tablets if you are about to be started on any new medicines.

There is little information about the way other medicines might affect the way that COMBIVIR works. You must tell your doctor or pharmacist that you are taking COMBIVIR 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 COMBIVIR tablets, or change the dose without first checking with your doctor.

Do not take COMBIVIR tablets to treat any other complaints unless your doctor tells you to.

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

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 COMBIVIR tablets affect you.

COMBIVIR tablets taken alone generally do not cause any problems with your ability to drive a car or operate machinery. However, as with many other medicines, COMBIVIR tablets may cause headache and tiredness in some people.

Side effects

Check with your doctor as soon as possible if you have any problems while taking COMBIVIR tablets, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like other medicines, COMBIVIR tablets 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 COMBIVIR in later stages of HIV disease.

While you are taking COMBIVIR, 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 COMBIVIR, or recommend standard treatment for these conditions. Ask your doctor any questions you may have.

It is not known whether many of these side effects are due to taking COMBIVIR or taking COMBIVIR while taking other medicines. Some of these symptoms may occur as part of HIV infection, AIDS or AIDS-related Complex.

The side effects listed below have been reported:

  • sweating, body odour, 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 and 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, changes 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

Treatment with COMBIVIR or other medicines that contain zidovudine may cause a loss of fat from legs, arms and face (lipoatrophy). Your doctor should monitor for signs of lipoatrophy. Tell your doctor if you notice any loss of fat from your legs, arms, and face. When these signs occur, your doctor will assess if COMBIVIR should be stopped and your HIV treatment changed. If you stop taking COMBIVIR, it may take several months to see any lost fat return. You may not regain all of your lost body fat.

Other effects may show up in blood tests including increased blood levels of sugar, fatty acids (triglycerides) and cholesterol.

Within the first few weeks of treatment with anti-HIV medicines, some people, particularly those that have been HIV positive for some time, may develop inflammatory reactions (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 new symptoms, or any changes in your health after starting HIV treatment, please discuss with your doctor immediately.

Ask your doctor or pharmacist 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 COMBIVIR tablets, TELL YOUR DOCTOR IMMEDIATELY or go to the 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 COMBIVIR tablets and tell your doctor immediately or go to the accident and emergency department at your nearest hospital.

  • Severe stomach pain or cramps.
  • Nausea.
  • Vomiting.

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

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

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

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 COMBIVIR alone, or also have taken other antiretroviral medication(s). Less is known about possible side-effects of taking COMBIVIR with other antiretrovirals.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not 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 taking COMBIVIR tablets

Storage

Keep this medicine where young children cannot reach them.

A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Keep COMBIVIR tablets in a cool, dry place where it stays below 30°C.

Do not store the tablets, or any other medicine, in a bathroom or near a sink.

Do not leave them in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep your COMBIVIR tablets in their pack until it is time to take them.

If you take COMBIVIR tablets out of their pack they may not keep well.

Disposal

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

Product description

What COMBIVIR tablets looks like.

COMBIVIR tablets are white to off-white, capsule-shaped and stamped with "GXFC3". Tablets are available in blister packs inside a carton. Each carton contains 60 tablets.

Ingredients

COMBIVIR contains the active ingredients lamivudine (150 mg) and zidovudine (300 mg).

COMBIVIR tablets also contain the following inactive ingredients:

microcrystalline cellulose, sodium starch glycollate, silicon dioxide, magnesium stearate, hypromellose, titanium dioxide, macrogol and polysorbate 80.

COMBIVIR does not contain gluten.

Supplier

ViiV Healthcare Pty Ltd
Level 4, 436 Johnston Street
Abbotsford, Victoria, 3067
Australia

Further Information

This is not all the information that is available on COMBIVIR tablets. If you have any more questions or are not sure about anything, ask your doctor or pharmacist.

Pharmaceutical companies are not in a position to give people an individual diagnosis or medical advice. Your doctor or pharmacist is the best person to give you advice on the treatment of your condition. You may also be able to find general information about your disease and its treatment from books, for example in public libraries.

Do not throw this leaflet away.

You may need to read it again.

This leaflet was prepared on 26 June 2017.

The information provided applies only to: COMBIVIR tablets.

Trade marks are owned by or licensed to the ViiV Healthcare group of companies.

COMBIVIR tablets, lamivudine 150 mg and zidovudine 300 mg:

AUST R 61489

© 2017 ViiV Healthcare group of companies or its licensor.

Version 7.0

BRAND INFORMATION

Brand name

Combivir Tablets

Active ingredient

Lamivudine; Zidovudine

Schedule

S4

 

Name of the medicine

Lamivudine 150 mg, zidovudine 300 mg.

Excipients.

Microcrystalline cellulose (460), sodium starch glycollate, silicon dioxide, magnesium stearate (572), hypromellose (464), titanium dioxide (171), macrogol 400 and polysorbate 80 (433).

Description

Lamivudine.

Chemical name: (2R-cis)- 4-amino-1- (2-hydroxymethyl- 1,3-oxathiolan- 5-yl)-(1H)- pyrimidin- 2-one (free base). Molecular formula: C8H11N3O3S. MW: 229.3. CAS: 134678-17-4. It is a white to off white crystalline solid which is highly soluble in water.

Zidovudine (formerly called azidothymidine (AZT)).

Chemical name: 3'-azido- 3'-deoxythymidine. Molecular formula: C10H13N5O4. MW: 267.24. CAS: 30516-87-1. It is a white to off white, odourless, crystalline solid.
Combivir tablets are a fixed combination product. Product information for 3TC (tablets and oral solution) and Retrovir Capsules and Syrup contain additional information specific for lamivudine and zidovudine, respectively.

Pharmacology

Mode 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. 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. No antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (tested agents: abacavir, didanosine, nevirapine, zalcitabine, and zidovudine). No antagonistic effects in vitro were seen with zidovudine and other antiretrovirals (tested agents: abacavir, didanosine, lamivudine and interferon-alpha).
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 naïve patients.

Pharmacokinetics.

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 Combivir and lamivudine (3TC) 150 mg tablets and zidovidine (Retrovir) 300 mg tablets taken together.
In fasted subjects, Combivir was shown to be bioequivalent to lamivudine 150 mg and zidovudine 300 mg administered together as separate tablets. Following Combivir 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 Combivir 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 Combivir is not known.

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 Combivir is not recommended in these patients (see Precautions).
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.

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 shows 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 sulphamethoxazole, 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 Dosage and 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.

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 microM.h or 10.7 microgram.h/mL) as doses of 200 mg six times daily in adults (40.7 microM.h or 10.9 microgram.h/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.

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 1840 HIV infected adults with 25 to 250 (median 126) CD4 cells/mm3 at baseline were enrolled. Median age was 36 years; 87% were male, 83% were nucleoside experienced, and 17% were therapy naïve. The median duration of treatment for each group was current therapy* 327 days, lamivudine plus current therapy* 360 days and lamivudine plus NNRTI** plus current therapy* 360 days. Results are summarised in Table 1.
The data showed there was a significant reduction in progression to the combined endpoint of a new AIDS event or death for patients who received lamivudine in combination with zidovudine containing regimens compared to patients maintained on zidovudine containing regimens alone (p < 0.0001). The hazard ratio (HR) was 0.427 (95% confidence interval 0.318-0.572), or a 57% reduction in risk. In addition, the data indicated a significant reduction in death, regardless of causality, in the combination lamivudine plus zidovudine containing regimens as compared to the zidovudine containing regimens alone (p = 0.0007); HR = 0.399 (95% CI 0.230-0.693) or a 60% reduction in risk.
ACTG320 was a randomised, double blind, placebo controlled study to compare indinavir, zidovudine (or stavudine) and lamivudine with the 2 drug regimen of zidovudine (or stavudine) and lamivudine in HIV infected patients with CD4 counts ≤ 200 cells/mm3. Patients had received ≥ 3 months prior zidovudine therapy and had no prior exposure to protease inhibitors. A total of 1156 patients were randomised. The median duration of follow-up was 38 weeks. During the study there were 96 new AIDS defining events or deaths, 63 (11%) in the zidovudine/ lamivudine arm and 33 (6%) in the zidovudine/ lamivudine/ indinavir arm (estimated Hazard Ratio 0.50). There were 13 (6%) deaths in the zidovudine/ lamivudine arm and 5 (2%) in the zidovudine/ lamivudine/ indinavir arm (Hazard Ratio 0.37). Both these results were statistically significant.

Surrogate endpoint studies in adults.

The approved indication for Combivir 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 2. All were randomised, double blind, multicentre studies. The characteristics of the patients at baseline are given in Table 3.
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 Combivir is based on extrapolation from clinical studies in which several other dosage regimens have been used.

After 24 weeks.

In zidovudine naïve patients the combination of lamivudine and zidovudine resulted in a highly significant (p < 0.001) increase in absolute CD4 cell count and reduction in log10 HIV RNA relative to zidovudine monotherapy (600 mg/day) or lamivudine monotherapy (600 mg/day). Similarly, in zidovudine experienced patients, the combination of lamivudine and zidovudine resulted in significantly greater improvements in CD4 cell count than either zidovudine monotherapy (600 mg/day) or a combination of zidovudine and zalcitabine (600 mg/day + 0.75 mg) and a significantly greater reduction in log10 HIV RNA than zidovudine monotherapy. 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 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.

Indications

Combivir is indicated for use alone or in combination with other antiretroviral therapies in the treatment of HIV infection.

Contraindications

Combivir 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), Combivir is contraindicated in these patients (see Precautions).

Precautions

Patients receiving Combivir 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 Combivir, 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 Combivir have not been completely defined, particularly in regard to prolonged use.

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 Adverse 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 Combivir (see 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 Combivir, or in patients with pre-existing bone marrow compromise e.g. haemoglobin < 9 g/dL or granulocyte count < 1000 cells/mm3 (see Dosage and Administration). As dosage adjustment of Combivir 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 Combivir should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.

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 Dosage and Administration).

Hepatic impairment or disease.

Combivir 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 Combivir in patients with hepatic impairment is discussed under Dosage and Administration.

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 Combivir, particularly to those with known risk factors for liver disease. Treatment with Combivir 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 coadministration 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.

Special precautions for use.

It is recommended that separate preparations of lamivudine and zidovudine should be administered in cases where dosage adjustment is necessary (see Dosage and Administration). Physicians should refer to the individual product information for these drugs.

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 Combivir 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 Interactions with Other Medicines).
Patients should be cautioned about the concomitant use of self administered medications (see Interactions with Other Medicines).

Use in the elderly.

See Dosage and Administration.

Paediatric use.

The dosing guidelines for the use of Combivir 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 14 kg, Combivir fixed dose tablet is not recommended for use, as long as correct dosing with it is not possible. Oral solutions must be used in these children.
For children < 3 months of age, sufficient data are not available to make specific dosing recommendations. (See Dosage and Administration.)

Carcinogenicity, mutagenicity.

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

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 effect on human female fertility. In men zidovudine has not been shown to affect sperm count, morphology or motility.

Use in pregnancy.

(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 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 Pharmacology, Pharmacokinetics). 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 Precautions, Carcinogenicity, mutagenicity). The relevance of these findings to either infected or uninfected infants exposed to zidovudine is unknown. However, pregnant women considering using Combivir 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 peripartum to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of developmental delay, seizures and other neurological disease. However, a causal relationship between these events and NRTI exposure in utero or peripartum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Use in lactation.

Health experts recommend that where possible HIV infected women do not breastfeed 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 breastfeeding 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 Combivir or Trizivir) and 300 mg zidovudine twice daily (given either as a single entity or as Combivir or Trizivir) 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.

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.

Effects on the ability to drive and operate machinery.

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.

Interactions

Interaction with other medicines.

As Combivir contains lamivudine and zidovudine, any interactions that have been identified with these agents individually may occur with Combivir. 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 micromolar, 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 Combivir 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 Combivir should be considered, particularly when the main route of elimination is active renal secretion especially via the cationic system e.g. trimethoprim.

Sorbitol.

Coadministration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose of lamivudine oral solution resulted in dose-dependent decreases of 14% (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 coadministration of sorbitol-containing medicines with lamivudine. Consider more frequent monitoring of HIV-1 viral load when chronic coadministration 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.

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. Combivir 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 Pharmacology, Pharmacokinetics).

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 Combivir.

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 Combivir and phenytoin since many patients with advanced HIV infections have CNS conditions which may predispose to seizure activity.

Rifampicin.

Limited data suggests that coadministration 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, flucytosine, vincristine, vinblastine, adriamycin or interferon) may increase the risk of adverse reactions to zidovudine. If concomitant therapy with Combivir 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 indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone) may alter the metabolism of zidovudine by competitively inhibiting glucuronidation or directly inhibiting hepatic microsomal metabolism (see Precautions). Careful thought should be given to the possibilities of drug interactions before using such drugs, particularly for chronic therapy, in combination with Combivir.
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 Combivir 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).

Adverse 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 Combivir, 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 Combivir contains 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 Combivir.

Clinical trial data.

In a clinical study in twenty-four healthy volunteers the following adverse reactions possibly or probably related to Combivir (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 Combivir currently.

Adverse reactions to combinations of lamivudine and zidovudine.

Clinical trial data.

Table 4 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 5.
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 6 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 Precautions).

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 7, 8 and 9 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/mm3. Dosage reduction or cessation of therapy may become necessary (see Dosage and 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 Interactions with Other Medicines).
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 the 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. Table 10 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 10, 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 Precautions).
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 11 and 12 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.

Dosage and Administration

Combivir 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 Pharmacology, Pharmacokinetics).
For situations where discontinuation of therapy with one of the active constituents of Combivir, or dose reduction is necessary, separate preparations of lamivudine (3TC tablets and oral solution) and zidovudine (Retrovir Capsules and Syrup) are available.
To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing. For patients who are unable to swallow tablets, the tablet(s) may be crushed and 100% of the crushed tablet could be added to a small amount of semisolid food or liquid, all of which should be consumed immediately (see Pharmacology, Pharmacokinetics).
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.
Combivir tablets should not be used for children weighing less than 14 kg, since doses cannot be appropriately adjusted for 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 Precautions.)

Adults and adolescents weighing at least 30 kg.

The recommended dose of Combivir 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.

The recommended oral dose of Combivir is one half tablet taken in the morning and one whole tablet taken in the evening.

Children weighing from 14 kg to 21 kg.

The recommended oral dose of Combivir is one half tablet taken twice daily. 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 Precautions). 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 Precautions). 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 Combivir 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 Precautions).
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 13).
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 Precautions).

Overdosage

There is no experience of overdosage with Combivir. 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 Adverse 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.
Contact the Poisons Information Centre (telephone 131 126) for advice on overdose management.

Presentation

Tablets, lamivudine 150 mg and zidovudine 300 mg (white to off white, capsule shaped, film coated, marked GXFC3 on one side (unscored tablet)* or on both sides (scored tablet)): 60's (blister pack, plastic bottle*).
* Not currently marketed in Australia.

Poison Schedule

S4.