Consumer medicine information

Fuzeon

Enfuvirtide

BRAND INFORMATION

Brand name

Fuzeon

Active ingredient

Enfuvirtide

Schedule

What is in this leaflet

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

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

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

What FUZEON is used for

FUZEON is used for the treatment of HIV (Human Immunodeficiency Virus), the virus which causes AIDS.

FUZEON belongs to a group of medicines called anti-HIV drugs.

FUZEON is the first in a new class of drugs called HIV fusion inhibitors.

It works by blocking the entry of HIV into cells that the virus attacks (called CD4 or T cells) in your blood.

FUZEON is used in combination with other anti-HIV medicines to treat people with HIV.

FUZEON has been shown to reduce the amount of HIV in the blood ("viral load") and increase the number of CD4 cells. Reducing the amount of HIV in the blood reduces the risk of death or infections which are due to your low immunity (called opportunistic infections).

You should always report any changes in your condition to your doctor to ensure that any opportunistic infections are treated promptly.

Your doctor may have prescribed FUZEON for another purpose.

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

FUZEON does not cure HIV infection or AIDS.

FUZEON does not reduce the risk of passing HIV to other people through unprotected sexual contact, sharing needles, or contaminated blood.

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

Before you use FUZEON

When you must not use it

Do not use FUZEON if:

you have allergies to enfuvirtide or any ingredients listed at the end of this leaflet

the package is torn or shows signs of tampering

the expiry date (EXP) printed on the pack has passed.
If you use this medicine after the expiry date has passed it may not work as well.

If you are not sure if you should be using FUZEON, talk to your doctor.

Use in children

Do not give FUZEON to children less than 6 years of age. Safety and effectiveness in children younger than 6 years have not been established. There is limited information available about the use of FUZEON in children older than 6 years of age.

Before you start to use it

Your doctor must know all about the following before you start to take FUZEON.

if you are pregnant or plan to become pregnant

It is not known whether FUZEON is harmful to an unborn baby when taken by a pregnant woman. If there is a need to use FUZEON when you are pregnant your doctor will discuss the risks and benefits to you and the unborn baby.

if you are breast-feeding or plan to breast-feed

It is not known whether FUZEON passes into breast milk.
To reduce the risk of passing the virus to the baby, breast-feeding by HIV infected women is not recommended.

if you are allergic to any other medicines, foods, dyes or preservatives
if you have any other health problems including:

kidney disease
poor liver function
a heart condition
problems with your immune system (e.g. Guillain-Barré syndrome, Grave's disease)

If you have not told your doctor about any of the above, tell them before you use FUZEON.

Taking other medicines

Tell your doctor if you are taking any other medicines including any that you have bought from a pharmacy, supermarket or health food shop.

FUZEON has been shown not to interact with other anti-HIV medicines or rifampicin (an antibiotic).

How to use FUZEON

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

How much to inject

Use FUZEON only when prescribed by your doctor.

For adults, the recommended dose of FUZEON is 90 mg two times a day.

For children aged 6 to 16 years, the recommended dose of FUZEON is 2.0 mg/kg up to a maximum dosage of 90 mg two times a day.

How to inject it

FUZEON is administered by subcutaneous injection (under the skin) into the upper arm, thigh or abdomen.

FUZEON should not be given intravenously (directly into your veins) or intramuscularly (directly into your muscle).

Directions for self-administration

The following is a basic, step-by-step guide to injecting your FUZEON.

Please follow these instructions carefully.

Contact your doctor or pharmacist if you have any further questions about administering FUZEON.

Safety Tips

Wash your hands well to reduce the risk of bacterial infections. Then do not touch anything except the medicine and supplies.
When handling the syringe, do not touch the needle. Do not touch the tops of the vials once they have been cleaned with the alcohol swabs.
Make sure none of the items in your kit have been opened. Do not use opened materials.
Never use a syringe with a bent or damaged needle.
Never mix FUZEON with tap water.
Never inject FUZEON with other injectable medicines.
Do not use FUZEON if you see any particles in the powder or in the solution after the water has been added. Also do not use the "water for injection" if you see any particles in the vial or if the water is cloudy.
Discard used syringes into your puncture proof (sharps) container. Consult your doctor if you have any questions about the safe disposal of these items.

When to have a carer's help

Certain injection sites, such as the upper arms, can be difficult to use at first. Have a friend or family member with you if you need help.

To reduce the risk of needlestick injury, you should have a caregiver attend an injection training session with your healthcare provider.

Your syringes

The syringes supplied with this medicine have a needle protection device that is attached to the needle. This safety device covers the needle after use and reduces the risk of needle-stick injuries.

Although these syringes offer this safety feature it is important that you dispose of used syringes properly and according to the instructions given to you by your healthcare provider.

Getting started

Gather the following supplies:

One vial of FUZEON powder
One vial of water for injections
One 3 mL syringe (larger syringe)
One 1 mL syringe (smaller syringe)
3 alcohol swabs
Puncture proof (sharps) container

Open syringe packages and remove vial caps

Discard packages and vial caps into the trash.
Place syringes and vials onto a clean surface.

Select injection site

Injection sites include the upper arms, thighs and abdomen.
Choose a site that is in a different area from the site used for your previous injection and where there are no current injection site reactions.
With the tips of your fingers, feel for any hard lumps that may be present from past injections. Do not inject in the areas where these lumps are present. Also, avoid areas that could be irritated by your belt or the waistline of your clothing.

Wash hands thoroughly

After washing hands, do not touch anything except the injection supplies and the injection site.

Clean the tops of vials

Wipe each vial top with a fresh alcohol swab. Let the tops air-dry.
Be sure not to touch the rubber tops after cleaning them. If you touch them, be sure to clean them again.

Mixing FUZEON

Draw up sterile water for injections

Step 1:
Pick up the 3 mL large syringe. Using your index finger, push back the needle protection device towards the syringe.

To ensure that the needle is secure, hold the clear plastic cap and tighten the needle with a gentle clockwise twist. Do not use too much force as the needle may loosen.

Step 2:
To remove the clear plastic cap, push towards the syringe and then pull the cap off.

Draw back 1.1 mL of air.

Step 3:
Insert the syringe needle into the rubber top of the water for injections vial and press the plunger, injecting the air.

Step 4:

Turn the vial upside down. Make sure the tip of the needle is always below the surface of the sterile water to help keep any air bubbles from entering the syringe.
Slowly pull back the plunger until the water reaches the 1.1 mL mark. The solvent vial contains 2 mL of water for injections. You only need to withdraw 1.1 mL of it to prepare your medication properly.

Step 5:

Tap the syringe gently to make any air bubbles rise to the top.
If excess air enters the syringe, gently press the plunger to force any air back into the vial and withdraw the sterile water again, making sure you have 1.1 mL of sterile water for injections in the syringe.

Step 6:

Remove the needle from the vial, making sure you never touch the needle with your fingers or any other object.
Discard the sterile water vial into the trash. The sterile water for injections vial is intended for single use only. The remaining water for injections in the vial should be discarded.

Inject sterile water into the FUZEON powder

Step 1:

Gently tap the vial to loosen the powder.
Hold the water-filled syringe by the barrel and push the needle through the rubber top of the vial at a slight angle.

Step 2:
Press the syringe plunger slowly. Allow the water to flow slowly down the inside of the vial.

Be careful not to forcefully shoot water into the powder, since this can cause foaming. If foaming occurs, it may take longer for the solution to completely dissolve.

Step 3:

After all of the sterile water has been added to the FUZEON vial, remove the syringe from the vial
Hold the barrel of the syringe with one hand and gently press the needle protection device down on a flat surface until it covers the needle. You will hear a click.
Do not use your free hand to press the device over the needle.
Discard the syringe into the puncture proof (sharps) container.

Mix the water with the FUZEON powder

Step 1:

Gently tap the vial with your fingertip until the powder begins to dissolve.
Never shake the vial or turn it upside down to mix - this will cause excessive foaming.

Step 2:

After the powder begins to dissolve, set the vial aside to allow it to completely dissolve. The FUZEON solution may take up to 45 minutes to dissolve. The vial can be gently rolled between your hands after adding the water until it is fully dissolved and this may reduce the time it takes for the powder to dissolve.
If you accidentally touch the rubber stopper, be sure to clean it again with a new alcohol swab.
Make sure the solution has dissolved completely, allowing any bubbles that may have formed to settle. If bubbles still exist, gently tap the side of the vial to help settle them.
As with all injectable medicines, it is important to inspect the solution for particles. If you notice any particles in the solution, discard the vial or return it to the pharmacy.
Once a dose is mixed with sterile water for injections, it must be used immediately or stored in a refrigerator and used within 24 hours.
FUZEON solution that has been refrigerated should be brought back to room temperature before being used.
If you are preparing both of your daily doses at one time, be sure to use new syringes, sterile water for injections, and FUZEON for each dose.

Giving the injection

Choose an injection site
The most suitable places for injection are the upper arm, thighs and the abdomen, except for the belly button area. Rotate injection sites to avoid the risk of soreness at any one site.

Clean the injection site:
cleanse the area for injection with an alcohol swab. Start at the centre, apply pressure, and cleanse in a circular motion, working outward. Allow to air-dry completely.

Draw up the FUZEON solution into the 1mL syringe

Step 1:

Wipe the top of the FUZEON vial again with a new alcohol swab.
Now, pick up the 1 mL small syringe. Using your index finger, push back the needle protection device towards the syringe.

Step 2:

To remove the clear plastic cap push towards the syringe and then pull the cap off.
Draw back 1 mL of air. Be careful not to pull the plunger too fast past the 1 mL marker and/or out of the barrel.
Insert the syringe needle into the rubber top of the FUZEON vial and press the plunger, injecting the air. Gently turn the vial upside down.
Make sure the tip of the needle is always below the surface of the solution to help keep air bubbles from entering the syringe.
Slowly pull back the plunger until the solution reaches the 1.0 mL mark. Be careful not to pull the plunger too fast past the 1 mL marker and/or out of the barrel.

Step 3:

Tap the syringe gently to make any air bubbles rise to the top.
If excess air enters the syringe, gently press the plunger to inject the air back into the vial and withdraw the solution again, making sure you have 1.0 mL of solution in the syringe (or the corresponding volume that your doctor prescribed, if different.) This step may be repeated until the correct amount of solution is in the syringe.
Remove the syringe from the vial.

Inject the FUZEON solution

FUZEON solution should be injected subcutaneously (under the skin) into the upper arm, thigh or abdomen.

Step 1:
Pinch as much of a skin fold as possible without making yourself uncomfortable.

Step 2:

Pierce the skin at a 45-degree angle.

Tip: Your healthcare provider may suggest different injection techniques that will work best for you.

Step 3:
When the needle is in, release the skin, and using the same hand, hold on to the syringe barrel to help steady it and prevent shifting.

Step 4:

Using the thumb, depress the plunger to inject the solution.
After the dose is fully delivered, remove the needle from the skin.
Hold the barrel of the syringe with one hand and gently press the needle protection device down on a flat surface until it covers the needle. You will hear a click.
Do not use your free hand to press the device over the needle.
Discard the syringe into the puncture proof (sharps) container.
Cover the injection site with a bandage if any blood or medicine is present.

Discarding used supplies

Discard all used syringes directly into the puncture proof (sharps) container. Keep the cover of this container tight and keep the container out of the reach of children. Check with your doctor or pharmacist about proper disposal of the container.

In addition, you should safely discard all used alcohol swabs and vials, even if the vials contain unused amounts of medicine or sterile water. The vials of FUZEON and water for injections are intended for single use only. Used supplies other than syringes (alcohol swabs and vials) may be discarded into the trash as long as no blood is visible. If blood is visible, discard the items into the puncture proof (sharps) container.

If you have any questions or concerns about the safe disposal of these materials, please call your doctor or pharmacist.

When to inject it

Use FUZEON two times a day.

It is best to use FUZEON at the same time each day. First thing in the morning and again in the evening are good times.

It is not important to take FUZEON with food but you still need to follow the instructions given for your other anti-HIV medicines.

How long to take FUZEON

FUZEON helps control your HIV infection but does not cure it. You must use FUZEON every day exactly as your doctor has prescribed. Do not change your dose or stop taking FUZEON without first talking to your doctor.

If you forget to use FUZEON

Take a dose as soon as you remember and return to your normal routine.

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

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

If you have trouble remembering when to use your medicine, ask your pharmacist for some hints.

If you miss or skip doses of FUZEON, HIV may develop resistance to FUZEON and become harder to treat.

In case of an overdose

If you think that you or anyone else may have taken too much FUZEON, immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at your nearest hospital. 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.

While you are using FUZEON

Things you must do

Use FUZEON exactly as your doctor has prescribed.

Tell all doctors, dentists and pharmacists who are treating you that you are using FUZEON.

Continue to use safe sexual practices while using FUZEON. FUZEON has not been shown to decrease the chance of giving HIV to your partner.

If you become pregnant while using FUZEON, tell your doctor.

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

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Things you must not do

Do not stop using FUZEON or change the dose without first checking with your doctor. Do not let yourself run out of medicine over the weekend or on holidays.

Do not give FUZEON to anyone else even if their symptoms seem similar to yours.

Do not take any other medicines, whether they require a prescription or not, without first telling your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how FUZEON affects you. FUZEON generally does not cause problems with your ability to drive a car or operate machinery. However, as with many medicines, FUZEON may cause dizziness in some people. Make sure you know how you react to FUZEON before you drive a car or operate machinery.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking FUZEON. FUZEON helps most people with HIV infection but it may have unwanted side effects in some people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Frequently it is difficult to tell whether side effects are the result of taking FUZEON, effects of the HIV disease or side effects of other medicines you may be taking. For this reason it is very important to inform your doctor of any change in your condition. Your doctor may advise you to stop using FUZEON.

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

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

diarrhoea or constipation,
nausea (feeling sick) or vomiting,
fever, chills,
cough (dry), sore throat, trouble swallowing,
general feeling of achiness and cramps, back pain, pain in your limbs,
anxiety, irritability,
less sensation in your fingers/feet,
tiredness, weakness,
loss of appetite, weight loss,
swollen runny eyes, eyes with discharge with itchiness and crusty eyelids,
swelling in the neck, armpit or groin,
dizziness or spinning sensation.

These are the more common side effects of FUZEON.

Injection site reactions:

Reactions at the site of injection are a common side effect of using FUZEON.

You may experience one or more of the following where you inject your medicine:

itchiness,
swelling,
redness,
pain or tenderness,
hardened skin, lumps/bumps or bruising.

These reactions are normally mild or moderate and can appear within the first week of treatment. They generally do not get worse with continued use of FUZEON and last less than 7 days.

Reactions may be worse when injections are repeated in the same place on the body, or when the injection is given deeper than intended (e.g. into the muscle).

If you experience reactions at an injection site, it is important not to stop using FUZEON until you have talked to your doctor.

Infection:

Tell your doctor immediately if you experience or notice any symptoms of infection.

skin infection (not at injection site): symptoms include hot, tender, red skin, fever, chills,
sinusitis: feeling of tension or fullness in the nose, cheeks and behind your eyes, sometimes with a headache, fever, stuffy nose and loss of the sense of smell,
sepsis (blood poisoning): high fever, chills, headache, confusion, rapid breathing,
pneumonia: symptoms include fever, chills, cough, rapid breathing, shortness of breath.

Hypersensitivity:

Stop using FUZEON and tell your doctor immediately, or go to Accident and Emergency at your nearest hospital if you experience any of the following symptoms of a hypersensitivity (allergic) reaction:

nausea (feeling sick) and vomiting,
fever, chills, shivering,
low blood pressure (lightheaded, dizzy)
fainting,
rash, itching or hives on the skin,
swelling of the face, lips, tongue or other parts of the body,
shortness of breath, wheezing or trouble breathing.

These are very serious side effects. if you have them, you may have had a serious allergic reaction to FUZEON. You may need urgent medical attention or hospitalisation.

These side effects are very rare.

This is not a complete list of all possible side effects. Other side effects not listed above may also occur in some people.

Some of these side effects (for example, changes in your liver function) can only be found when your doctor does tests from time to time to check your progress.

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 using FUZEON

Storage

Keep FUZEON and the Water for Injections vials in a cool dry place where the temperature stays below 30°C.

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

Once the solution has been prepared for your injection it should be used immediately. If it is not used immediately it must be stored at 2-8°C in a refrigerator and used within 24 hours.

Do not leave your medicine in the car or on window sills. Heat and dampness can destroy some medicines.

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

Disposal

The syringe is intended for single use only and must be thrown away after the injection.

Dispose of the syringe with the needle (protected in the needle guard) in a puncture proof (sharps) container as instructed by your doctor, nurse or pharmacist.

Never put the used syringe in your normal household garbage.

Dispose of full puncture proof (sharps) container as instructed by your doctor, nurse or pharmacist.

Keep puncture proof (sharps) container out of reach of children.

If your doctor tells you to stop using FUZEON, or the vial has passed its expiry date, ask your pharmacist what to do with it.

Product Description

Availability

FUZEON vials are available in the following packs:

Patient Convenience Pack

60 vials of FUZEON powder
60 vials of water for Injections
60 x 3 mL (larger) syringes + needles
60 x 1 mL (smaller) syringes + needles
180 alcohol swabs

What FUZEON looks like

FUZEON is a white to off-white powder and comes in a glass vial.

Ingredients

Active ingredient - enfuvirtide

each vial contains 108 mg enfuvirtide. Reconstituted FUZEON solution contains 90 mg/mL enfuvirtide.

Inactive ingredients - FUZEON vials also contain:

sodium carbonate
mannitol
sodium hydroxide
hydrochloric acid

Manufacturer

FUZEON is distributed by:

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
AUSTRALIA
Medical enquiries: 1800 233 950

Please check with your pharmacist for the latest Consumer Medicine Information.

Registration Numbers

AUST R 94314
AUST R 96669

This leaflet was prepared on 29 October 2020.

Published by MIMS December 2020

BRAND INFORMATION

Brand name

Fuzeon

Active ingredient

Enfuvirtide

Schedule

1 Name of Medicine

Enfuvirtide.

2 Qualitative and Quantitative Composition

Each Fuzeon vial contains 108 mg enfuvirtide.
Reconstituted Fuzeon solution contains 90 mg/mL of enfuvirtide.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder and solvent for solution for injection.
White to off-white lyophilised powder for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Fuzeon (enfuvirtide) is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in antiretroviral experienced patients with treatment failure due to intolerance to previous antiretroviral agents or with evidence of HIV-1 replication despite ongoing therapy. Evidence to support this indication is based on surrogate endpoints (change in viral load and CD4 count) in controlled studies following 48 weeks of treatment (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Dosage.

Fuzeon should be administered only by subcutaneous injection.

Adults.

The recommended dose of Fuzeon is 90 mg twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. The injection should be given at a site different from the preceding injection site and where there is no current injection site reaction.

Special populations.

Children.

There are insufficient data available to establish a dose recommendation of Fuzeon in paediatric patients below the age of 6 years. In paediatric patients 6 years through 16 years of age, the recommended dosage of Fuzeon is 2.0 mg/kg twice daily up to a maximum dose of 90 mg bid injected subcutaneously into the upper arm, anterior thigh or abdomen. The injection should be given at a site different from the preceding injection site and where there is no current injection site reaction. Paediatric dosing guidelines for Fuzeon based on bodyweight are included in Table 1. Weight should be monitored periodically and the Fuzeon dose adjusted accordingly.

Renal impairment.

No dose adjustment is recommended for patients with impaired renal function including those receiving haemodialysis.

Hepatic impairment.

No data are available to establish a dose recommendation for patients with hepatic impairment.

Method of administration.

Instructions for use and handling and disposal.

Patients and caregivers must be instructed in the use of aseptic techniques when administering Fuzeon in order to avoid injection site infections. Appropriate instructions for reconstitution and self injection must be given, including a careful review of the detailed instructions given in the patient information leaflet provided with the medicine. It is recommended that the first injection be performed under the supervision of an appropriately qualified healthcare professional. It is also recommended that the patient and/or caregiver's understanding and use of aseptic self injection techniques and procedures be periodically re-evaluated.
Patients and caregivers should be instructed in the proper techniques for preparation, injection and disposal of needles and syringes in order to avoid needle stick injuries. Patients must be cautioned against the reuse of needles or syringes, instructed in safe disposal procedures including the use of a puncture resistant container for disposal of used needles and syringes. Patients must be instructed on the safe disposal of full containers as per local requirements and to keep this container out of reach of children. Caregivers who experience an accidental needle stick after patient injection should contact a healthcare provider immediately.
Fuzeon must only be reconstituted with 1.1 mL of Sterile Water for Injections. After adding sterile water, the vial should be gently tapped for 10 seconds and then gently rolled between the hands to avoid foaming and to ensure all particles of drug are in contact with the liquid and no drug remains on the vial wall. The vial should then be allowed to stand until the powder goes completely into solution, which could take up to 45 minutes. Reconstitution time can be reduced by gently rolling the vial between the hands until the powder is completely dissolved. Before the solution is withdrawn for administration, the vial should be inspected visually to ensure that the contents are fully dissolved in solution, and that the solution is clear, colourless and without bubbles or particulate matter. If there is evidence of particulate matter, the vial must not be used and should be discarded or returned to the pharmacy.
The solvent vials contain 2 mL of water for injections, of which 1.1 mL must be withdrawn for the reconstitution of the powder. Patients should be instructed to discard the remaining volume of solvent.
Fuzeon contains no preservative. Once reconstituted 1.0 mL of the solution should be injected immediately. If the reconstituted solution cannot be injected immediately, it must be kept refrigerated until use and used within 24 hours. Refrigerated reconstituted solution should be brought to room temperature before injection and the vial should be inspected visually again to ensure that the contents are fully dissolved in solution and that the solution is clear, colourless and without bubbles or particulate matter.
The reconstituted solution should be injected subcutaneously in the upper arm, abdomen or anterior thigh. The injection should be given at a site different from the preceding injection site and only where there is no current injection site reaction. Also, do not inject into moles, scar tissue, bruises or the navel.
A vial is for use in one patient on one occasion only.

4.3 Contraindications

Fuzeon is contraindicated in patients with known hypersensitivity to enfuvirtide or any of its components.

4.4 Special Warnings and Precautions for Use

General.

As with other antiretrovirals, Fuzeon must be taken as part of a combination regimen.
Patients should be informed that Fuzeon is not a cure for HIV-1 infection and its use does not preclude the need to maintain practices and behaviour designed to prevent transmission of HIV.

Local injection site reactions.

The most common adverse events associated with Fuzeon use are local injection site reactions. Manifestations may include pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis. Eleven percent of patients had local reactions that required analgesics or limited usual activities (see Section 4.8 Adverse Effects (Undesirable Effects)). Reactions are often present at more than one injection site. Patients must be familiar with the Fuzeon injection instructions in order to inject Fuzeon appropriately and how to monitor carefully for signs or symptoms of cellulitis or local infection.

Bacterial pneumonia and other infections.

A higher rate of pneumonia (primarily bacterial) has been observed in patients treated with Fuzeon in the Phase III clinical trials compared to the control arm. Risk factors for pneumonia included low initial CD4 lymphocyte count, high initial viral load, intravenous drug use, smoking and prior history of lung disease. Patients should be monitored closely for signs and symptoms of pneumonia especially if they have underlying conditions which may predispose them to pneumonia.
In phase III studies there were trends to higher rates of sinusitis, skin infections (not at injection site), abscess, cellulitis and sepsis in patients treated with Fuzeon compared to the control arm, although differences were not statistically significant. Patients should be monitored for signs and symptoms of these infections.

Hypersensitivity reactions.

Hypersensitivity reactions have been occasionally associated with enfuvirtide therapy and in rare cases hypersensitivity reactions have recurred on rechallenge. Events included rash, fever, nausea and vomiting, chills, rigors, low blood pressure, and elevated serum liver transaminases in various combinations, and possibly primary immune complex reaction, respiratory distress, glomerulonephritis and anaphylaxis. Patients developing signs/ symptoms suggestive of a systemic hypersensitivity reaction should discontinue enfuvirtide treatment and should seek medical evaluation immediately. Therapy with enfuvirtide should not be restarted following systemic signs and symptoms consistent with a hypersensitivity reaction considered related to enfuvirtide. Risk factors that may predict the occurrence or severity of hypersensitivity to enfuvirtide have not been identified.
Administration of Fuzeon to non-HIV-1 infected individuals (e.g. postexposure prophylaxis) may induce antienfuvirtide antibodies that cross react with HIV gp-41. This may result in a false positive HIV test with the anti-HIV ELISA test; a confirmatory Western blot and RNA testing would be expected to be negative.

Immune reconstitution syndrome (also referred to as immune reactivation syndrome, immune restoration disease or immune reconstitution inflammation syndrome).

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Fuzeon. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), tuberculosis or others), which may necessitate immediate evaluation and treatment.
Autoimmune disorders such as Grave's disease and Guillain-Barré syndrome have also been reported in the setting of immune reconstitution; however, the time to onset is variable and can occur many months after initiation of treatment.

Use in the elderly.

Clinical studies of Fuzeon did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or other drug therapy.

Paediatric use.

The safety and pharmacokinetics of Fuzeon have not been established in paediatric patients below 6 years of age. Limited efficacy data is available in paediatric patients greater than 6 years of age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

There are no clinically significant pharmacokinetic interactions between enfuvirtide and concomitantly given drugs metabolized by CYP450 enzymes.

Influence of enfuvirtide on metabolism of concomitant drugs.

Based on the results from an in vitro human microsomal study enfuvirtide is not an inhibitor of CYP450 enzymes and therefore will not alter the metabolism of drugs metabolized by CYP450 enzymes. In an in vivo human metabolism study enfuvirtide, at the recommended dose of 90 mg bid, did not inhibit the metabolism of substrates by CYP3A4 (dapsone), CYP2D6 (debrisoquine), CYP1A2 (caffeine), CYP2C19 (mephenytoin) and CYP2E1 (chlorzoxazone).

Influence of concomitant drugs on enfuvirtide metabolism.

In separate pharmacokinetic interaction studies, coadministration of rifampicin, ritonavir or saquinavir in combination with a booster dose of ritonavir, did not result in clinically significant pharmacokinetic interactions with enfuvirtide. In the case of the ritonavir study, a 22% increase in AUC and a 24% increase in C_max of enfuvirtide was observed (see Table 2).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Enfuvirtide produced no adverse effects on fertility in male or female rats at subcutaneous doses up to 15 mg/kg bid (1.6x the adult clinical dose, adjusted for body surface area).
(Category B2)
After subcutaneous administration of radiolabelled enfuvirtide to pregnant rats on gestation day 18, radioactivity representing enfuvirtide and/or its metabolites was detected in foetuses.
In embryofoetal development studies with enfuvirtide subcutaneous doses up to 250 mg/kg bid in rats and up to 15 mg/kg bid in rabbits (relative systemic exposures, based in AUC, of 8.9x and 3.2x, respectively), there were no adverse embryofoetal effects. Peri-postnatal development was unaffected in rats at subcutaneous doses up to 15 mg/kg bid (1.6x the adult clinical dose, adjusted for body surface area).
There are no adequate and well controlled studies in pregnant women. Enfuvirtide should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
After subcutaneous administration of radiolabelled enfuvirtide to lactating rats, it was estimated that approximately 3% of the total radioactivity was secreted in milk over 48 h, with small amounts of enfuvirtide detectable up to 1 h, and only metabolites thereafter. It is not known whether enfuvirtide is secreted in human milk. Mothers should be instructed not to breastfeed if they are receiving enfuvirtide because of both the potential for HIV transmission and any possible adverse effects in nursing infants.

4.7 Effects on Ability to Drive and Use Machines

No studies have been conducted on the ability to drive or operate machinery while taking enfuvirtide. There is no evidence that enfuvirtide may alter the patient's ability to drive and use machines, however, the adverse event profile of enfuvirtide should be taken into account (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

The overall safety profile of Fuzeon is based on 2120 patients who received at least one dose of enfuvirtide during various clinical trials. The safety population consisted of 2051 adults (including 1181 adults who were exposed to the recommended dose for ≥ 24 weeks and 631 adults who were exposed for ≥ 48 weeks) and 69 paediatric patients (including 44 children who were exposed to Fuzeon for ≥ 24 weeks and 27 children who were exposed for ≥ 48 weeks).
At week 48 of the study the cumulative exposure on the Fuzeon + OB regimen was 557 patient years, and on the OB alone regimen the cumulative exposure was 162 patient years. Due to this difference in exposure, the adjusted safety results are expressed as the number of patients with an adverse event per 100 patient years of exposure (except for injection site reactions).

Local injection site reactions.

The most frequently reported adverse reactions following enfuvirtide administration were local injection site reactions (ISRs), which occurred in 98% of the 663 Fuzeon treated patients in TORO-1 and TORO-2 (Table 3). Four percent of patients discontinued use of Fuzeon due to ISRs. The vast majority (85.6% in TORO-1 and TORO-2) of ISRs occurred within the first week of Fuzeon administration and were associated with mild to moderate pain or discomfort at the injection site without limitation of usual activities. The severity of the pain and discomfort associated with ISRs did not increase with treatment duration. The signs and symptoms characterising the injection site reactions generally lasted less than 7 days. Seventy two percent (72%) of patients had lesions evident on at least one of the given study visits; the number of lesions evident at any given visit was ≤ 5. Infection at the injection site (including abscess and cellulitis) occurred in 1.5% of patients.

Other adverse reactions.

The events most frequently reported in subjects receiving the Fuzeon + OB regimen (n = 663), excluding injection site reactions, were diarrhoea (38 patients with event per 100 patient years) and nausea (27 patients with event per 100 patient years). These events were also commonly observed among subjects that received the OB alone regimen (n = 334): diarrhoea (73 patients with event per 100 patient years) and nausea (50 patients with event per 100 patient years). The addition of Fuzeon to background antiretroviral therapy generally did not increase the frequency or severity of most adverse events.
Shown in Table 4 are events seen more commonly among patients receiving Fuzeon + OB regimen (n = 663) than among patients on the OB alone regimen (n = 334) (excluding injection site reactions), with an exposure adjusted rate of at least 2 patients with event per 100 patient years (data from clinical trials TORO-1 and TORO-2). Rates of adverse events for patients who switched to Fuzeon after virological failure were similar. The only adverse events with a statistically significant risk ratio between the Fuzeon regimen and the OB alone regimen, were pneumonia and lymphadenopathy. Most adverse events were of mild or moderate intensity.

Hypersensitivity reactions.

In addition there have been a small number of hypersensitivity reactions attributed to Fuzeon and in some cases recurrence has occurred upon rechallenge (see Section 4.4 Special Warnings and Precautions for Use). Events included rash, fever, nausea and vomiting, chills, rigors, low blood pressure and elevated serum liver transaminases in various combinations, and possibly, primary immune complex reaction, respiratory distress, glomerulonephritis and anaphylaxis.

Laboratory testing.

The majority of patients had no change in the toxicity grade of any laboratory parameter during the study. Table 5 shows the treatment emergent laboratory abnormalities that occurred at a rate of at least 2 patients per 100 patient years of exposure and that occurred more frequently (either as a grade 3 or 4 laboratory abnormality) among patients receiving Fuzeon + OB regimen than among patients on the OB alone regimen, to week 48 of the pooled studies TORO-1 and TORO-2.
Through week 48, treatment emergent eosinophilia [greater than the Upper Limit of Normal (ULN) of > 0.7 x 10⁹/L] occurred at a higher rate among patients in the Fuzeon containing group (12.4 per 100 patient years) compared with OB alone regimen (5.6 per 100 patient years). When using a higher threshold for eosinophilia (> 1.4 x 10⁹/L), the patient exposure adjusted rate of eosinophilia is equal in both groups (1.8 patients with event per 100 patient years).

Additional adverse events or laboratory abnormalities.

The following additional adverse events or laboratory abnormalities were reported from the 24 week analysis of the two pivotal studies as occurring in > 2% of patients and more frequently in patients receiving Fuzeon + OB regimen than in those taking OB alone regimen. A causal relationship of these events to Fuzeon has not been established.

Nervous system disorders.

Headache, dizziness (excl. vertigo), taste disturbance.

Psychiatric disorders.

Insomnia, depression.

Respiratory, thoracic and mediastinal disorders.

Cough.

Investigations.

Increased gamma-glutamyltransferase, amylase, lipase, AST.

Infections and infestations.

Oral candidiasis, herpes simplex, folliculitis.

General disorders and administration site conditions.

Asthenia.

Skin and subcutaneous tissue disorders.

Pruritus, night sweats, sweating increased.

Musculoskeletal, connective tissue and bone disorders.

Arthralgia, back pain, pain in limb, muscle cramps.

Gastrointestinal disorders.

Abdominal pain upper, constipation, sore throat.

Postmarketing experience.

Skin and subcutaneous tissue disorders.

Cutaneous amyloidosis at the injection site.

Postmarketing observational study in bacterial pneumonia.

A higher rate of pneumonia (primarily bacterial) has been observed in patients treated with Fuzeon in the Phase III clinical trials compared to the control arm. Because it was unclear whether the higher rate of pneumonia was related to Fuzeon use, an observational study in 1150 HIV infected patients (740 Fuzeon arm with 2,045 patient years of observation and 1110 comparator population with 3,501 patient years of observation) was conducted to carefully evaluate the risk of pneumonia from Fuzeon while controlling for other known risk factors. The incidence of pneumonia was 3.82 events/100 patient years in the Fuzeon treatment arm and 2.31 events/100 patient years in the nonexposed cohort. The adjusted risk ratio for incidence of pneumonia was 0.989 for confirmed pneumonia only, and 1.228 for confirmed or probable pneumonia, with the lower limit of the 95% confidence interval of 0.437 and 0.862, respectively.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There are no reports of overdose with Fuzeon in humans. The highest dose administered to 12 patients in a clinical trial was 180 mg as a single dose subcutaneously. These patients did not experience any adverse events that were not seen with the recommended dose.
There is no specific antidote for overdose with Fuzeon. Treatment of overdose should consist of general supportive measures.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other antivirals, ATC code: J05AX07.

Mechanism of action.

Enfuvirtide is a member of the therapeutic class called fusion inhibitors. It is an inhibitor of the structural rearrangement of HIV-1 gp41 that functions by specifically binding to this virus protein extracellularly and thereby blocking the virus from entering the cell. The antiviral activity of enfuvirtide results from its association with a heptad repeat motif, HR1, within native gp41 on the viral surface.

Microbiology.

Antiviral activity in vitro.

The in vitro antiviral activity of enfuvirtide has been demonstrated for acute infection of T lymphoblastoid cell lines, monocyte/ macrophage cells and primary peripheral blood mononuclear cells (PBMC) by laboratory and clinical HIV-1 isolates. Enfuvirtide demonstrated selective anti-HIV-1 activity against both prototypic and primary virus isolates. Enfuvirtide susceptibility for 130 PBMC baseline virus isolates from enfuvirtide treated patients in Phase II clinical studies was determined in a cMAGI cell assay (CCR5 expressing derivative of the Multinuclear Activation of a Galactosidase Indicator cell line). Enfuvirtide had a geometric mean EC₅₀ of 0.016 microgram/mL (SD = 0.057) against these virus isolates. Enfuvirtide also inhibited HIV-1 envelope mediated cell/ cell fusion. Drug combination studies of enfuvirtide with representative members of the various antiretroviral classes (nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitors and protease inhibitors; namely zidovudine, lamivudine, nelfinavir, indinavir, and efavirenz) exhibited additive to synergistic effects in cell culture assays. The relationship between the in vitro susceptibility of HIV-1 to enfuvirtide and inhibition of HIV-1 replication in humans has not been established. The in vitro antiviral activity of enfuvirtide against HIV-2 isolates is low.

Viral resistance.

In vitro resistance to enfuvirtide.

HIV-1 isolates with reduced susceptibility to enfuvirtide have been selected in vitro. These isolates harboured substitutions in amino acids 36-38 of the gp41 ectodomain and these substitutions were correlated with varying levels of reduced enfuvirtide susceptibility in HIV site directed mutants. Mutations in gp41 amino acids 36-45 were observed with clinical isolates exhibiting decreased in vitro susceptibility to enfuvirtide in comparison to their respective baseline (i.e. pretreatment) isolate. Site directed mutagenesis in the HIV-1 NL4-3 molecular clone confirmed that mutations in gp41 amino acid residues 36-45 could confer decreased in vitro sensitivity to enfuvirtide.

In vivo resistance to enfuvirtide.

Post-treatment HIV-1 virus from 246 subjects experiencing protocol defined virological failure exhibited decreases in susceptibility to enfuvirtide ranging from 4-fold to 6318-fold relative to respective baseline virus and exhibited genotypic changes in gp41 amino acids 36 to 45. The substitutions observed in decreasing frequency were at amino acid positions 38, 43, 40 and 36. In isolates from subjects experiencing virological failure in Phase III clinical studies the two most common amino acid substitutions were V38A and N43D.

Cross resistance.

Due to its novel viral target enfuvirtide is equally active in vitro against both wild type laboratory and clinical isolates and those with resistance to 1, 2 or 3 classes of antiretrovirals (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors). These isolates had genotypic resistance specifically identified for: zidovudine, lamivudine, stavudine, didanosine, zalcitabine, abacavir, nevirapine, delavirdine, efavirenz, indinavir, saquinavir, nelfinavir, ritonavir and amprenavir; all were sensitive to enfuvirtide. Conversely, mutations in amino acids 36-45 of gp41 which give resistance to enfuvirtide would not be expected to give cross resistance to other classes of antiretrovirals.

Clinical trials.

Studies in antiretroviral experienced patients.

The clinical activity of Fuzeon (in combination with other antiretroviral agents) on surrogate markers for clinical efficacy (plasma HIV-1 RNA levels and CD4 counts) has been investigated in two randomised, multicentre, controlled studies (TORO-1 and TORO-2). Analyses have been performed following 48 weeks of treatment.
The HIV-1 infected patients enrolled into these studies all had at least 3 to 6 months of prior treatment with (or documented resistance or intolerance to) nucleoside and non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Patients had prior exposure to a median of 12 antiretrovirals for a median of 7 years.
All patients received an optimized background (OB) regimen consisting of 3 to 5 antiretroviral agents selected on the basis of the patient's prior treatment history, as well as baseline genotypic and phenotypic viral resistance measurements. Patients were randomized at a 2:1 ratio to Fuzeon (90 mg bid) + OB or OB alone.
There were 995 patients in the pooled intention to treat (ITT) population and demographic characteristics for patients in studies TORO-1 and TORO-2 are shown in Table 6.

Compared to the OB treatment group, the Fuzeon + OB treatment group experienced a significantly greater decrease in plasma HIV-1 RNA with a treatment difference of 0.85 log₁₀ copies/mL and a significantly greater increase in CD4 cell count after 48 weeks of treatment (see Table 7).
The percentages of patients who achieved a decrease in HIV-1 RNA plasma levels of ≥ 1 log₁₀, and decreases to < 400 copies/mL and < 50 copies/mL after 48 weeks of treatment were significantly higher in the Fuzeon + OB treatment group (see Table 7).
The proportion of patients achieving viral load of < 400 copies/mL at week 48 was 30% among patients on the Fuzeon + OB regimen compared to 12% among patients receiving OB regimen only (see Table 7).

The studies were not designed to assess differences in AIDS defining events or mortality as patients switched from OB to Fuzeon + OB upon virological failure.
Virological failure was defined in the protocols as failure to achieve 0.5 log response by week 6 and 8, failure to achieve a 1.0 log response by weeks 14 and 16, or having ≥ 2 log decrease from baseline followed by > 1 log rebound at any time. Overall, 301 (46%) and 236 (71%) of patients on Fuzeon + OB and OB, respectively, met virological failure criteria by week 24.

Paediatric population.

Limited efficacy data is available from 39 HIV-1 infected paediatric patients age 3 through 16 years. The evaluation of the safety and antiviral activity of Fuzeon in paediatric patients in clinical trials is ongoing.
Study T20-204 is an ongoing open label, multicentre trial evaluating the pharmacokinetics, safety and antiviral activity of Fuzeon in 14 paediatric patients aged 3 to 12 years. All patients had experience with at least two classes of licensed antiretrovirals.
Study T20-204 patients added either 30 or 60 mg/m²/dose Fuzeon bid to their existing background antiretroviral regimen. After 7 days, the background regimen was changed to 3 new or sensitive antiretrovirals and Fuzeon dosing was continued. Patients had a median age of 8 years (range 3.7 through 11.9 years). Median baseline CD4 cell count was 523 cells/microL and the median baseline HIV-1 RNA was 4.4 log₁₀ c/mL.
Following day 7 analysis for safety, pharmacokinetics and antiviral activity, all but 1 patient was switched to 60 mg/m²/dose of Fuzeon. The median change from baseline HIV RNA at day 7 was -1.15 log₁₀ copies/mL for 10 paediatric patients receiving the 60 mg/m² dose.
All but 3 patients completed 48 weeks of chronic therapy. By week 48, 6/14 (43%) patients had > 1 log₁₀ decline in HIV-1 RNA and 4/14 (29%) patients were below 400 copies/mL of HIV-1 RNA. The median changes from baseline in HIV-1 RNA and CD4 cell count were -1.24 log₁₀ c/mL and 237 cells/microL, respectively, but no control group was included in these studies.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of enfuvirtide have been evaluated in HIV-1 infected adult and paediatric patients.

Absorption.

The pharmacokinetics of enfuvirtide has been explored by both intravenous (iv) and subcutaneous (sc) administration and they provide similar exposures. The absolute bioavailability (using the 90 mg iv dose as a reference) was 84.3 ± 15.5%. Following 90 mg bid dosing of enfuvirtide subcutaneously in 11 HIV-1 infected patients, the mean (± SD) steady state C_max was 5.0 ± 1.7 microgram/mL, C_trough was 3.3 ± 1.6 microgram/mL, AUC_(0-12h) was 48.7 ± 19.1 microgram.hour/mL and the median T_max was 4 hours. The subcutaneous absorption of enfuvirtide is proportional to the administered dose over the 45 to 180 mg dose range. Subcutaneous absorption at the 90 mg dose is comparable when injected into the abdomen, thigh or arm. In four separate studies (n = 9 to 12) the mean steady state trough plasma concentration ranged from 2.6 to 3.4 microgram/mL.

Distribution.

The mean (± SD) steady state volume of distribution with intravenous administration of a 90 mg dose of enfuvirtide (n = 12) was 5.5 ± 1.1 L. Enfuvirtide is 92% bound to plasma proteins in HIV infected plasma over a plasma concentration range of 2 to 10 microgram/mL. It is bound predominantly to albumin and to a lower extent to α-1 acid glycoprotein. No data is available on distribution to semen, breast milk or vaginal secretions.
Enfuvirtide levels in the cerebrospinal fluid measured in a small number of HIV infected patients were reported to be negligible. The molecule may be too large to pass the blood brain barrier.

Metabolism.

As a peptide, enfuvirtide is expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool. In vitro human microsomal studies indicate that enfuvirtide is not an inhibitor of CYP450 enzymes. In in vitro human microsomal and hepatocyte studies, hydrolysis of the amide group of the C-terminus amino acid, phenylalanine results in a deamidated metabolite and the formation of this metabolite is not NADPH (nicotinamide adenine dinucleotide phosphate) dependent. This metabolite is detected in human plasma following administration of enfuvirtide, with an AUC ranging from 2.4 to 15% of the enfuvirtide AUC.

Excretion.

Following a 90 mg subcutaneous dose of enfuvirtide (n = 12) the mean ± SD elimination half-life of enfuvirtide was 3.8 ± 0.6 h and the mean ± SD clearance was 1.7 ± 0.4 L/h. Mass balance studies to determine elimination pathway(s) of enfuvirtide have not been performed in humans.

Pharmacokinetics in special populations.

Hepatic impairment.

The pharmacokinetics of enfuvirtide have not been studied in patients with hepatic impairment.

Renal impairment.

Analysis of plasma concentration data from patients in clinical trials indicated that the clearance of enfuvirtide is not affected to any clinically relevant extent in patients with creatinine clearance greater than 35 mL/min. The results of a renal impairment study indicate clearance of enfuvirtide was reduced by 38% in patients with severe renal impairment and by 14-28% in patients with endstage renal disease maintained on dialysis compared to patients with normal renal function. The results were within the range seen in patients in the pivotal studies with normal renal function. Haemodialysis did not significantly alter enfuvirtide clearance. Thus, no dose adjustment is required for patients with impaired renal function.

Elderly patients.

The pharmacokinetics of enfuvirtide have not been formally studied in elderly patients over 65 years of age.

Gender and weight.

Analysis of plasma concentration data from patients in clinical trials indicated that the clearance of enfuvirtide is 20% lower in females than males irrespective of weight and is increased with increased bodyweight irrespective of gender (20% higher in a 100 kg and 20% lower in a 40 kg bodyweight patient relative to a 70 kg reference patient). However, these changes are not clinically significant and no dose adjustment is required.

Race.

Analysis of plasma concentration data from patients in clinical trials indicated that the clearance of enfuvirtide was not different in Blacks compared to Caucasians. Other pharmacokinetic studies suggest no difference between Asians and Caucasians after adjusting exposure for bodyweight.

Paediatric patients.

The pharmacokinetics of enfuvirtide have been studied in 32 paediatric patients. A dose of 2 mg/kg bid (maximum 90 mg bid) provided enfuvirtide plasma concentrations similar to those obtained in adult patients receiving 90 mg bid dosage. In 23 paediatric patients ranging in age from 6 to 16 years and receiving the 2 mg/kg bid dose into the upper arm, anterior thigh or abdomen, the mean ± SD steady state AUC was 56.3 ± 22.3 microgram.hour/mL, C_max was 6.3 ± 2.4 microgram/mL and C_trough was 3.1 ± 1.5 microgram/mL.

5.3 Preclinical Safety Data

Genotoxicity.

Enfuvirtide was not mutagenic in a series of assays including the Ames bacterial reverse mutation assay, a mammalian cell forward gene mutation assay in AS52 Chinese Hamster ovary cells, nor did it induce micronuclei in an in vivo mouse micronucleus assay.

Carcinogenicity.

Long-term animal carcinogenicity studies of enfuvirtide have not been performed.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium carbonate, mannitol, sodium hydroxide, hydrochloric acid.

6.2 Incompatibilities

Fuzeon should not be mixed with other medicinal products except for the solvent supplied (water for injections).

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.
After reconstitution with water for injection the product may only be stored at 2 to 8°C for no longer than 24 hours.

6.5 Nature and Contents of Container

Fuzeon is available in packs of 60 vials.
Fuzeon is also available as a combination pack containing the following:
60 vials powder for injection;
60 vials solvent;
60 3 mL syringes + needle;
60 1 mL syringes + needle;
180 alcohol swabs.

6.6 Special Precautions for Disposal

Disposal of syringes and sharps.

The following points should be strictly adhered to regarding the use and disposal of syringes and other medicinal sharps:
Needles and syringes should never be reused.
Place all used needles and syringes into a sharps container (puncture-proof disposable container).
Keep the sharps container out of the reach of children.
Placing used sharps container in household waste should be avoided.
Dispose of the full sharps container according to local requirements or as instructed by your healthcare provider.
For home use, a puncture resistant container for the disposal of used syringes and needles should be supplied to the patients.

Disposal of medicines.

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

The empirical formula of enfuvirtide is C₂₀₄H₃₀₁N₅₁O₆₄, and the molecular weight is 4,492. It has the following primary amino acid sequence:
Ac-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln-Asn-Gln-Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-NH₂.

Fuzeon (enfuvirtide) is derived from a naturally occurring motif, amino acid residues (643-678) within the gp41 transmembrane glycoprotein of human immunodeficiency virus type 1 strain LAI (HIV-1_LAI). Enfuvirtide is a linear 36-amino acid synthetic peptide, composed of naturally occurring L-amino acid residues.

CAS number.

159519-65-0.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

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