Consumer medicine information

Benlysta

Belimumab

BRAND INFORMATION

Brand name

Benlysta

Active ingredient

Belimumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Benlysta.

SUMMARY CMI

BENLYSTA

Consumer Medicine Information (CMI) summary

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

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I being given BENLYSTA?

BENLYSTA contains the active ingredient belimumab. BENLYSTA is used to treat systemic lupus erythematosus (SLE) and lupus-related kidney inflammation (active lupus nephritis) in adults aged 18 years and over.

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

2. What should I know before I am given BENLYSTA?

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

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

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

3. What if I am taking other medicines?

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

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

4. How is BENLYSTA given?

  • BENLYSTA powder for intravenous infusion will be given to you by a doctor or nurse into a vein as a drip over 1 hour.
  • BENLYSTA solution for subcutaneous injection comes in a pre-filled syringe or pen and will be injected by you or your caregiver, as instructed by your doctor or nurse.

More instructions can be found in Section 4. How is BENLYSTA given? in the full CMI.

5. What should I know while using BENLYSTA?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using BENLYSTA.
  • Tell your doctor immediately if you get an infection, have memory loss, trouble thinking, difficulty talking or walking or loss of vision, feel low in mood, have mental health problems or have thoughts of harming yourself or committing suicide.
  • Women of child-bearing potential must use contraception while using BENLYSTA and for four months after the last dose.
Things you should not do
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Do not use BENLYSTA to treat other complaints unless your doctor says to.
Driving or using machines
  • Be careful driving or operating machinery until you know how BENLYSTA affects you.
Looking after your medicine
  • Keep BENLYSTA in a refrigerator (2°C - 8°C) until it is time to use. Do not freeze.
  • Store BENLYSTA in the original package to protect it from light and keep it where children cannot reach it.

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

6. Are there any side effects?

Side effects can occur, including allergic reactions to the infusion or injection, depression, suicide or infections. Tell your doctor or nurse immediately if you experience any of these symptoms or notice them worsening.

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

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

BENLYSTA

Active ingredient: belimumab

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I being given BENLYSTA?

BENLYSTA contains the active ingredient belimumab. Belimumab belongs to a group of medicines called monoclonal antibodies.

BENLYSTA is used to treat lupus (systemic lupus erythematosus, SLE) in adults (18 years of age and over). BENLYSTA is also used to treat adults with lupus-related kidney inflammation (active lupus nephritis) who are receiving standard treatment.

Lupus is a disease of the immune system (the body system that fights infection). People with active lupus often have high levels of a protein called BLyS in their blood.

BENLYSTA binds to BLyS and limits the activity of BLyS.

You will be given BENLYSTA as well as your usual treatment for lupus.

Your doctor may have prescribed BENLYSTA for another reason.

BENLYSTA is not addictive.

2. What should I know before I am given BENLYSTA?

Warnings

Do not use BENLYSTA if:

  • you are allergic to belimumab or any of the ingredients listed at the end of this leaflet.
  • always check the ingredients to make sure you can use this medicine.
  • the expiry date (EXP) printed on the pack has passed.
  • the packaging is torn or shows signs of tampering.

Check with your doctor if:

  • you have had an allergic reaction (hypersensitivity) to foods, dyes, preservatives or any other medicines or injections. You may be given medicines before you are given BENLYSTA to help reduce any infusion reactions to BENLYSTA.
  • you have a history of depression, suicidal thoughts or behaviour.
  • you think you have an infection.
  • you need a vaccination or have recently received a vaccination. Your doctor will decide if you can be given the vaccination.
  • you have had cancer. Your doctor will decide if you can be given BENLYSTA.
  • you are taking any other medicines, including medicines you buy without a prescription.

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

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. Your doctor will decide if you can be given BENLYSTA.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is likely that BENLYSTA can pass into breast milk. Your doctor will discuss with you whether you should stop being treated with BENLYSTA while you are breast-feeding or you should stop breastfeeding while you are being treated with BENLYSTA.

3. What if I am taking other medicines?

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

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

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

4. How is BENLYSTA given?

How much is given

Powder for intravenous infusion

Your doctor will decide on the correct dose of BENLYSTA depending on your body weight. The usual dose is 10 mg for each kilogram (kg) of your body weight.

Solution for subcutaneous injection

Always use this medicine exactly as your doctor or pharmacist has told you to. Check with your doctor or pharmacist if you are not sure.

BENLYSTA should be injected under your skin on the same day each week. If you have lupus nephritis, one dose may be 2 individual injections administered at least 5 cm apart.

Systemic lupus erythematosus (SLE):

The recommended dose is 200 mg once a week.

Lupus nephritis:

At the start of your treatment the recommended dose is 400 mg (two 200 mg injections in one day) once a week for 4 doses. After this, the recommended dose is 200 mg (one injection) once a week.

How is it given

Powder for intravenous infusion

A nurse or doctor will give you BENLYSTA into a vein (intravenously) as a drip (infusion). It usually takes 1 hour to give the drip.

You are usually given BENLYSTA on the first day of treatment then again 14 and 28 days later. After this, BENLYSTA is usually given once every 4 weeks.

Solution for subcutaneous injection

BENLYSTA comes in a pre-filled syringe or pre-filled pen. Your doctor or nurse will show you or your caregiver how to inject BENLYSTA. Your doctor or nurse may then decide that you or your caregiver may inject BENLYSTA. In this case you or your caregiver will get training on how to inject BENLYSTA and what the signs and symptoms of allergic reactions are - see Section 6. Are there any side effects?

You or your caregiver should inject BENLYSTA under your skin in your stomach area (abdomen) or upper leg (thigh). You or your caregiver should inject a different area of your body for each injection. Don't inject in exactly the same place every time. You should not inject BENLYSTA into areas where the skin is tender, bruised, red or hard.

BENLYSTA subcutaneous injection must not be injected into a vein (intravenously).

If you forget to take your BENLYSTA subcutaneous injection

If you miss a dose, inject the next dose as soon as possible. After that, you can go back to having your dose on the usual day or start a new weekly schedule from the day that the missed dose was injected. If you are unsure consult your doctor or nurse.

Medication given before an infusion

If you have had an allergic reaction to other medicines or injections, your doctor may decide to give you medicines which help to reduce any infusion reactions before you are given BENLYSTA. These may include a type of medicine called an anti-histamine and a medicine to prevent a high temperature. You will be checked closely and if you do have any reactions these will be treated.

Stopping treatment with BENLYSTA

Your doctor will decide if you need to stop being given BENLYSTA.

Use in children and adolescents

Your doctor will decide if you need to stop being given BENLYSTA is not recommended for use in children and adolescents under 18 years.

If you use too much BENLYSTA

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

You should immediately:

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

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

5. What should I know while using BENLYSTA?

Things you should do

  • Women of child-bearing potential must use an effective method of contraception while being treated with BENLYSTA and for at least 4 months after the last dose.
  • Tell your doctor if you have any mental health problems. Symptoms of mental health problems can include, new or worse depression, new or worse anxiety, thoughts of hurting yourself or others, acting on dangerous impulses or other unusual changes in your behaviour or mood.

Call your doctor straight away:

  • if you feel low in mood, have thoughts of harming yourself or committing suicide. You may find it helpful to tell a relative or close friend and ask them to read this leaflet. You should also ask them to tell you if they are worried about changes in your mood or behaviour. If you experience new or worsening symptoms at any time, contact your doctor or go to a hospital straight away.
  • if you get an infection while you are being treated with BENLYSTA. Your doctor will want to check that your infection is being properly treated. Symptoms of an infection can include, fever, chills, headache, sore throat, cough, diarrhoea, stinging or burning on passing urine, aching muscles and pain, redness, swelling or discharge at the site of the wound.

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

Things you should not do

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

Progressive multifocal leukoencephalopathy (PML)

Tell your doctor immediately if you have memory loss, trouble thinking, difficulty with talking or walking, loss of vision, or similar problems that have lasted over several days.

If you had these symptoms prior to treatment with BENLYSTA tell your doctor immediately about any changes in these symptoms.

These could be symptoms of Progressive multifocal leukoencephalopathy (PML).

PML is a serious and life-threatening brain condition. Your chance of getting PML may be higher if you are treated with medicines that weaken your immune system, including BENLYSTA.

Driving or using machines

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

Looking after your medicine

Keep BENLYSTA in a refrigerator (2°C - 8°C) until it's time to use. Do not freeze.

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

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

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Some of these serious side effects may cause death, including serious infection, risk of cancer and mental effects such as depression, but it is not known if BENLYSTA causes these side effects. You should discuss risks of serious side effects with your doctor before commencing treatment with BENLYSTA.

Allergic reaction to the infusion or injection

Medicines of this type (monoclonal antibodies) can cause allergic (hypersensitivity) reactions, which can affect between 1 in 10 and 1 in 100 people, and can occasionally be severe. These reactions usually occur within 1 to 2 hours after starting the infusion. They are more likely to happen during the first treatment.

Allergic reactions can also occur later with BENLYSTA generally 5-10 days after a dose of medication (but can occur before or after that time) and include a combination of symptoms such as rash, nausea, fatigue, muscle aches, headache, and/or facial swelling. If you experience these symptoms, particularly if you experience a combination of such symptoms tell your doctor or nurse.

Depression and suicide

There have been reports of depression, suicidal thoughts and suicide attempts during treatment with BENLYSTA. Depression can affect up to 1 in 10 users, suicidal thoughts and suicide attempts can affect up to 1 in 100 users. If you experience any new or worsening symptoms such as low mood, suicidal thoughts or behaviour, contact your doctor or go to a hospital straight away.

Infections

BENLYSTA can cause infection which can be of different types including chest infection, kidney infection, infection of nose and throat, bowel infection etc. These can affect more than 1 in 10 users, which can be severe and can uncommonly cause death.

Tell your doctor or a nurse immediately if you get symptoms of an infection, for example:

  • Fever
  • Cough
  • Breathing problems
  • Diarrhoea
  • Vomiting
  • Burning sensation while passing urine

Less serious side effects

Less serious side effectsWhat to do
Administration site reactions
  • rash, redness, itching or swelling of the skin where you have injected BENLYSTA solution for subcutaneous injection**
Gastrointestinal system disorders
  • diarrhoea*
  • nausea*
General disorders
  • high temperature or fever (pyrexia)**
  • pain in hands and feet**
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Infections
  • nose, throat, chest, bladder or stomach infections**
Allergic or infusion/injection related reactions
  • swelling of face or mouth causing difficulty in breathing (anaphylactic reactions)***
  • swelling of the face, lips and tongue (angioedema)***
  • rash, possibly with itchy raised bumps or hives (urticaria)***
  • low blood pressure (can cause light-headedness when you stand up) (hypotension)
  • slow heart beat (bradycardia)
  • difficulty breathing, shortness of breath (dyspnoea)
Blood disorders
  • low white blood cell count**
Psychiatric disorders
  • depression**
  • suicidal thoughts or behaviour***
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

* Can affect more than 1 in 10 patients

**Can affect between 1 in 10 and 1 in 100 patients

***Can affect between 1 in 100 and 1 in 1000 patients

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

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

Reporting side effects

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

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

7. Product details

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

What BENLYSTA contains

Active ingredient
(main ingredient)		Belimumab
Other ingredients
(inactive ingredients)		Powder for infusion
  • citric acid monohydrate
  • sodium citrate dihydrate
  • sucrose
  • polysorbate 80
Pre-filled pen (autoinjector) and pre-filled syringe solution for subcutaneous injection
  • arginine hydrochloride
  • histidine
  • histidine hydrochloride monohydrate
  • polysorbate 80
  • sodium chloride
  • water for injections

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

What BENLYSTA looks like

Powder for intravenous infusion

BENLYSTA is supplied as a white to off-white powder, in a glass vial with a latex-free, siliconised rubber stopper and a flip-off aluminium seal.

Each 5 mL vial delivers 120 mg of BENLYSTA.

Each 20 mL vial delivers 400 mg of BENLYSTA.

There is 1 vial in each pack.

BENLYSTA is dissolved and diluted before being given to you.

Pre-filled pen (autoinjector) solution for subcutaneous injection

BENLYSTA is supplied as a colourless to slightly yellow solution in a 1 mL siliconised, USP Type I glass syringe with 13mm, 27G, stainless steel needle assembled as an auto-injector.

Each 1mL pre-filled pen (autoinjector) contains 200 mg belimumab.

Pre-filled syringe solution for subcutaneous injection

BENLYSTA is supplied as a colourless to slightly yellow solution in a 1 mL siliconised, USP Type I glass syringe with 13mm, 27G, stainless steel needle assembled with a needle guard.

Each 1mL pr pre-filled syringe contains 200 mg belimumab.

Each 1mL pre-filled pen (autoinjector) and pre-filled syringe contains 200 mg belimumab.

BENLYSTA:

120 mg powder for infusion - AUST R 173077

400 mg powder for infusion - AUST R 173078

200 mg pre-filled autoinjector pen - AUST R 314922

200 mg pre-filled syringe - AUST R 314903

Who distributes BENLYSTA

GlaxoSmithKline Australia Pty Ltd
Level 4, 436 Johnston Street
Abbotsford, Victoria, 3067
Australia.

Trademarks are owned by or licenced to the GSK group of companies.

© 2022 GSK group of companies or its licensor.

This leaflet was prepared in July 2022.

Version 11.0

Published by MIMS November 2022

BRAND INFORMATION

Brand name

Benlysta

Active ingredient

Belimumab

Schedule

S4

 

1 Name of Medicine

Belimumab (rmc).

2 Qualitative and Quantitative Composition

Belimumab is a human IgG1λ monoclonal antibody specific for soluble human B-lymphocyte stimulator protein (BLyS). It has a molecular weight of approximately 147 kDa.
Belimumab is produced by recombinant DNA technology in a mammalian cell expression system.

Powder for intravenous infusion.

Each vial contains a sufficient amount of belimumab to deliver 120 mg in 1.5 mL or 400 mg in 5 mL when reconstituted as recommended with sterile water for injections. After reconstitution, each mL of solution contains 80 mg belimumab.

Solution for subcutaneous injection.

Each pre-filled syringe or pre-filled pen delivers 200 mg belimumab in 1 mL (200 mg/mL).

List of excipients with known effect.

For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for intravenous infusion.

Benlysta is a sterile, white to off-white lyophilized powder in a single-use vial.

Solution for subcutaneous injection.

A clear to opalescent, colourless to pale yellow solution in a single-use, pre-filled syringe or pre-filled pen.

4 Clinical Particulars

4.1 Therapeutic Indications

Benlysta is indicated for:
Add-on therapy for reducing disease activity in adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g. ANA titre ≥ 1:80 and/or anti-dsDNA titre ≥ 30 IU/mL) despite standard therapy.
Treatment of active lupus nephritis in adult patients who are receiving standard therapy.
The safety and efficacy of Benlysta have not been evaluated in patients with severe active central nervous system lupus.

4.2 Dose and Method of Administration

Powder for intravenous infusion.

Benlysta treatment should be initiated and supervised by a healthcare professional experienced in the diagnosis and treatment of SLE. Benlysta infusions should be administered in an environment where full resuscitation facilities are available, and under the close supervision of an experienced healthcare professional.
Benlysta is administered intravenously by infusion and must be reconstituted and diluted prior to administration (see Method of administration).
Benlysta should be infused over a 1-hour period.
Benlysta must not be administered as an intravenous push or bolus. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. The infusion must be discontinued immediately if the patient experiences a potentially life-threatening adverse reaction (see Section 4.4 Special Warnings and Precautions for Use).
Patients should be monitored during and for an appropriate period of time after administration of Benlysta (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
There is limited data to support the benefit or durability of treatment beyond 52 weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials). It is recommended to regularly monitor the patient to ensure continued benefit/ durability of treatment are maintained.
Premedication. Premedication with an oral antihistamine, with or without an antipyretic, may be administered before the infusion of belimumab. There is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions.
Adults.

SLE.

The recommended dosage regimen is 10 mg/kg Benlysta on days 0, 14 and 28, and at 4-week intervals thereafter. Discontinuation of treatment with Benlysta should be considered if there is no improvement in disease control after 6 months of treatment. Beyond 52 weeks of treatment the physician should regularly monitor the patient to ensure benefit and durability of treatment are maintained (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Lupus nephritis.

The recommended dosage interval is 10 mg/kg on Days 0, 14 and 28, and at 4-week intervals thereafter.

Solution for subcutaneous injection.

Pre-filled syringe or pre-filled pen must not be used for intravenous injection.
It is recommended that the first subcutaneous injection of Benlysta should be under the supervision of a healthcare professional. The healthcare professional must provide proper training in subcutaneous technique and education about signs and symptoms of hypersensitivity reactions (see Section 4.4 Special Warnings and Precautions for Use). A patient may self-inject or the patient's caregiver may administer Benlysta after the healthcare professional determines that it is appropriate (see enclosed Instructions for Use).
Benlysta may be given as a subcutaneous injection in the abdomen or thigh. When injecting in the same region, patients should be advised to use a different injection site for each injection; never give injections into areas where the skin is tender, bruised, red, or hard. When a 400 mg dose is administered at the same site, it is recommended that 2 individual 200 mg injections be administered at least 5 cm (approximately 2 inches) apart.
If a dose is missed, it should be administered as soon as possible. Thereafter, patients can resume dosing on their usual day of administration or start a new weekly schedule from the day that the missed dose was administered. It is not necessary to administer two doses on the same day.
If a patient with SLE is being transitioned from Benlysta intravenous therapy to Benlysta subcutaneous therapy, administer the first subcutaneous dose 1 to 4 weeks after the last intravenous dose (see Section 5.2 Pharmacokinetic Properties).
If a patient with lupus nephritis is being transitioned from Benlysta intravenous therapy to Benlysta subcutaneous therapy, administer the first 200 mg subcutaneous dose 1 to 2 weeks after the last intravenous dose. This transition should occur any time after the patient completes the first 2 intravenous doses (see Section 5.2 Pharmacokinetic Properties).
Adults.

SLE.

The recommended dosage is 200 mg once weekly given as a subcutaneous injection in the abdomen or thigh, preferably on the same day each week. Discontinuation of treatment with Benlysta should be considered if there is no improvement in disease control after 6 months of treatment. Beyond 52 weeks of treatment, the physician should regularly monitor the patient to ensure benefit and durability of treatment are maintained (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Lupus nephritis.

In patients initiating therapy with Benlysta for active lupus nephritis (see Clinical trials), the recommended dosage regimen is a 400 mg dose (two 200 mg injections) once weekly for 4 doses, then 200 mg (one injection) once weekly thereafter. In patients continuing therapy with Benlysta for lupus nephritis, the recommended dosage is 200 mg once weekly. The dosage should be given weekly as subcutaneous injection(s) in the abdomen or thigh, preferably on the same day each week.

Powder for intravenous infusion and solution for subcutaneous injection.

Children.

Data supporting the safety and efficacy of Benlysta in children below 18 years of age have not been established, therefore, an indication for use in children is not approved.

Elderly (> 65 years).

Although data are limited, dosage adjustment is not recommended (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Renal impairment.

No formal studies with Benlysta have been performed in patients with renal impairment.
Benlysta has been studied in a limited number of SLE patients with renal impairment. On the basis of the available information, dosage adjustment is not required in patients with mild, moderate or severe renal impairment. Caution is however recommended in patients with severe renal impairment due to the limited data available (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Hepatic impairment.

No formal studies with Benlysta have been conducted in patients with hepatic impairment. However, patients with hepatic impairment are unlikely to require dose modification (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Method of administration.

Powder for intravenous infusion.

Reconstitution and dilution.

 Benlysta does not contain a preservative; therefore, reconstitution and dilution must be carried out under aseptic conditions.
Allow 10-15 minutes for the vial to warm to room temperature.
It is recommended that a 21-25 gauge needle be used when piercing the vial stopper for reconstitution and dilution.
The 120 mg single-use vial of Benlysta is reconstituted with 1.5 mL of sterile water for injections to yield a final concentration of 80 mg/mL belimumab. The 400 mg single use vial of Benlysta is reconstituted with 4.8 mL of sterile water for injections to yield a final concentration of 80 mg/mL belimumab.
The stream of sterile water should be directed toward the side of the vial to minimize foaming. Gently swirl the vial for 60 seconds. Allow the vial to sit at room temperature during reconstitution, gently swirling the vial for 60 seconds every 5 minutes until the powder is dissolved. Do not shake. Reconstitution is typically complete within 10 to 15 minutes after the sterile water has been added, but it may take up to 30 minutes. Protect the reconstituted solution from direct sunlight.
If a mechanical reconstitution device is used to reconstitute Benlysta it should not exceed 500 rpm and the vial should be swirled for no longer than 30 minutes.
Once reconstitution is complete, the solution should be opalescent and colourless to pale yellow and without particles. Small air bubbles, however, are expected and acceptable.
The reconstituted product is diluted to 250 mL with 0.9% sodium chloride (normal saline), 0.45% sodium chloride (half normal saline) or lactated Ringer's solution for IV infusion.
5% glucose IV solutions are incompatible with Benlysta and should not be used.
From a 250 mL infusion bag or bottle of normal saline, half normal saline, or lactated Ringer's solution, withdraw and discard a volume equal to the volume of the reconstituted Benlysta solution required for the patient's dose. Then add the required volume of the reconstituted Benlysta solution into the infusion bag or bottle. Gently invert the bag or bottle to mix the solution. Any unused solution in the vials must be discarded.
Inspect the Benlysta solution visually for particulate matter and discoloration prior to administration. Discard the solution if any particulate matter or discoloration is observed.
The reconstituted solution, if not used immediately, should be protected from direct sunlight and stored refrigerated at 2-8°C. Solutions diluted in normal saline, half normal saline, or lactated Ringer's solution may be stored at 2-8°C or room temperature.
Benlysta does not contain a preservative and is for single use in one patient only. Therefore, it is recommended that the diluted solution be used as soon as possible after preparation. The total time from reconstitution of Benlysta to completion of infusion should not exceed 8 hours. Any unused solution remaining after this time should be discarded.

Administration.

Benlysta is infused over a 1 hour period.
Benlysta should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of Benlysta with other agents.
No incompatibilities between Benlysta and polyvinylchloride or polyolefin bags have been observed.
Solution for subcutaneous injection. Benlysta does not contain a preservative and is for single use in one patient only. The pre-filled syringe and pre-filled pen should be used once only and then discarded.

4.3 Contraindications

Benlysta is contraindicated in patients who have demonstrated anaphylaxis to belimumab or to any of the excipients (see Section 2 Qualitative and Quantitative Composition).

4.4 Special Warnings and Precautions for Use

Benlysta has not been studied in the following patient groups: severe active central nervous system lupus; HIV; a history of, or current, hepatitis B or C; hypogammaglobulinaemia (IgG < 400 mg/dL) or IgA deficiency (IgA < 10 mg/dL); a history of major organ transplant or hematopoietic stem/ cell/ marrow transplant or renal transplant.

Concomitant use with B cell targeted therapy.

Available data do not support the safety and efficacy of rituximab co-administered with Benlysta in patients with SLE. The safety and efficacy of Benlysta in combination with other B cell targeted therapy have not been established. Caution should be exercised if belimumab is co-administered with other B-cell targeted therapy.

Infusion or injection-related systemic reactions and hypersensitivity.

As with all protein products, administration of Benlysta may result in infusion or injection-related systemic and hypersensitivity reactions, which can be severe, or fatal. In the event of a severe reaction, Benlysta administration must be interrupted and appropriate medical therapy administered (see Section 4.2 Dose and Method of Administration). Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk (see Section 4.8 Adverse Effects (Undesirable Effects)).
In clinical trials, serious infusion and hypersensitivity reactions affected less than 1% of patients, and included anaphylactic reaction, bradycardia, hypotension, angioedema, and dyspnoea. Infusion or injection-related systemic and hypersensitivity reactions occurred more frequently with the first two doses and tended to decrease with subsequent doses. Delay in the onset of acute hypersensitivity reactions has been observed. Patients treated with belimumab should be made aware of the potential risk, the signs and symptoms of such reactions, and the importance of immediately seeking medical attention. Delayed type, nonacute hypersensitivity reactions may also occur and include symptoms such as rash, nausea, fatigue, myalgia, headache and facial oedema.

Serious infections.

Severe infections, including fatal cases, have been reported in SLE patients receiving immunosuppressant therapy, including Benlysta (see Section 4.8 Adverse Effects (Undesirable Effects)). The mechanism of action of Benlysta may increase the risk for the development of serious and fatal infections. In controlled clinical studies, fatal infections such as pneumonia and sepsis were found to occur more frequently in patients receiving belimumab compared with placebo, while the incidence of serious infections was similar across the belimumab and placebo groups (see Section 4.8 Adverse Effects (Undesirable Effects)). Benlysta should not be initiated in patients with active serious infections (including serious chronic infections). Patients who develop an infection while undergoing treatment with Benlysta should be monitored closely, and consideration should be given to stopping immunosuppressant therapy. Physicians should exercise caution when considering the use of Benlysta in patients with recurrent, severe or chronic infections. The risk of using Benlysta in patients with active or latent tuberculosis is unknown.

Progressive multifocal leukoencephalopathy (PML).

Progressive multifocal leukoencephalopathy (PML) resulting in neurological deficits, including fatal cases, has been reported in SLE patients receiving immunosuppressant pharmacotherapy, including Benlysta. A diagnosis of PML should be considered in any patient presenting with new onset or deteriorating neurological signs and symptoms. The patient should be referred to a neurologist or other appropriate specialist for evaluation as clinically indicated. If PML is suspected, immunosuppressant therapy, including Benlysta, must be suspended until PML has been excluded. If PML is confirmed, immunosuppressant therapy, including belimumab, must be discontinued.

Immunisation.

Live vaccines should not be given concurrently with Benlysta as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving Benlysta. Because of its mechanism of action, Benlysta may interfere with the response to immunisations. However, in a study evaluating the response to a 23-valent pneumococcal vaccine, overall immune responses to the different serotypes were similar in SLE patients receiving Benlysta compared with those not receiving treatment at the time of vaccination. Limited data suggest that Benlysta does not significantly affect the ability to maintain a protective immune response to immunisations received prior to administration of Benlysta.

Risk of malignancies.

As with other immunomodulating agents, the mechanism of action of Benlysta may increase the potential for the development of malignancies. Caution should be exercised when considering belimumab therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop malignancy. In the intravenous clinical studies for SLE clinical trials, there was no difference in the rate of malignancies between Benlysta treated and placebo treated groups. In the controlled clinical trials, malignancies (including nonmelanoma skin cancers) were reported in 0.4% of patients receiving Benlysta and 0.4% of patients receiving placebo. In the controlled clinical trials, malignancies, excluding nonmelanoma skin cancers, were observed in 0.2% (3/1458) and 0.3% (2/675) of patients receiving Benlysta and placebo, respectively. In the intravenous lupus nephritis clinical trial, 3 subjects (1.3%) in belimumab group (during on-treatment phase) experienced malignancies and no malignancies were reported in the placebo group. Patients with malignant neoplasm within the last 5 years have not been studied, with the exception of those with basal or squamous cell cancers of the skin, or cancer of the uterine cervix, that has been fully excised or adequately treated.

Depression and suicidality.

In controlled clinical intravenous and subcutaneous studies, psychiatric disorders (depression, suicidal ideation and behaviour) have been reported more frequently in patients receiving Benlysta (see Section 4.8 Adverse Effects (Undesirable Effects)). Physicians should carefully assess the risk of depression and suicide considering the patient's medical history and current psychiatric status before treatment with belimumab and continue to monitor patients during treatment. Physicians should advise patients (and caregivers where appropriate) to contact their healthcare professional about new or worsening psychiatric symptoms. The risk and benefit of continued treatment with belimumab should be carefully assessed for patients who develop such symptoms.

Mortality.

There were more deaths reported with Benlysta than with placebo during the controlled period of the intravenous clinical trials. Out of 2133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo controlled, double blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the placebo, Benlysta 1 mg/kg, Benlysta 4 mg/kg, and Benlysta 10 mg/kg groups, respectively. No single cause of death predominated. Aetiologies included infection, cardiovascular disease and suicide.
In the controlled trial of Benlysta administered subcutaneously (N = 836), a total of 5 deaths occurred during the placebo-controlled, double-blind treatment period (0.7% [2/280] of patients receiving placebo and 0.5% [3/556] of patients receiving Benlysta). Infection was the most common cause of death.
The physicians should discuss this imbalance with their patients prior to initiating therapy.

Use in hepatic impairment.

No formal studies were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. IgG1 molecules such as belimumab are catabolised by widely distributed proteolytic enzymes, which are not restricted to hepatic tissue; therefore, changes in hepatic function are unlikely to have any effect on the elimination of belimumab.

Use in renal impairment.

No formal studies were conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. During clinical development, belimumab was studied in a limited number of SLE patients with renal impairment (creatinine clearance < 60 mL/min, including a small number with creatinine clearance < 30 mL/min). Although proteinuria (≥ 2 g/day) increased belimumab clearance, and decreases in creatinine clearance decreased belimumab clearance, these effects were within the expected range of variability. Therefore, no dose adjustment is recommended for patients with renal impairment. Caution is however recommended in patients with severe renal impairment due to the limited data available (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Use in the elderly.

No substantial differences were seen in safety and efficacy related to age (see Section 4.2 Dose and Method of Administration). However, there is insufficient experience in this age group to draw firm conclusions.

Paediatric use.

The safety and efficacy of Benlysta in children below 18 years of age have not yet been established. No data are available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No in vivo interaction studies have been performed. The formation of some CYP450 enzymes is suppressed by increased levels of certain cytokines during chronic inflammation. It is not known if belimumab could be an indirect modulator of such cytokines. A risk for indirect reduction of CYP activity by belimumab cannot be excluded. On initiation or discontinuation of belimumab, therapeutic monitoring should be considered for patients being treated with CYP substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g. warfarin).
In clinical trials of patients with SLE, Benlysta was administered concomitantly with other drugs, including corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, cyclophosphamide, methotrexate, and mycophenolate), angiotensin pathway antihypertensives, HMG-CoA reductase inhibitors (statins), and NSAIDs without evidence of a clinically meaningful effect of these concomitant medications on belimumab pharmacokinetics.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effects of Benlysta on human fertility. Effects on male and female fertility have not been evaluated in animal studies.
(Category C)
There are a limited amount of data from the use of Benlysta in pregnant women. Reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab 150 mg/kg by intravenous infusion (approximately 9 times the anticipated maximum human clinical exposure) every 2 weeks for up to 21 weeks, and Benlysta treatment was not associated with direct or indirect harmful effects with respect to maternal toxicity, developmental toxicity, or teratogenicity. Treatment related findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of IgM in infant monkeys. B cell numbers recovered after the cessation of belimumab treatment by about 1 year postpartum in adult monkeys and by 3 months of life in infant monkeys; IgM levels in infants exposed to belimumab in utero recovered by 6 months of age. Foetal deaths were observed in 14%, 24% and 15% of pregnant females monkeys in the 0, 5 and 150 mg/kg groups, respectively. Infant deaths occurred with an incidence of 0%, 8% and 5%. The cause of foetal and infant deaths in monkeys is not known. The relevance of these findings to humans is not known.
Benlysta should not be used during pregnancy unless clearly necessary.
Women of childbearing potential must use effective contraception during Benlysta treatment and for at least 4 months after the last treatment.
If a woman treated with Benlysta gives birth to a child, monitor infants of treated mothers for B-cell reduction and depending upon the results, consider delaying infant vaccination with live viral vaccines. B-cell reduction in infants may also interfere with the response to immunisations (see Section 4.4 Special Warnings and Precautions for Use).
 The safety of Benlysta for use during lactation has not been established. It is unknown whether Benlysta is excreted in human milk or is absorbed systemically after ingestion. However, belimumab was detected in the milk from female cynomolgus monkeys administered 150 mg/kg every 2 weeks.
It is recommended that a decision should be made about Benlysta therapy in breast-feeding mothers, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother, and any potential adverse effects on the breastfed child from Benlysta or from the underlying maternal condition.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Summary of safety profile.

The safety of Benlysta in patients with SLE has been evaluated in three pre-registration placebo-controlled intravenous studies and one subsequent regional placebo-controlled intravenous study, two post-marketing placebo-controlled intravenous studies, and one placebo-controlled subcutaneous study; the safety in patients with active lupus nephritis has been evaluated in one placebo-controlled intravenous study.
The data described below reflect exposure in 674 patients with SLE from the three pre-registration clinical studies and 470 patients in the subsequent placebo-controlled study administered Benlysta intravenously (10 mg/kg over a 1 hour period on days 0, 14, 28, and then every 28 days up to 52 weeks), and 556 patients with SLE administered Benlysta subcutaneously (200 mg once weekly up to 52 weeks. The safety data presented include data beyond Week 52 in some patients with SLE. The data reflect additional exposure in 224 patients with active lupus nephritis who received Benlysta intravenously (10 mg/kg for up to 104 weeks). Data from post-marketing reports are also included.
The majority of patients were also receiving one or more of the following concomitant treatments for SLE: corticosteroids, immunomodulatory agents, antimalarials, nonsteroidal anti-inflammatory drugs.
The following have been observed with Benlysta and are discussed in detail (see Section 4.4 Special Warnings and Precautions for Use): mortality, serious infections, infusion or injection-related systemic reactions and hypersensitivity, PML, depression, malignancy.
Adverse reactions were reported in the majority of Benlysta-treated and placebo-treated patients. The most frequently reported adverse reactions (≥ 5% of patients with SLE treated with Benlysta plus standard of care and at a rate ≥ 1% greater than placebo) were viral upper respiratory tract infections, bronchitis, and diarrhoea. The proportion of patients who discontinued treatment due to adverse reactions was 7% for Benlysta-treated patients and 8% for placebo-treated patients.

Tabulated summary of adverse reactions.

Adverse reactions are listed in Table 1 by MedDRA body system organ class and by frequency. The frequency categories used are: very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1000 to < 1/100.

Description of selected adverse reactions.

Infusion or injection-related systemic reactions and hypersensitivity.

Infusion or injection-related systemic reactions and hypersensitivity were generally observed on the day of administration, but acute hypersensitivity reactions may also occur several days after dosing. Patients with a history of multiple drug allergies or significant hypersensitivity reactions may be at increased risk.
The incidence of infusion reactions and hypersensitivity reactions after intravenous administration occurring within 3 days of an infusion was 12% in the group receiving Benlysta and 10% in the group receiving placebo, with 1.2% and 0.3%, respectively, requiring permanent treatment discontinuation.
Delay in the onset of acute hypersensitivity reactions for several hours after infusion, and recurrence of clinically significant reactions after initial resolution of symptoms following appropriate treatment, have been observed. Delayed-type, non-acute hypersensitivity reactions have also been observed and included symptoms such as rash, nausea, fatigue, myalgia, headache, and facial oedema.
The incidence of post-injection systemic reactions and hypersensitivity reactions occurring within 3 days of subcutaneous administration was 7% in the group receiving Benlysta and 9% in the group receiving placebo. In the subcutaneous SLE clinical study, clinically significant hypersensitivity reactions associated with Benlysta and requiring permanent treatment discontinuation were reported in 0.2% of patients and in no patients receiving placebo.

Infections.

In the three intravenous SLE pre-registration clinical studies, the overall incidence of infections was 70% in the group receiving Benlysta and 67% in the group receiving placebo. Infections occurring in at least 3% of patients receiving Benlysta and at least 1% more frequently than patients receiving placebo were nasopharyngitis, bronchitis, pharyngitis, cystitis, and gastroenteritis viral. Serious infections occurred in 5% of patients receiving either Benlysta or placebo; serious opportunistic infections accounted for < 1% and 0% of these, respectively. Some infections were severe or fatal.
In a randomised (1:1), double-blind, placebo-controlled, 52-week, post-marketing safety study (BEL115467) which assessed mortality and specific adverse events in adults, serious infections occurred in 3.7% of patients receiving belimumab 10 mg/kg intravenously and in 4.1% of patients receiving placebo. Fatal infections occurred in 0.45% (9/2002) of patients receiving belimumab and in 0.15% (3/2001) of patients receiving placebo, while the incidence of all-cause mortality was 0.50% (10/2002) in patients receiving belimumab and 0.40% (8/2001) in patients receiving placebo.
In the subcutaneous SLE clinical study, the overall incidence of infections was 55% in the group receiving Benlysta and 57% in the group receiving placebo. Only bacterial urinary tract infection occurred in at least 3% of patients receiving Benlysta and at least 1% more frequently than patients receiving placebo. Serious infections occurred in 4% of patients receiving Benlysta and 5% of patients receiving placebo; serious opportunistic infections accounted for 0.2% and 0% of these, respectively. Some infections were severe or fatal.
In the lupus nephritis study, patients were receiving a background of standard therapy (see Clinical trials) and the overall incidence of infections was 82% in patients receiving Benlysta compared with 76% in patients receiving placebo. Serious infections occurred in 13.8% of patients receiving belimumab and in 17.0% of patients receiving placebo. Fatal infections occurred in 0.9% (2/224) of patients receiving belimumab and in 0.9% (2/224) of patients receiving placebo.

Psychiatric disorders.

In the three pre-registration SLE intravenous clinical studies, serious psychiatric events were reported in 1.2% (8/674) of patients receiving belimumab 10 mg/kg and 0.4% (3/675) of patients receiving placebo. Serious depression was reported in 0.6% (4/674) of patients receiving belimumab 10 mg/kg and 0.3% (2/675) of patients receiving placebo. One suicide was reported in a patient receiving belimumab 10 mg/kg (and one was reported in a patient receiving belimumab 1 mg/kg); there were no reports in patients receiving placebo.
In a large post-marketing SLE study, serious psychiatric events were reported in 1.0% (20/2002) of patients receiving belimumab and 0.3% (6/2001) of patients receiving placebo. Serious depression was reported in 0.3% (7/2002) of patients receiving belimumab and < 0.1% (1/2001) receiving placebo. The overall incidence of serious suicidal ideation or behaviour or self-injury without suicidal intent was 0.7% (15/2002) in the belimumab group and 0.2% (5/2001) in the placebo group. On the Columbia-Suicide Severity Rating Scale (C-SSRS), 2.4% (48/1974) of patients receiving belimumab reported suicidal ideation or behaviour compared with 2.0% (39/1988) of patients receiving placebo. No suicide was reported in either group.
The SLE intravenous studies above did not exclude patients with a history of psychiatric disorders.
In the subcutaneous clinical study, which excluded patients with a history of psychiatric disorders, serious psychiatric events were reported in 0.2% (1/556) of patients receiving belimumab and in no patients receiving placebo. There were no serious depression-related events or suicides reported in either group. On the C-SSRS, 1.3% (7/554) of patients receiving belimumab reported suicidal ideation or behaviour and 0.7% (2/277) of patients receiving placebo.

Injection site reactions.

In the subcutaneous SLE clinical study, the frequency of injection site reactions was 6.1% (34/556) and 2.5% (7/280) for patients receiving Benlysta and placebo, respectively. These injection site reactions (most commonly pain, erythema, hematoma, pruritus, and induration) were mild to moderate in severity. The majority did not necessitate drug discontinuation.

Adverse events.

The most common (> 10% in any treatment group) adverse events by MedDRA preferred term reported in the intravenous studies are shown in Table 2.
Adverse events occurring in at least 3% of patients treated with Benlysta 10 mg/kg (intravenous administration) plus standard of care and at least 1% more frequently than in patients receiving placebo plus standard of care in 3 controlled SLE studies are shown in Table 3.
Adverse events occurring in at least 5% of patients treated with Benlysta 10 mg/kg (intravenous administration) plus standard of care and at least 1% more frequently than in patients receiving placebo plus standard of care in Benlysta LN study in Table 4.
The adverse event summary for Benlysta intravenous administration and subcutaneous administration compared to placebo treated patients is shown in Table 5. The adverse event profile was consistent between the different routes of administration.
The adverse event summary for Benlysta administration compared to placebo treated patients in the LN study is shown in Table 6.

Reporting suspected adverse effects.

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

4.9 Overdose

There is limited clinical experience with overdosage of Benlysta. Adverse reactions reported in association with cases of overdose have been consistent with those expected for Benlysta.
Two doses up to 20 mg/kg administered 21 days apart by intravenous infusion have been given to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg.
In the case of inadvertent overdose, patients should be carefully observed and supportive care administered, as appropriate.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

B-lymphocyte stimulator (BLyS, also referred to as BAFF and TNFSF13), a member of the tumour necrosis factor (TNF) ligand family, inhibits B cell apoptosis and stimulates the differentiation of B cells into immunoglobulin producing plasma cells. BLyS is overexpressed in patients with SLE. There is a strong association between SLE disease activity (as assessed by the Safety of Estrogen in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index [SELENA-SLEDAI]) and plasma BLyS levels.
Belimumab is a fully human IgG1λ monoclonal antibody that specifically binds to soluble human BLyS and inhibits its biological activity. Belimumab does not bind B cells directly, but by binding and neutralising BLyS, belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin producing plasma cells.

Pharmacodynamic effects.

Powder for intravenous infusion. In adult patients with SLE, reductions in elevated levels of serum IgG and in anti-dsDNA antibodies were observed as early as week 8 and continued to week 52. In patients with hypergammaglobulinemia at baseline, normalization of IgG levels was observed by week 52 in 49% and 20% of patients receiving belimumab and placebo, respectively. In patients with anti-dsDNA antibodies at baseline, reductions in patients receiving belimumab were evident as early as week 8, and by week 52, 16% of patients treated with belimumab had converted to anti-dsDNA negative compared with 7% of the patients receiving placebo.
In patients with SLE with low complement levels at baseline, belimumab treatment resulted in increases in complement C3 and C4 which were seen as early as week 4 and continued over time. By week 52, levels of C3 and C4 had normalized in 38% and 44% of patients receiving belimumab compared with 17% and 19% of patients receiving placebo.
The target of belimumab, BLyS, is a critical cytokine for B cell survival, differentiation, and proliferation. Belimumab significantly reduced circulating B cells, naïve, activated, plasma, and the SLE B cell subset at week 52. Reductions in naïve, plasma and short-lived plasma cells as well as the SLE B cell subset were observed as early as week 8. Memory cells increased initially and slowly declined toward baseline levels by week 52.
Study BEL112233, a long-term uncontrolled extension study of BLISS-76 (see Clinical trials), enrolled 268 patients. B cells and IgG levels were followed for 7 years or longer with ongoing belimumab treatment in varying numbers (n) of subjects depending on the pharmacodynamic measure. Sustained decreases relative to baseline levels of BLISS-76 in various B cell subsets were observed leading to median reductions of 87% in naive B cells (n = 107), 67% in memory B cells (n = 106), 99% in activated B cells (n = 116), and 92% in plasma cells (n = 118) after more than 7 years of treatment. After about 7 years, a 28% median reduction in IgG levels (n = 150) was observed. Throughout the period of follow-up, 8 out of 268 participants (3.0%) recorded IgG levels below 400 mg/dL and 1.6% (2/129) recorded a decrease in IgG levels to below 400 mg/dL in the 7th year. Over the course of the study, the reported incidence of AEs generally remained stable or declined.

Lupus nephritis study.

In patients with lupus nephritis, following treatment with belimumab or placebo, there was an increase in serum IgG levels which was associated with decreased proteinuria. Relative to placebo, smaller increases in serum IgG levels were observed in the belimumab group as expected with the known mechanism of belimumab. At Week 104, the median percent increase from baseline in IgG was 17% for belimumab and 37% for placebo. Reductions in autoantibodies, increases in complement, and reductions in circulating total B cells and B-cell subsets observed were consistent with the SLE studies.
Solution for subcutaneous injection.

SLE studies.

Reductions in elevated levels of serum IgG and in anti-dsDNA antibodies were observed as early as week 8 and week 4, respectively, and continued to week 52. Median IgG levels at week 52 were reduced by 11% in patients receiving belimumab compared with an increase of 0.7% in patients receiving placebo. In patients with anti-dsDNA antibodies at baseline, median anti-dsDNA antibodies levels at week 52 were reduced by 56% in patients receiving belimumab compared with 41% in patients receiving placebo. In patients with anti-dsDNA antibodies at baseline, by week 52, 18% of patients treated with belimumab had converted to anti-dsDNA negative compared with 15% of the patients receiving placebo.
In patients with low complement levels at baseline, belimumab treatment resulted in increases in complement C3 and C4 which were seen as early as week 12 and continued to week 52. By week 52, levels of C3 and C4 had normalised in 42% and 53% of patients receiving belimumab compared with 21% and 20% of patients receiving placebo.
The target of belimumab, BLyS, is a critical cytokine for B cell survival, differentiation, and proliferation. Belimumab significantly reduced circulating B cells, transitional, naïve, plasma, and the SLE B cell subset at week 52. Reductions in naïve and transitional B cells, as well as the SLE B cell subset were observed as early as week 8. Memory cells increased initially and slowly declined toward baseline levels by week 52.

Immunogenicity.

In the two phase III SLE studies with belimumab administered intravenously, 4 out of 563 (0.7%) patients in the 10 mg/kg group and 27 out of 559 (4.8%) patients in the 1 mg/kg group developed persistent antibelimumab antibodies. The reported frequency for the 10 mg/kg group may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations.
Neutralising antibodies were detected in 3 patients receiving belimumab 1 mg/kg intravenously. However, the presence of antibelimumab antibodies was relatively uncommon in patients with belimumab administered intravenously and no definitive conclusions can be drawn regarding the effect of immunogenicity on belimumab pharmacokinetics due to low numbers of antibelimumab antibody positive subjects.
Serum samples from more than 550 patients with SLE were tested; no anti-belimumab antibodies were detected during or after treatment with belimumab 200 mg administered subcutaneously.
In a Phase III study with belimumab 10 mg/kg administered intravenously to adult patients with lupus nephritis, none of the 224 patients developed anti-belimumab antibodies.

Clinical trials.

Powder for intravenous infusion.

SLE.

Phase II study.

The efficacy of belimumab administered intravenously in the treatment of SLE was evaluated in a randomised, placebo controlled phase II study in patients with a SELENA-SLEDAI score of > 4 at baseline and a history of autoantibodies (patients were not required to be autoantibody positive; 28% of the population was autoantibody negative at baseline). Patients with severe active lupus nephritis and severe active CNS lupus were excluded. Patients were receiving a stable standard of care SLE treatment regimen comprising any of the following (alone or in combination): corticosteroids, antimalarials, NSAIDs, and immunosuppressives. These medications could be changed during the study as clinically indicated. Other biological agents and intravenous cyclophosphamide were not permitted. This study enrolled 449 patients and evaluated doses of 1, 4, and 10 mg/kg belimumab plus standard of care compared with placebo plus standard of care. The coprimary endpoints of this study, percent change in SELENA-SLEDAI score at week 24 and time to first mild, moderate or severe flare over 52 weeks, were not met. However, post hoc analysis identified a large subgroup of patients (72%), who were autoantibody positive (ANA or anti-dsDNA), in whom belimumab appeared to offer benefit. The results of this study informed the design of the phase 3 program including the patient population, dose selection and concomitant medication controls.

Phase III studies.

The efficacy of Benlysta was evaluated in two randomised, double blind, placebo controlled phase III studies in 1,684 patients with a clinical diagnosis of SLE according to the American College of Rheumatology (ACR) classification criteria. Eligible patients had active SLE disease, defined as a SELENA-SLEDAI score ≥ 6 and positive antinuclear antibody (ANA or anti-dsDNA) test results (ANA titre ≥ 1:80 and/or a positive anti-dsDNA [≥ 30 units/mL]) at screening. Patients were on a stable SLE treatment regimen (standard of care) consisting of any of the following (alone or in combination): corticosteroids, antimalarials, NSAIDs or other immunosuppressives. Patients were excluded from the study if they had severe active central nervous system lupus or severe active lupus nephritis, had ever received treatment with any B cell targeted therapy, if they had received another biological investigational agent in the previous year, or if they had a positive response to testing for HIV antibody, hepatitis B surface antigen, or hepatitis C antibody. The two studies were similar in design except that BLISS-76 was a 76 week study and BLISS-52 was a 52 week study. Both studies had 52 week primary endpoints.
BLISS-76 (HGS1006-C1057) was conducted primarily in North America and Western Europe. The racial distribution was 70% white/ Caucasian, 14% black/ African American, 13% Alaska native or American Indian, and 3% Asian. Background medications included corticosteroids (76%), immunosuppressives (56%), and antimalarials (63%).
BLISS-52 (HGS1006-C1056) was conducted in South America, Eastern Europe, Asia, and Australia. The racial distribution was 38% Asian, 26% white/ Caucasian, 32% Alaska native or American Indian, and 4% black/ African American. Background medications included corticosteroids (96%), immunosuppressives (42%), and antimalarials (67%).
Patient median age across both studies was 37 years (range: 18 to 73 years), and the majority (94%) were female. At screening, patients were stratified by disease severity based on their SELENA-SLEDAI score (< 9 vs ≥ 10), proteinuria level (< 2 g per 24 hr vs ≥ 2 g per 24 hr), and race, and then randomly assigned to receive Benlysta 1 mg/kg, Benlysta 10 mg/kg, or placebo in addition to standard of care. The patients were administered study medication intravenously over a 1 hour period on days 0, 14, 28, and then every 28 days for 48 or 72 weeks.
The primary efficacy endpoint was a composite endpoint (SLE Responder Index) that defined response as meeting each of the following criteria at week 52 compared with baseline:
≥ 4 point reduction in the SELENA-SLEDAI score; and
no new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores; and
no worsening (> 0.30 point increase) in Physician's Global Assessment score (PGA).
The SLE Responder Index uses the SELENA-SLEDAI score as an objective measure of reduction in global disease activity; the BILAG index to ensure no significant worsening in any specific organ system; and the PGA to ensure that improvements in disease activity are not achieved at the expense of the patient's overall condition.
Benlysta produced significant improvements in the SLE Responder Index as well as in the individual component SELENA-SLEDAI score in both studies, see Table 7.
In a pooled analysis of the two studies, the percentage of patients receiving > 7.5 mg/day prednisone (or equivalent) at baseline whose average corticosteroid dose was reduced by at least 25% from baseline to a dose equivalent to prednisone ≤ 7.5 mg/day during weeks 40 through 52, was 17.9% (58/324) in the group receiving Benlysta and 12.3% (39/318) in the group receiving placebo (P = 0.0451).
Flares in SLE were defined by the Modified SELENA-SLEDAI SLE Flare Index where the modification excludes severe flares that are triggered only by an increase of SELENA-SLEDAI score to > 12. The median time to the first flare was delayed in the pooled group receiving Benlysta compared to the group receiving placebo (hazard ratio = 0.84, 95% CI (0.74, 0.96), P = 0.012). The risk of severe flares was also reduced by 36% over the 52 weeks of observation in the group receiving Benlysta relative to the group receiving placebo (hazard ratio = 0.64, 95% CI (0.49, 0.84), P = 0.0011).
There were too few males, patients over 65 years of age, or black/ African American patients enrolled in the controlled clinical trials to draw meaningful conclusions about the effects of gender, age, or race on clinical outcomes.
At week 76 in study 2, the SRI response rate with belimumab was not significantly different from that of placebo (39% and 32% respectively).
Post hoc analysis has identified high responding subgroups such as those patients with low complement and positive anti-dsDNA at baseline, see Table 8.

Lupus nephritis.

The efficacy and safety of belimumab 10 mg/kg administered intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days, were evaluated in a 104-week randomised (1:1), double-blind, placebo-controlled, Phase III study (BEL114054) in 448 patients with active lupus nephritis. The patients had a clinical diagnosis of SLE according to ACR classification criteria, biopsy-proven lupus nephritis Class III(A or A/C), IV(A or A/C), and/or V and had active renal disease at screening requiring standard therapy. Patients with Class III(C), IV-S(C), and IV-G(C) disease were excluded.
Standard therapy included corticosteroids, 0 to 3 intravenous administrations of methylprednisolone (500 to 1000 mg per administration), followed by oral prednisone 0.5 to 1 mg/kg/day with a total daily dose ≤ 60 mg/day and tapered to ≤ 10 mg/day by Week 24, with:
mycophenolate mofetil 1 to 3 g/day orally or mycophenolate sodium 720 to 2160 mg/day orally for induction and maintenance; or
cyclophosphamide 500 mg intravenously every 2 weeks for 6 infusions for induction followed by azathioprine orally at a target dose of 2 mg/kg/day for maintenance.
This study was conducted in Asia, North America, South America, and Europe. Patient median age was 31 years (range: 18 to 77 years); the majority (88%) of patients were female.
The primary efficacy endpoint was Primary Efficacy Renal Response (PERR) at Week 104 defined as a response at Week 100 confirmed by a repeat measurement at Week 104 of the following parameters: urinary protein:creatinine ratio (uPCR) ≤ 0.7 and estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 or no decrease in eGFR of > 20% from pre-flare value.
The major secondary endpoints included:
Complete Renal Response (CRR) defined as a response at Week 100 confirmed by a repeat measurement at Week 104 of the following parameters: uPCR < 0.5 and eGFR ≥ 90 mL/min/1.73 m2 or no decrease in eGFR of > 10% from pre-flare value.
PERR at Week 52.
Time to renal-related event or death (renal-related event defined as first event of end-stage renal disease, doubling of serum creatinine, renal worsening [defined as increased proteinuria, and/or impaired renal function], or receipt of renal disease-related prohibited therapy).
For PERR and CRR endpoints, steroid treatment had to be reduced to ≤ 10 mg/day from Week 24 to be considered a responder. For these endpoints, patients who discontinued treatment early were considered non-responders.
The proportion of patients achieving PERR at Week 104 was significantly higher in patients receiving belimumab compared with placebo. The major secondary endpoints also showed significant improvement with belimumab compared with placebo (Table 9).
A numerically greater percentage of patients receiving belimumab achieved PERR beginning at Week 24 compared with placebo, and this treatment difference was maintained through to Week 104. Beginning at Week 12, a numerically greater percentage of patients receiving belimumab achieved CRR compared with placebo and the numerical difference was maintained through to Week 104 (Figure 1).
In descriptive subgroup analyses, key efficacy endpoints (PERR and CRR) were examined by induction regimen (mycophenolate or cyclophosphamide) and biopsy class (Class III or IV, Class III + V or Class IV + V, or Class V) (Figure 2).
Solution for subcutaneous injection. The efficacy of belimumab administered subcutaneously was evaluated in a randomised, double blind, placebo controlled, 52-week Phase III study (HGS1006-C1115; BEL112341) in 836 patients with a clinical diagnosis of SLE according to the American College of Rheumatology classification criteria. Eligible patients had active SLE disease, defined as a SELENA-SLEDAI score greater than or equal to 8 and positive anti-nuclear antibody (ANA or anti-dsDNA) test results (ANA titre greater than or equal to 1:80 and/or anti-dsDNA greater than or equal to 30 units/mL) at screening. Patients were on a stable SLE treatment regimen (standard of care) consisting of any of the following (alone or in combination): corticosteroids, anti-malarials, non-steroidal anti-inflammatory medications or other immunosuppressives. Patients were excluded from the study if they had severe active central nervous system lupus or severe active lupus nephritis, if they had received another biological investigational agent in the previous 3 months, or if they had a positive response to testing for HIV antibody, hepatitis B surface antigen, or hepatitis C antibody.
This study was conducted in the US, South America, Europe and Asia. Patient median age was 37 years (range: 18 to 77 years), and the majority (94%) were female. Patients were randomised in a 2:1 ratio to receive belimumab 200 mg or placebo subcutaneously once weekly for 52 Weeks.
The primary efficacy endpoint was a composite endpoint (SLE Responder Index) that defined response as meeting each of the following criteria at Week 52 compared with baseline:
greater than or equal to 4 point reduction in the SELENA-SLEDAI score; and
no new British Isles Lupus Assessment Group (BILAG) A organ domain score or two new BILAG B organ domain scores; and
no worsening (less than 0.30 point increase) in Physician's Global Assessment score (PGA).
The SLE Responder Index uses the SELENA-SLEDAI score as an objective measure of reduction in global disease activity; the BILAG index to ensure no significant worsening in any specific organ system; and the PGA to ensure that improvements in disease activity are not achieved at the expense of the patient's overall condition.
Secondary efficacy endpoints included time to first severe flare (as measured by the modified SELENA-SLEDAI SLE Flare Index) and the proportion of patients whose average prednisone dose has been reduced by ≥ 25% from baseline to ≤ 7.5 mg/day during Weeks 40 through 52. A health outcomes endpoint included mean change in the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale score at Week 52.
Belimumab produced significant improvements in the SLE Responder Index as well as in the individual component SELENA-SLEDAI score, see Table 10.
The differences between the treatment groups were apparent by week 16 and sustained through week 52 (Figure 3).
A severe flare in SLE was defined by the modified SELENA-SLEDAI SLE Flare Index where the modification excludes severe flares that are triggered only by an increase of the SELENA-SLEDAI score to greater than 12. The risk of severe flares was reduced by 49% during the 52 weeks of observation in the group receiving belimumab compared with the group receiving placebo (hazard ratio = 0.51; P = 0.0004). Of the patients experiencing a severe flare, the median time to the first severe flare was delayed in patient receiving belimumab compared with placebo (171 days vs. 118 days).
At baseline, 60% of patients were receiving prednisone at doses > 7.5 mg/day (or equivalent). Among these patients, 18.2% of patients receiving belimumab reduced their average prednisone dose by at least 25% to ≤ 7.5 mg/day during weeks 40 through 52 compared to 11.9% of patients on placebo. However, the difference was not statistically significant (P = 0.0732).
Belimumab demonstrated improvement in fatigue compared with placebo as measured by the FACIT-Fatigue Scale score. The mean improvement in FACIT-Fatigue Scale score from baseline to week 52 was significantly greater with belimumab (4.4) compared with placebo (2.7); (P = 0.0130). Among patients receiving belimumab, 44.4% of patients experienced improvement in FACIT-Fatigue Scale score exceeding the minimally important clinical difference (improvement greater than or equal to 4) at week 52 compared with 36.1% of patients receiving placebo (P = 0.0245).
Subgroup analysis of the primary endpoint demonstrated that the greatest benefit was observed in patients with higher disease activity at baseline, including patients with SELENA-SLEDAI scores greater than or equal to 10 or patients requiring steroids to control their disease or patients with low complement levels.
An additional, previously identified serologically active group, those patients with low complement and positive anti-dsDNA at baseline, also demonstrated a greater relative response, see Table 11 for results of this example of a higher disease activity group.

5.2 Pharmacokinetic Properties

SLE studies.

The intravenous pharmacokinetic parameters below are based on population pharmacokinetic analysis using data from SLE patients who received single or multiple IV infusions of belimumab. The pharmacokinetic parameters reported are the geometric means (5th percentile-95th percentile) of the individual pharmacokinetic parameter estimates from 563 patients with SLE who received belimumab 10 mg/kg intravenously (Days 0, 14, 28 and then every 28 days up to 52 weeks) in the two phase III studies.
The subcutaneous pharmacokinetic parameters below are based on population parameter estimates from 661 subjects, comprised of 554 patients with SLE and 107 healthy subjects, who received belimumab 200 mg subcutaneously once weekly.

Absorption.

Following intravenous administration, maximum serum concentrations (Cmax) of belimumab were generally observed at, or shortly after, the end of the infusion. The Cmax was 311 (231-448) microgram/mL at steady-state based on simulating the concentration time profile using the typical parameter values of the population pharmacokinetic model.
Following subcutaneous administration, the maximum serum concentration (Cmax) of belimumab at steady state was 108 microgram/mL and the time to reach steady-state Cmax after administration (Tmax) was 2.6 days. The bioavailability of belimumab was approximately 74%.

Distribution.

Belimumab was distributed to tissues with an overall volume of distribution of 5.22 (4.31-6.41) L.

Metabolism.

Belimumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by widely distributed proteolytic enzymes. Classical biotransformation studies have not been conducted.

Excretion.

Following intravenous administration, serum belimumab concentrations declined in a biexponential manner, with a distribution half-life of 1.68 (1.35-2.09) days and terminal half-life 18.0 (11.6-28.0) days. The systemic clearance was 232 (134-397) mL/day.
Following subcutaneous administration, belimumab had a terminal half-life of 18.3 days. The distribution half-life was 1.1 days. For subcutaneous administration, the biphasic decline observed with intravenous belimumab was masked by the slow absorption phase. The systemic clearance was 204 mL/day.

Lupus nephritis study.

A population pharmacokinetic analysis was conducted in 224 adult patients with lupus nephritis who received belimumab 10 mg/kg intravenously (Days 0, 14, 28, and then every 28 days up to 104 weeks). In patients with lupus nephritis, due to renal disease activity, belimumab clearance was initially higher than observed in SLE studies; however, after 24 weeks of treatment and throughout the remainder of the study, belimumab clearance and exposure were similar to that observed in adult patients with SLE who received belimumab 10 mg/kg intravenously.
Based on population pharmacokinetic modelling and simulation, the steady-state average concentrations of subcutaneous administration of belimumab 200 mg once weekly in adults with lupus nephritis are predicted to be similar to those observed in adults with lupus nephritis receiving belimumab 10 mg/kg intravenously every 4 weeks.

Transitioning from intravenous to subcutaneous administration.

SLE.

Patients with SLE transitioning from 10 mg/kg intravenously every 4 weeks to 200 mg subcutaneously weekly using a 1 to 4 week switching interval had pre-dose belimumab serum concentrations at their first subcutaneous dose close to their eventual subcutaneous steady-state trough concentration (see Section 4.2 Dose and Method of Administration). Based on simulations with population pharmacokinetic parameters the steady-state average belimumab concentrations for 200 mg subcutaneous every week were similar to 10 mg/kg intravenous every 4 weeks.

Lupus nephritis.

One to 2 weeks after completing the first 2 intravenous doses, patients with lupus nephritis transitioning from 10 mg/kg intravenously to 200 mg subcutaneously weekly, are predicted to have average belimumab serum concentrations similar to patients dosed with 10 mg/kg intravenously every 4 weeks based on population PK simulations (see Section 4.2 Dose and Method of Administration).

Special patient populations.

The following information is based on the population pharmacokinetic analysis.

Elderly.

Belimumab has been studied in a limited number of elderly patients. Age did not affect belimumab exposure in the intravenous and subcutaneous population pharmacokinetic analysis. However, given the small number of subjects 65 years or older (less than 1.6% of the studies population), an effect of age cannot be ruled out conclusively and belimumab should be administered with caution in this age group.

Children and adolescents.

No pharmacokinetic data are available in paediatric patients.

Renal impairment.

No formal studies were conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. During clinical development, belimumab administered intravenously and subcutaneously was studied in a limited number of SLE patients with renal impairment (creatinine clearance < 60 mL/min, including a small number with creatinine clearance < 30 mL/min). Following belimumab administered intravenously, proteinuria (≥ 2 g/day) increased belimumab clearance, and decreases in creatinine clearance decreased belimumab clearance. Similar effects were observed but were not statistically significant for belimumab administered subcutaneously. These effects were within the expected range of variability for belimumab administered intravenously and subcutaneously. Therefore, no dose adjustment is recommended for patients with renal impairment.

Hepatic impairment.

No formal studies were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. IgG1 molecules such as belimumab are catabolised by widely distributed proteolytic enzymes, which are not restricted to hepatic tissue; therefore, changes in hepatic function are unlikely to have any effect on the elimination of belimumab.

Other patient characteristics.

There was no significant effect of gender, race or ethnicity on the pharmacokinetics of belimumab administered intravenously or subcutaneously. The effects of body size on belimumab exposure after intravenous administration are accounted for by weight normalised dosing. The effects of body weight and BMI on belimumab exposure after subcutaneous administration were not considered clinically meaningful. There was no significant impact on efficacy or safety based on weight. Therefore, no dose adjustment is recommended.

5.3 Preclinical Safety Data

Genotoxicity.

As belimumab is a monoclonal antibody, no genotoxicity studies have been conducted.

Carcinogenicity.

The carcinogenic potential of Benlysta has not been investigated.

6 Pharmaceutical Particulars

6.1 List of Excipients

Powder for intravenous infusion.

Benlysta also contains sodium citrate dihydrate, citric acid-monohydrate, sucrose and polysorbate 80.

Solution for subcutaneous injection.

Benlysta also contains arginine hydrochloride, histidine, histidine hydrochloride monohydrate, polysorbate 80, sodium chloride and water for injections.

6.2 Incompatibilities

Benlysta should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of Benlysta with other agents.
No incompatibilities between Benlysta and polyvinylchloride or polyolefin bags have been observed.

6.3 Shelf Life

Powder for intravenous infusion.

Unopened vials.

60 months.

Solution for subcutaneous injection.

36 months.

6.4 Special Precautions for Storage

Powder for intravenous infusion.

Unopened vials.

Store at 2°C to 8°C (Refrigerate. Do not freeze).
Protect from light. Store in the original carton until use.

Reconstituted solution.

After reconstitution with sterile water for injections, the reconstituted solution, if not used immediately, should be protected from direct sunlight, and stored refrigerated at 2-8°C and must be used within 7 hours.

Reconstituted and diluted solution for infusion.

Solutions of Benlysta diluted in normal saline may be stored at 2-8°C or room temperature.
Benlysta does not contain a preservative and is for single use in one patient only. Therefore, it is recommended that the diluted solution be used as soon as possible after preparation. The total time from reconstitution of Benlysta to completion of infusion should not exceed 8 hours. The 8 hour time period includes a 1 hour infusion time plus up to 7 hours either as a reconstituted solution of Benlysta stored protected from direct sunlight and refrigerated at 2° to 8°C or as a solution of Benlysta diluted in 0.9% sodium chloride (normal saline), half normal saline, or lactated Ringer's solution and stored at 2° to 8°C or room temperature. Any unused solution remaining after this time should be discarded.

Solution for subcutaneous injection.

Store at 2°C to 8°C (Refrigerate. Do not freeze).
Protect from light. Store in the original carton until use.
The pre-filled pen or pre-filled syringe must be administered within 12 hours once the pack is opened. Discard if not administered within 12 hours.

6.5 Nature and Contents of Container

Powder for intravenous infusion.

Benlysta is supplied as a lyophilised formulation for infusion in sterile, single-use, Type 1 glass vials, sealed with a siliconised rubber stopper and a flip-off aluminum seal.
Each 5 mL vial delivers 120 mg of Benlysta.
Each 20 mL vial delivers 400 mg of Benlysta.
Benlysta is available in packs of 1 x 5 mL or 1 x 20 mL vials.

Solution for subcutaneous injection.

Pre-filled pen (autoinjector) (single dose).

1 mL siliconised, USP Type I glass syringe with 12.7 mm, 27G, stainless steel needle assembled as a pre-filled pen.

Pre-filled syringe (single dose).

1 mL siliconised, USP Type I glass syringe with 12.7 mm, 27G, stainless steel needle assembled with a needle guard.
Available in packs of 1 or 4 pre-filled pens or syringes.
Each pre-filled syringe and pre-filled pen delivers 200 mg belimumab in 1 mL.
Not all pack sizes may be distributed in Australia.

6.6 Special Precautions for Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Belimumab is a human IgG1λ monoclonal antibody specific for soluble human B-lymphocyte stimulator protein (BLyS). It has a molecular weight of approximately 147 kDa.
Belimumab has a pH of 6.5.
Belimumab is produced by recombinant DNA technology in a mammalian cell expression system.

CAS number.

356547-88-1.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes