Consumer medicine information

Hadlima Pre-filled Syringe 40 mg

Adalimumab

BRAND INFORMATION

Brand name

Hadlima

Active ingredient

Adalimumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Hadlima Pre-filled Syringe 40 mg.

SUMMARY CMI

Hadlima® Pre-filled Syringe 40 mg

Consumer Medicine Information (CMI) summary

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

1. Why am I using Hadlima?

Hadlima contains the active ingredient adalimumab. Hadlima is used to treat various inflammatory conditions.

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

2. What should I know before I use Hadlima?

Do not use if you have ever had an allergic reaction to Hadlima 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 Hadlima? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Hadlima and affect how it works, or Hadlima may interfere with other medicines and affect how they work.

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

4. How do I use Hadlima?

Hadlima is injected under the skin (subcutaneous).

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

5. What should I know while using Hadlima?

Things you should do
  • Remind any doctor or dentist or pharmacist you visit that you are using Hadlima.
  • Keep all your appointments, including for blood tests.
  • Tell your doctor if you develop an infection or you notice new or changed spots on your skin.
  • Tell your doctor if you are scheduled for any vaccines.
Things you should not do
  • Do not stop using this medicine or change the dose unless your doctor tells you to.
Driving or using machines
  • Be careful before you drive or use any machines until you know how Hadlima affects you. The effects on your ability to drive or use machines whilst taking Hadlima are not known.
Drinking alcohol
  • There is no information on the effects of taking Hadlima with alcohol.
Looking after your medicine
  • Store Hadlima in the refrigerator (2°C to 8°C). Do not freeze.
  • Keep syringes in the pack to protect your medicine from light.

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

6. Are there any side effects?

Side effects that require urgent medical attention include: Signs of an allergic reaction, such as chest tightness, difficulty breathing, swelling of face lips and tongue, rash; signs of heart failure, such as shortness of breath on exertion or lying down, swelling of the feet; signs suggesting a blood disorder, such as persistent fever, bruising, bleeding, paleness.

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



FULL CMI

Hadlima® Pre-filled Syringe 40 mg

Active ingredient(s): adalimumab (rch) (a-da-li-mue-mab)

Consumer Medicine Information (CMI)

This leaflet provides important information about using Hadlima. 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 Hadlima.

Where to find information in this leaflet:

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

1. Why am I using Hadlima?

Hadlima contains the active ingredient adalimumab.

Hadlima is used for the treatment of a number of inflammatory diseases:

Rheumatoid arthritis

Rheumatoid arthritis is an inflammatory disease of the joints. Signs and symptoms of rheumatoid arthritis include joint pain, tenderness, swelling and stiffness.

Hadlima is used to reduce the signs and symptoms of moderate to severely active rheumatoid arthritis, as well as to slow down and protect the joints from further damage to help them move more freely.

Your doctor will decide if Hadlima should be used with another medicine called methotrexate, or on its own.

Hadlima can also be used to treat severe, active and progressive rheumatoid arthritis without previous methotrexate treatment.

Polyarticular Juvenile Idiopathic Arthritis (pJIA)

pJIA is an inflammatory disease of the joints. Hadlima is used to reduce the signs and symptoms of moderate to severely active pJIA, in patients 2 years of age and older, when other medicines are not appropriate. Your doctor will decide whether Hadlima should be used with another medicine called methotrexate or used alone.

Enthesitis-related arthritis (ERA)

ERA is an inflammatory disease of the joints and the places where tendons join the bone. Hadlima is used to treat ERA in children.

You may have already been given other medicines to treat your condition. Your doctor has prescribed Hadlima for you as you haven't responded well enough to these medicines.

Psoriatic arthritis (PsA)

PsA is an inflammatory disease of the joints that is usually associated with psoriasis. Signs and symptoms include joint pain, tenderness and swelling. Hadlima is used to reduce the signs and symptoms, of moderate to severely active PsA, as well as to slow down and protect the joints from further damage, to help them move more freely.

You may have already been given other medicines to treat your condition. Your doctor has prescribed Hadlima for you as you haven't responded well enough to these medicines.

Ankylosing spondylitis

Ankylosing spondylitis is an inflammatory disease of the spine. Signs and symptoms of ankylosing spondylitis include back pain and stiffness. Hadlima is used to reduce the signs and symptoms in patients with active disease.

Crohn's Disease

Crohn's disease is an inflammatory disease of the digestive tract. Hadlima is used to treat moderate to severe Crohn's disease in adults and children aged 6 years and over to reduce the signs and symptoms of the disease and to induce and maintain periods where the symptoms are no longer present (remission).

You may have already been given other medicines to treat your condition. Your doctor has prescribed Hadlima for you as you may either have not responded well enough, or you may have lost response or cannot tolerate these medicines.

Ulcerative Colitis

Ulcerative colitis is an inflammatory disease of the large intestine (bowel).

Hadlima is used to treat moderate to severe ulcerative colitis when other medicines are not appropriate.

Psoriasis

Psoriasis is an inflammatory disease of the skin. Plaque psoriasis, the most common form, is a skin condition that causes red, flaky, crusty patches of the skin covered with silvery scales. Plaque psoriasis can also affect nails, causing them to crumble, thicken and lift away from the nail bed which can be painful. Hadlima is used to treat moderate to severe forms of the disease in adults and severe forms in children and adolescents from 4 years of age for whom topical therapy (such as creams, lotions and ointments and phototherapy (also known as light therapy) have either not worked very well, or are not suitable.

Hidradenitis suppurativa (HS)

HS (sometimes called acne inversa) is a chronic and often painful inflammatory skin disease.

Symptoms may include tender nodules (lumps) and abscesses (boils) that may leak pus, which can have an unpleasant odour. It most commonly affects specific areas of the skin, such as under the breasts, the armpits, inner thighs, groin and buttocks. Scarring may also occur in affected areas.

Hadlima is used for the treatment of adults and adolescents from 12 years of age with active moderate to severe HS, Hadlima can reduce the number of nodules and abscesses caused by the disease, and the pain that is often associated with it.

You may have already been given other medicines to treat your condition. Your doctor has prescribed Hadlima for you as you haven't responded well enough to these medicines.

Your doctor will schedule follow-up appointments to check on your progress to determine whether you should continue treatment.

Uveitis

Uveitis is an inflammatory disease affecting certain parts of the eye. This inflammation may lead to a decrease of vision and/or the presence of floaters in the eye (black dots or wispy lines that move across the field of vision). Hadlima is used to treat non-infectious intermediate, posterior and pan-uveitis.

You may have already been given other medicines to treat your condition. Your doctor has prescribed Hadlima for you as you may either have not responded well enough, or you have lost response or cannot tolerate these medicines.

The active ingredient in this medicine is adalimumab, which is a fully human monoclonal antibody. Monoclonal antibodies are proteins made by a type of blood cell to fight a foreign protein in the body.

Adalimumab recognises and binds to a specific protein (tumour necrosis factor or TNF-alpha), which is present at higher levels in some inflammatory diseases.

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

This medicine is not addictive.

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

2. What should I know before I use Hadlima?

Warnings

Do not use Hadlima if:

  1. you are allergic to adalimumab, or any of the ingredients listed at the end of this leaflet. Symptoms of an allergic reaction may include:
  • chest tightness
  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • hives, itching or skin rash
  1. you have a severe infection such as sepsis (a serious infection of the blood) or tuberculosis (a serious infection of the lungs caused by bacteria), or other severe infection caused by a virus, fungus, parasite or bacteria.
  2. you have heart failure considered by your doctor to be moderate or severe.

Check with your doctor if you:

  • have or have had an infection that does not go away or keeps coming back, this can include leg ulcers
  • you have ever had tuberculosis, or you have been in close contact with someone who has tuberculosis. Tuberculosis can develop during therapy even if you have received treatment for the prevention of tuberculosis.
  • you currently have active hepatitis B, have ever had hepatitis B, are a carrier of the hepatitis B virus or you think you may be at risk of contracting hepatitis B
  • you have or have had an infection caused by a fungus, or you have lived or travelled in countries where fungal infections are common
  • you have or have had uveitis, where the middle layer of the eyeball is inflamed
  • you have or have had allergic reactions such as chest tightness, wheezing, dizziness, swelling or rash
  • you have a disease that affects the insulating layer of the nerves, e.g. multiple sclerosis (MS)
  • you have or have had a blood disorder
  • you have or have had low resistance to disease
  • you have or have had a heart condition
  • you have or have had cancer or autoimmune disease
  • you have a lung disease called chronic obstructive pulmonary disease (COPD)
  • you have or have had kidney or liver problems
  • you have any vaccinations scheduled
  • you have or have had psoriasis (a skin disease that produces patches of thickened, scaly skin that is not contagious)
  • you have had phototherapy, also known as light therapy, for psoriasis
  • you have any surgery planned
  • you take any medicines for any other condition.

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

Make sure your doctor is aware that you are pregnant or plan to become pregnant. Hadlima should only be used in pregnancy if clearly needed.

If you use Hadlima during pregnancy your baby may have a higher risk of getting an infection.

You should consider the use of effective contraception to prevent pregnancy and continue its use for at least 5 months after the last Hadlima injection.

Tell your baby's doctors if you have taken Hadlima while you are pregnant, especially before your baby receives any vaccinations.

Make sure your doctor is aware that you are breastfeeding, or you plan to do so.

Use in children

  • Wherever possible, it is recommended that children are up to date with all vaccinations, according to current immunisation guidelines, before they are started on Hadlima treatment.
  • Treatment of Crohn's disease in children should be supported by good nutrition to allow appropriate growth.
  • The long-term effects of Hadlima on the growth and development of children is not known.

Use in the elderly

  • If you are over 65, you may be more likely to get an infection while taking Hadlima.

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 Hadlima and affect how it works, while Hadlima may affect how other medicines work.

Do not take Hadlima if you are taking the following medicine:

  • anakinra, a medicine used to treat rheumatoid arthritis, juvenile idiopathic arthritis and conditions associated with a defect in a protein called cryoprin.

Medicines that may increase the risk of infection when taken with Hadlima include:

  • anakinra, a medicine used to treat rheumatoid arthritis,
  • juvenile idiopathic arthritis and conditions associated with a defect in a protein called cryoprin
  • abatacept, a medicine used to treat rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis
  • azathioprine, a medicine used for suppressing the immune system to treat various conditions
  • 6-mercaptopurine, a medicine used to treat certain types of leukaemia, a blood disorder.

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

4. How do I use Hadlima?

How much to use

  • Rheumatoid arthritis in adults
    Inject one 40 mg dose every fortnight.
    If you are not taking methotrexate, your doctor may change this dose to 40 mg every week, or 80 mg every fortnight, depending on your response.
  • Psoriatic arthritis and ankylosing spondylitis in Adults
    Inject one 40 mg dose every fortnight.
  • Crohn's disease and Ulcerative Colitis in adults
    Inject 160 mg on day 1, followed by 80 mg on day 15 and 40 mg on day 29. Then, continue to inject 40 mg every fortnight (maintenance dose).
    Your doctor may change this maintenance dose to 40 mg every week, or 80 mg every fortnight, depending on your response.
    (See Special dosing instructions at the end of this section.)
  • Psoriasis in adults
    Inject 80 mg on day 1, followed by 40 mg on day 8 and 40 mg on day 22. Then, continue to inject 40 mg every fortnight (maintenance dose).
    Your doctor may change this maintenance dose to 40 mg every week, or 80 mg every fortnight, depending on your response.
    (See Special dosing instructions at the end of this section.)
  • Uveitis in adults
    Inject 80 mg on day 1, followed by 40 mg on day 8 and 40 mg on day 22. Then continue to inject 40 mg every fortnight (maintenance dose).
    (See Special dosing instructions at the end of this section.)
  • Hidradenitis suppurativa in adults
    Inject 160 mg on day 1, followed by 80 mg on day 15.
    Then continue to inject 40 mg every week or 80mg every fortnight from day 29 (maintenance dose).
    (See Special dosing instructions at the end of this section.)
  • Polyarticular juvenile idiopathic arthritis (pJIA) and enthesitis-related arthritis (ERA)
    If the patient's body weight is at least 30 kg, inject one 40 mg dose every fortnight.
    If the patient's body weight is between 10 and 30 kg, inject one 20 mg dose every fortnight.
  • Crohn's disease in children
    If the patient's body weight is at least 40 kg, inject 160 mg on day 1, followed by 80 mg on day 15 and 40 mg on day 29. Then, continue to inject 40 mg every fortnight (maintenance dose).
    Your doctor may change this maintenance dose to 40 mg every week, or 80 mg every fortnight, depending on your response.
    (See Special dosing instructions at the end of this section.)
  • Psoriasis in children
    If the patient's body weight is at least 40 kg, inject 40 mg on day 1, followed by 40 mg on day 8 and 40 mg on day 22. Then continue to inject 40 mg every fortnight (maintenance dose).
  • Hidradenitis suppurativa (HS) in adolescents
    Inject 80 mg on day 1, followed by 40 mg on day 8, and 40 mg on day 22. Then continue to inject 40 mg every fortnight (maintenance dose).
    Your doctor may change this maintenance dose to 40 mg every week, or 80 mg every fortnight depending on your response
    (See Special dosing instructions at the end of this section.)
    Use an antiseptic face wash on the affected areas.

Special dosing instructions

  • When a dose of 160 mg is required, this can be given as four 40 mg injections in one day, or two 40 mg injections per day over two consecutive days.
  • When a dose of 80 mg is required, this can be given as two 40 mg injections in one day.

In some instances, Hadlima needs to be taken with other medicines. Your doctor will let you know which medicines, how to take them and how long to take them.

Follow all instructions given to you and use Hadlima until your doctor tells you to stop.

How to use Hadlima

  • Hadlima is injected under the skin (sub-cutaneous injection).
  • It can be injected by the patient, or by someone else, such as a family member, friend or carer.
  • An injection should not be attempted until proper training has been received on the correct injection technique.
  • Do not mix the injection with any other medicine.
  • Instructions for preparing and giving an injection are provided on the Product Information/Consumer medicines information and Instructions for use leaflet with the product.

If you forget to use Hadlima

It is important that you use your medicine as prescribed by your doctor.

If you miss your dose at the usual time, inject Hadlima as soon as you remember, and continue injecting the next dose at the usual time on your scheduled day.

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

If you use too much Hadlima

If you think that you have used too much Hadlima, 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 Hadlima?

Things you should do

  • Keep all your doctor's appointments so your progress can be tracked.
  • Keep your appointments for blood tests. Some side effects are seen in blood results before you have any symptoms.
  • Remind any doctor, dentist or pharmacist you visit that you are using Hadlima, especially if you are scheduled for surgery or to receive any live vaccines (e.g. Bacille Calmette-Guerin or oral polio vaccine).

Call your doctor straight away if you:

  • get symptoms of an infection, such as a fever, skin sores, feeling tired, any problems with your teeth or gums or pain when passing urine or blood in your urine.
  • become pregnant while using Hadlima
  • notice new skin lesions (skin spots or sores), or if existing lesions change appearance.

Things you should not do

  • Do not stop taking Hadlima, without checking with your doctor.

Driving or using machines

Be careful driving or operating machinery until you know how Hadlima affects you.

Drinking alcohol

There is no information on the use of alcohol with Hadlima.

Looking after your medicine

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

  • Keep Hadlima in the carton protected from light.
  • Keep Hadlima in a refrigerator (at 2°C to 8°C). Do not freeze.

Keep it where young children cannot reach it.

When to discard your medicine

  • When necessary, a single Hadlima pre-filled syringe 40 mg in 0.8 mL may be stored at room temperature (25°C) for a maximum of 28 days, protected from light.
  • Once removed from the refrigerator, the syringe 40 mg in 0.8 mL must be used within 28 days or discarded, even if it has been returned to the refrigerator.
  • When necessary, a single Hadlima pre-filled syringe 40 mg in 0.4 mL may be stored at room temperature (25°C) for a maximum of 31 days, protected from light.
  • Once removed from the refrigerator, the syringe 40 mg in 0.4 mL must be used within 31 days or discarded, even if it has been returned to the refrigerator.
  • After injecting Hadlima, immediately throw away the used syringe in a special sharps container as instructed by your doctor, nurse or pharmacist.

Getting rid of any unwanted medicine

If your doctor advises that you no longer need to use this medicine or it is out of date, follow local guidelines for safe disposal.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
Injection site:
  • pain
  • swelling
  • redness
  • itching
Lungs and upper airways
  • cold
  • flu
  • runny nose
  • cough
  • sore throat
  • sinus infection
  • asthma or worsening asthma
  • bronchitis or pneumonia (congestions on the chest)
Ears, eyes and mouth
  • pain in the ear
  • pain, redness or swelling of the eye or eye lid
  • changes to vision
  • mouth ulcers
  • pain in the gums
  • excessive bleeding from the gums
Brain and nerves
  • headache or migraine
  • dizziness
  • muscle weakness
  • muscle, bone or joint pain
  • numbness
  • difficulty balancing
Gut and digestion
  • nausea
  • vomiting
  • tummy pain
  • reflux or heartburn
Skin and nails
  • rash
  • itching
  • redness
  • scaly skin patches
  • problems with your fingernails or toenails
  • hair loss
  • cold sore blisters
  • chicken pox.
Blood
  • bleeding
  • bruising more easily than usual
Body as a whole
  • tiredness
  • chest pain
  • lack of energy
  • increased heart rate
  • feeling overwhelmed or sad, lacking motivation (depression)
  • feeling especially fearful or worried (anxiety)
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
Signs of tuberculosis, such as:
  • persistent cough
  • weight loss
  • listlessness
  • fever
Signs of an infection, such as:
  • fever
  • lack of energy
  • skin bump or sore that doesn't heal
  • problems with your teeth or gums
  • pain when passing urine or blood in the urine.
Signs of problems with your nervous system, such as:
  • numbness
  • tingling throughout your body
  • arm or leg weakness
  • double or blurred vision.
Signs suggesting a blood clot, such as:
  • swelling, tenderness, redness and a warm feeling of an area of the arm or leg
Speak to your doctor as soon as possible if you have any of these side effects.

Very Serious side effects

Very Serious side effectsWhat to do
Signs of an allergic reaction, such as:
  • chest tightness,
  • shortness of breath, wheezing or difficulty breathing,
  • swelling of the face lips, tongue or other parts of the body,
  • hives itching or skin rash.
Signs of heart failure, such as:
  • shortness of breath on exertion or lying down,
  • swelling of the feet.
Signs suggesting a blood disorder, such as:
  • persistent fever,
  • bruising,
  • bleeding very easily
  • paleness.
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Reporting side effects

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

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

7. Product details

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

What Hadlima contains

Hadlima 40 mg in 0.8 mL (50 mg/mL):

40 mg adalimumab in 0.8 mL solution in a prefilled syringe (AUST R 284249)

Active ingredient
(main ingredient)		adalimumab
Other ingredients
(inactive ingredients)		Sodium citrate dihydrate
Citric acid monohydrate
Histidine
Histidine hydrochloride monohydrate
Sorbitol
Polysorbate 20
Water for injections

Hadlima 40 mg in 0.4 mL (100 mg/mL):

40 mg adalimumab in 0.4 mL solution in a prefilled syringe (AUST R 385133)

Active ingredient
(main ingredient)		adalimumab
Other ingredients
(inactive ingredients)		Histidine
Histidine hydrochloride monohydrate
Mannitol
Polysorbate 20
Dibasic sodium phosphate heptahydrate
Monobasic sodium phosphate monohydrate
Sodium succinate
Succinic acid
Water for injections

What Hadlima looks like

Hadlima is a clear to opalescent, colourless to pale brown, sterile solution of 40 mg adalimumab in 0.8 mL or 0.4 mL solution in a syringe available in a pre-filled syringe for patient use in packs containing 2 pre-filled syringes.

Who distributes Hadlima

Hadlima is distributed in Australia by:

Sponsor:

Samsung Bioepis AU Pty Ltd
Suite 1, Level 11, 66 Goulburn Street,
Sydney NSW 2000, Australia

Distributor:

Organon Pharma Pty Limited
Building A, 26 Talavera Road,
Macquarie Park, NSW 2113, Australia

This leaflet was prepared in:
February 2024

Version 10.0

Instructions for Use:

Your pre-filled syringe (40 mg/0.8 mL):

Step 1: Gather supplies

  • Place your syringe and unopened alcohol swabs on a clean, dry surface.
  • Remember to wash your hands!
  • Don't remove the cap just yet!

Step 2: Wait 15-30 minutes

  • Wait 15-30 minutes for your syringe to warm-up to room temperature, which helps reduce your pain during injection.
  • Don't remove the cap just yet!

Step 3: Inspect medicine & date

  • Make sure your medicine is clear to opalescent, free of particles, and colorless to pale brown and hasn't expired.
  • You may see 1 or more air bubbles, and that's okay. There is no need to remove it.
  • Don't remove the cap just yet!

Step 4: Choose site & clean skin

  • Choose an injection site on your body. Your abdomen or thighs are best.
  • Wipe your skin at the injection site with an alcohol swab.
  • Avoid skin that's sore, bruised, scarred, scaly or has red patches.

Step 5: Pull off needle cap

  • Carefully pull off the needle cap.

Step 6: Pinch skin & insert needle

  • Gently pinch your skin and insert the needle all the way.

Step 7: Push plunger all the way

  • Hold the syringe steady and press the plunger all the way down.
  • Then lift your thumb to let the needle retract into the body of the syringe.

Step 8: Remove syringe & dispose

  • Pull the syringe away from your skin.
  • Confirm that the needle has retracted and discard the syringe in a sharps container.

Your pre-filled syringe (40 mg/0.4 mL):

Step 1: Gather supplies

  • Place your syringe and unopened alcohol swabs on a clean, dry surface.
  • Remember to wash your hands!
  • Don't remove the cap just yet!

Step 2: Wait 15-30 minutes

  • Wait 15-30 minutes for your syringe to warm-up to room temperature, which helps reduce your pain during injection.
  • Don't remove the cap just yet!

Step 3: Inspect medicine & date

  • Make sure your medicine is clear to opalescent, free of particles, and colorless to pale brown and hasn't expired.
  • You may see 1 or more air bubbles, and that's okay. There is no need to remove it.
  • Don't remove the cap just yet!

Step 4: Choose site & clean skin

  • Choose an injection site on your body. Your abdomen or thighs are best.
  • Wipe your skin at the injection site with an alcohol swab.
  • Avoid skin that's sore, bruised, scarred, scaly or has red patches.

Step 5: Pull off needle cap

  • Carefully pull off the needle cap.

Step 6: Pinch skin & insert needle

  • Gently pinch your skin and insert the needle all the way.

Step 7: Push plunger all the way

  • Hold the syringe steady and press the plunger all the way down.
  • Then lift your thumb to let the needle retract into the body of the syringe.

Step 8: Remove syringe & dispose

  • Pull the syringe away from your skin.
  • Confirm that the needle has retracted and discard the syringe in a sharps container.

Published by MIMS May 2024

BRAND INFORMATION

Brand name

Hadlima

Active ingredient

Adalimumab

Schedule

S4

 

Notes

Distributed by Organon Pharma Pty Limited

1 Name of Medicine

Adalimumab.
Hadlima (adalimumab) is a biosimilar medicine to Humira (adalimumab). The evidence for comparability supports the use of Hadlima for the listed indication.

2 Qualitative and Quantitative Composition

Adalimumab is a recombinant human immunoglobulin (IgG1) monoclonal antibody containing only human peptide sequences. Adalimumab was created using phage display technology resulting in fully human heavy and light chain variable regions, which confer specificity to human tumour necrosis factor (TNF), and human IgG1 heavy chain and kappa light chain sequences. Adalimumab binds with high affinity and specificity to soluble tumour necrosis factor (TNF-alpha) but not lymphotoxin (TNF-beta). Adalimumab is produced by recombinant DNA technology in a mammalian cell expression system. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.
The presentations contain 40 mg adalimumab per 0.8 mL (50 mg/mL) or 40 mg adalimumab per 0.4 mL (100 mg/mL).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Hadlima is supplied as a sterile, preservative-free solution of adalimumab for subcutaneous administration. The solution of Hadlima is clear to opalescent and colourless to pale brown solution with a pH of 5.2 ± 0.3. The drug product is supplied as either a single-use, pre-filled syringe, or as a single-use, auto-injector (Hadlima PushTouch). Enclosed within the autoinjector is a single-use, pre-filled glass syringe.

4 Clinical Particulars

4.1 Therapeutic Indications

Rheumatoid arthritis.

Hadlima is indicated for reducing signs and symptoms, as well as inhibiting the progression of structural damage in adult patients with moderate to severely active rheumatoid arthritis. This includes the treatment of patients with recently diagnosed moderate to severely active disease who have not received methotrexate.
Hadlima can be used alone or in combination with methotrexate.

Juvenile idiopathic arthritis.

Polyarticular juvenile idiopathic arthritis.

Hadlima in combination with methotrexate is indicated for reducing the signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older who have had an inadequate response to one or more disease modifying anti-rheumatic drugs (DMARDs). Hadlima can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.

Enthesitis-related arthritis.

Hadlima is indicated for the treatment of enthesitis-related arthritis in children, who have had an inadequate response to, or who are intolerant to, conventional therapy.

Psoriatic arthritis.

Hadlima is indicated for the treatment of signs and symptoms, as well as inhibiting the progression of structural damage, of moderate to severely active psoriatic arthritis in adult patients where response to previous DMARDs has been inadequate.

Ankylosing spondylitis.

Hadlima is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.

Crohn's disease in adults and children (≥ 6 years).

Hadlima is indicated for the treatment of moderate to severe Crohn's disease, to reduce the signs and symptoms of the disease and to induce and maintain clinical remission in patients: who have had an inadequate response to conventional therapies or; who have lost response to or are intolerant to infliximab.

Ulcerative colitis.

Hadlima is indicated for the treatment of moderate to severe ulcerative colitis in adult patients who have had an inadequate response to conventional therapy or who are intolerant to or have medical contraindications for such therapies. Patients should show a clinical response within 8 weeks of treatment to continue treatment beyond that time. (See Section 5.1 Pharmacodynamic Properties, Clinical trials.)

Psoriasis in adults and children.

Hadlima is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.
Hadlima is indicated for the treatment of severe chronic plaque psoriasis in children and adolescent patients from 4 years of age who have had an inadequate response to or are inappropriate candidates for topical therapy and phototherapy.

Hidradenitis suppurativa in adults and adolescents (from 12 years of age).

Hadlima is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne inversa) in patients with an inadequate response to conventional systemic hidradenitis suppurativa therapy.

Uveitis.

Hadlima is indicated for the treatment of non-infectious intermediate, posterior and pan-uveitis in adult patients who have had an inadequate response to corticosteroids, in patients in need of corticosteroid sparing, or in whom corticosteroid treatment is inappropriate.

4.2 Dose and Method of Administration

Hadlima is administered by subcutaneous injection. This product is for one dose in one patient only.
Healthcare providers should be advised that there is no dosage form of Hadlima available which allows dosing of less than 40 mg. As a result, there are no suitable Hadlima dosage forms available for a subset of the following paediatric indications:
Juvenile idiopathic arthritis: children weighing less than 30 kg.
Paediatric Crohn's disease (6 to 17 years): maintenance therapy in children weighing less than 40 kg.
Paediatric plaque psoriasis (4 to 17 years): children weighing less than 40 kg.
Other adalimumab products with suitable dosage forms are available.
Hadlima is intended for use under the guidance and supervision of a physician. Patients may self-inject Hadlima if their physician determines that it is appropriate and with medical follow-up, as necessary, after proper training in subcutaneous injection technique.
Sites for self-injection include thigh or abdomen. Injection sites should be rotated. New injections should never be given into areas where the skin is tender, bruised, red or hard.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.
Hadlima should not be mixed in the same syringe with any other medicine. Any unused medicine or waste material should be disposed of in accordance with local requirements.
Hadlima contains no antimicrobial agent. Discard any residue.
Hadlima is only available as 40 mg pre-filled syringe and 40 mg PushTouch auto-injector.

Rheumatoid arthritis.

The recommended dose of Hadlima for adult patients with rheumatoid arthritis is 40 mg administered fortnightly as a single dose. Methotrexate, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs or analgesics may be continued during treatment with Hadlima.
Some patients not taking concomitant methotrexate may derive additional benefit from increasing the dosage of Hadlima to 40 mg every week, or 80 mg fortnightly (as two 40 mg injections).

Juvenile idiopathic arthritis.

The recommended dose of Hadlima for patients 2 years of age and older with polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis is based on weight as shown in Table 1. Methotrexate, glucocorticoids, NSAIDs and/or analgesics may be continued during treatment with Hadlima.
Healthcare providers should be advised that there is no dosage form of Hadlima available which allows dosing of less than 40 mg.
Available data suggest that a clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.
Adalimumab has not been studied in patients with JIA less than 2 years of age, or in patients with a weight below 10 kg.
Adalimumab has not been studied in patients with enthesitis-related arthritis aged less than 6 years or any child weighing less than 10 kg.

Psoriatic arthritis.

The recommended dose of Hadlima for patients with psoriatic arthritis is 40 mg adalimumab administered fortnightly as a single dose.
Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, analgesics or disease-modifying anti-rheumatic drugs can be continued during treatment with Hadlima.

Ankylosing spondylitis.

The recommended dose of Hadlima for patients with ankylosing spondylitis is 40 mg adalimumab administered every fortnight as a single dose.
Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, analgesics or disease-modifying anti-rheumatic drugs can be continued during treatment with Hadlima.

Crohn's disease.

The recommended Hadlima dose regimen for adult patients with Crohn's disease is shown in Table 2.
Some patients who experience a decrease in their response may benefit from an increase in dosage to 40 mg Hadlima every week, or 80 mg fortnightly (as two 40 mg injections).
Aminosalicylates, corticosteroids, and/or immunomodulatory agents (e.g. 6-mercaptopurine and azathioprine) may be continued during treatment with Hadlima.

Paediatric Crohn's disease (6 to 17 years).

The recommended dose of Hadlima for patients from 6 to 17 years of age with Crohn's disease is shown in Table 3.
Healthcare providers should be advised that there is no dosage form of Hadlima available which allows dosing of less than 40 mg.
Some patients may benefit from increasing the dosage if a disease flare or an inadequate response is experienced during maintenance dosing:
≥ 40 kg: 40 mg every week or 80 mg fortnightly (as two 40 mg injections).
Continued therapy should be carefully considered in a subject not responding by week 12.
Good nutrition should be encouraged alongside pharmacological therapy to allow appropriate growth.

Ulcerative colitis.

The recommended Hadlima dose regimen for adult patients is shown in Table 4.
During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines.
Some patients who experience a decrease in their response may benefit from an increase in dosage to 40 mg Hadlima every week, or 80 mg fortnightly (as two 40 mg injections).
Hadlima should not be continued in patients who do not achieve a clinical response in the first 8 weeks of treatment. Efficacy of adalimumab in the treatment of ulcerative colitis has not been demonstrated in patients who have failed previous anti-TNF therapy (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Psoriasis.

Adults.

The recommended dose of Hadlima for adult patients is an initial dose of 80 mg (as two 40 mg injections), followed by 40 mg fortnightly, starting one week after the initial dose.
Continued therapy beyond 16 weeks should be carefully reconsidered in a patient not responding within this time period. Beyond 16 weeks, patients with inadequate response may benefit from an increase in dosage frequency to 40 mg every week, or 80 mg fortnightly (as two 40 mg injections). Response should be periodically evaluated (for example, every 12 weeks). Patients with continued inadequate response should discontinue treatment. If an adequate response is achieved with an increased dosing frequency, the dose may subsequently be reduced to 40 mg fortnightly.

Paediatric plaque psoriasis (4 to 17 years).

The recommended dose of Hadlima is based on body weight as shown in Table 5. Doses are administered subcutaneously weekly for the first two doses and fortnightly thereafter. Continued therapy beyond 16 weeks should be carefully considered in a patient not responding within this time period. Healthcare providers should be advised that there is no dosage form of Hadlima available which allows dosing of less than 40 mg.
If retreatment with Hadlima is indicated, the above guidance on dose and treatment duration should be followed.
There is no relevant use of adalimumab in children aged less than 4 years in this indication.
There is limited data on the efficacy or safety of the use of adalimumab for paediatric plaque psoriasis beyond 52 weeks.

Hidradenitis suppurativa.

Adults.

The recommended Hadlima dose regimen for adult patients with hidradenitis suppurativa (HS) is 160 mg initially at day 1 (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later at day 15 (given as two 40 mg injections). Two weeks later (day 29) continue with a dose of 40 mg every week or 80 mg fortnightly (as two 40 mg injections). Antibiotics may be continued during treatment with Hadlima if necessary. Should treatment need to be interrupted, Hadlima may be re-introduced. In patients without any benefit after 12 weeks of treatment, therapy should be discontinued.
Ongoing evidence of benefit, potential loss of response and the risks of treatment in patients continuing adalimumab beyond 12 weeks should be periodically evaluated (for example, after a further 12 weeks and every 6 months thereafter). In the two pivotal studies, the primary measure of efficacy was hidradenitis suppurativa clinical response (HiSCR), defined as ≥ 50% reduction from baseline in total abscess and inflammatory nodule (AN) count, with no observed increase in either abscess or draining fistula counts (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Adolescents (from 12 years of age, weighing at least 30 kg).

The recommended Hadlima dose is 80 mg at Week 0 (given as two 40 mg injections), followed by 40 mg fortnightly, starting at Week 1 via subcutaneous injection.
In adolescent patients with inadequate response to Hadlima 40 mg fortnightly, an increase in dosage frequency to 40 mg every week or 80 mg fortnightly (as two 40 mg injections), may be considered.
Antibiotics may be continued during treatment with Hadlima if necessary. It is recommended that the patient should use a topical antiseptic wash on their HS lesions on a daily basis during treatment with Hadlima.
In patients without any benefit after 12 weeks of treatment, therapy should be discontinued. (See Section 5.1 Pharmacodynamic Properties, Clinical trials for hidradenitis suppurativa, Adults.)
Should treatment be interrupted, Hadlima may be re-introduced as appropriate. The benefit and risk of continued long-term treatment should be periodically evaluated (see Section 5.1 Pharmacodynamic Properties, Clinical trials for hidradenitis suppurativa, Adults).
There is no relevant use of adalimumab in children aged less than 12 years of age with HS.

Uveitis.

Ophthalmologists are advised to consult with an appropriate specialist before initiation of treatment with Hadlima. Use of Hadlima for uveitis should be supervised by an ophthalmologist or other appropriate specialist. Patients treated with Hadlima should be given the special alert card.
The recommended dose of Hadlima for adult patients with uveitis is an initial dose of 80 mg (given as two 40 mg injections), followed by 40 mg fortnightly, starting one week after the initial dose.
Treatment with Hadlima can be initiated in combination with corticosteroids and/or with other non-biologic immunomodulatory agents. There is limited experience in the initiation of treatment with adalimumab alone.
Concomitant corticosteroids may be tapered in accordance with clinical practice starting two weeks after initiating treatment with Hadlima.
It is recommended that the benefit and risk of continued long-term treatment should be evaluated on a yearly basis.

4.3 Contraindications

Hadlima should not be administered to patients with known hypersensitivity to Hadlima or any of its excipients.
Hadlima is contraindicated in severe infections including sepsis, active tuberculosis and opportunistic infections (see Section 4.4 Special Warnings and Precautions for Use).
Concurrent administration of Hadlima and anakinra (interleukin-1 receptor antagonist) is contraindicated (see Section 4.4 Special Warnings and Precautions for Use).
Moderate to severe heart failure (NYHA class III/IV).

4.4 Special Warnings and Precautions for Use

Traceability.

In order to improve the traceability of biological medicines, the trade name and the batch number of the administered product should be clearly recorded in the patient's medical record and/or dispensing record.

Infections.

Serious infections, due to bacterial, mycobacterial, invasive fungal (disseminated or extrapulmonary histoplasmosis, aspergillosis, coccidioidomycosis), viral, parasitic or other opportunistic infections such as listeriosis, legionellosis and pneumocystis have been reported in patients receiving TNF-blocking agents, including adalimumab. Sepsis, rare cases of tuberculosis and candidiasis have also been reported with the use of TNF antagonists, including adalimumab. Other serious infections seen in clinical trials include pneumonia, pyelonephritis, septic arthritis and septicaemia. Hospitalisation or fatal outcomes associated with infections have been reported. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their underlying disease could predispose them to infections.
Treatment with adalimumab should not be initiated in patients with active infections including chronic or localised infections until infections are controlled. In patients who have been exposed to tuberculosis, and patients who have travelled in areas of high risk of tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis, the risk and benefits of treatment with adalimumab should be considered prior to initiating therapy (see Section 4.4 Special Warnings and Precautions for Use, Other opportunistic infections).
Patients should be monitored closely for infections including tuberculosis before, during and after treatment with Hadlima.
Patients who develop a new infection while undergoing treatment with adalimumab should be monitored closely and undergo a complete diagnostic evaluation.
Administration of adalimumab should be discontinued if a patient develops a new serious infection or sepsis, and appropriate antimicrobial or antifungal therapy should be initiated. Physicians should exercise caution when considering the use of adalimumab in patients with a history of recurring infection or with underlying conditions, which may predispose patients to infections.

Hepatitis B virus.

Use of TNF blockers, including adalimumab, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients at risk for HBV infection should be evaluated for evidence of prior HBV infection before initiating TNF blocker therapy. Prescribers should exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Patients who are carriers of HBV and require treatment with TNF blockers should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.
Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. In patients who develop HBV reactivation, Hadlima should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.

Tuberculosis.

Tuberculosis including reactivation and new onset of tuberculosis, has been reported in patients receiving adalimumab. Reports included cases of pulmonary and extrapulmonary (i.e. disseminated).
Before initiation of therapy with adalimumab, all patients should be evaluated for both active and inactive (latent) tuberculosis infection. This evaluation should include a detailed medical assessment of patient history of tuberculosis or possible previous exposure to people with active tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests (e.g. chest X-ray and tuberculin skin test) should be performed in accordance with local recommendations. Treatment of latent tuberculosis infections should be initiated prior to therapy with Hadlima. When tuberculin skin testing is performed for latent tuberculosis infection, an induration size of 5 mm or greater should be considered positive, even if vaccinated previously with Bacille Calmette-Guerin (BCG).
The possibility of undetected latent tuberculosis should be considered especially in patients who have immigrated from or travelled to countries with a high prevalence of tuberculosis or who had close contact with a person with active tuberculosis.
If active tuberculosis is diagnosed, Hadlima therapy must not be initiated.
If latent tuberculosis is diagnosed, appropriate treatment must be started with anti-tuberculosis prophylactic treatment before the initiation of Hadlima in accordance with local recommendations. Use of anti-tuberculosis prophylactic treatment should also be considered before the initiation of Hadlima in patients with several or significant risk factors for tuberculosis despite a negative test for tuberculosis and in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. The decision to initiate anti-tuberculosis therapy in these patients should only be made after taking into account both the risk for latent tuberculosis infection and the risks of anti-tuberculosis therapy. If necessary, consultation should occur with a physician with expertise in the treatment of tuberculosis. The benefit/risk balance of therapy with adalimumab should be very carefully considered.
Anti-tuberculosis treatment of patients with latent tuberculosis infection reduces the risk of reactivation in patients receiving treatment with adalimumab. Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with adalimumab. Also, active tuberculosis has developed in patients receiving adalimumab whose screening for latent tuberculosis infection was negative, and some patients who have been successfully treated for active tuberculosis have redeveloped tuberculosis while being treated with TNF blocking agents.
Patients receiving Hadlima should be monitored for signs and symptoms of active tuberculosis, particularly because tests for latent tuberculosis infection may be falsely negative. The risk of false negative tuberculin skin test results should be considered especially in patients who are severely ill or immunocompromised.
Patients should be instructed to seek medical advice if signs/symptoms suggestive of a tuberculosis infection (e.g. persistent cough, wasting/weight loss, low grade fever) occur during or after therapy with Hadlima.

Other opportunistic infections.

Opportunistic infections, including invasive fungal infections, have been observed in patients receiving adalimumab. These infections are not consistently recognised in patients taking TNF blockers and this has resulted in delays in appropriate treatment, sometimes resulting in fatal outcomes.
Patients taking TNF blockers are more susceptible to serious fungal infections such as histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, candidiasis, and other opportunistic infections. Those who develop fever, malaise, weight loss, sweats, cough, dyspnoea, and/or pulmonary infiltrates, or other serious systemic illness with or without concomitant shock should promptly seek medical attention for a diagnostic evaluation.
For patients who reside or travel in regions where mycoses are endemic, invasive fungal infections should be suspected if they develop the signs and symptoms of possible systemic fungal infection. Patients are at risk of histoplasmosis and other invasive fungal infections and hence clinicians should consider empiric antifungal treatment until the pathogen(s) are identified. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy. Patients who develop a severe fungal infection are also advised to stop the TNF blocker until infections are controlled.

Neurologic events.

Adalimumab has been associated in rare cases with new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis, and optic neuritis, and peripheral demyelinating disease, including Guillain Barré syndrome. Prescribers should exercise caution in considering the use of Hadlima in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of Hadlima should be considered if any of these disorders develop.
There is a known association between intermediate uveitis and central demyelinating disorders. Neurologic evaluation should be performed in patients with non-infectious intermediate uveitis prior to the initiation of adalimumab therapy and regularly during treatment to assess for pre-existing or developing central demyelinating disorders.

Hypersensitivity reactions.

Serious allergic reactions associated with adalimumab were rare during clinical trials. Allergic reactions overall (e.g. allergic rash, anaphylactoid reaction, fixed-drug reaction, non-specific drug reaction, urticaria) have been observed in approximately 1% of patients. Reports of serious allergic reactions including anaphylaxis have been received following adalimumab administration. If an anaphylactic reaction or other serious allergic reaction occurs, administration of Hadlima should be discontinued immediately and appropriate therapy initiated.

Haematologic events.

Rare reports of pancytopaenia including aplastic anaemia have been reported with TNF blocking agents. Adverse events of the haematologic system, including medically significant cytopaenia (e.g. thrombocytopaenia, leukopaenia) have been infrequently reported with adalimumab (see Section 4.8 Adverse Effects (Undesirable Effects)). The causal relationship of these reports to adalimumab remains unclear. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g. persistent fever, bruising, bleeding, pallor) while on Hadlima. Discontinuation of Hadlima therapy should be considered in patients with confirmed significant haematologic abnormalities.

Immunosuppression.

The possibility exists for TNF blocking agents, including adalimumab, to affect host defenses against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 64 patients with rheumatoid arthritis treated with adalimumab, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector T and B-cells and NK-cells, monocyte/macrophages, and neutrophils. The impact of treatment with adalimumab on the development and course of malignancies, as well as active and/or chronic infections is not fully understood. The safety and efficacy of adalimumab in patients with immunosuppression have not been evaluated. (See Section 4.4 Special Warnings and Precautions for Use, Infections; Section 4.8 Adverse Effects (Undesirable Effects), Infections, Malignancies.)

Vaccinations.

In a randomised, double-blind, placebo-controlled study in 226 adult rheumatoid arthritis patients treated with adalimumab, antibody responses to concomitant pneumococcal and influenza vaccines were assessed. Protective antibody levels to the pneumococcal antigens were achieved by 86% of patients in the adalimumab group compared to 82% in the placebo group. A total of 37% of adalimumab-treated subjects and 40% of placebo-treated subjects achieved at least a 2-fold increase in at least 3 out of 5 pneumococcal antigens. In the same study 98% of patients in the adalimumab group and 95% in the placebo group achieved protective antibody levels to the influenza antigens. A total of 52% of adalimumab-treated subjects and 63% of placebo-treated subjects achieved at least a 4-fold increase in at least 2 out of 3 influenza antigens.
Patients on adalimumab may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving adalimumab.
Administration of live vaccines to infants exposed to adalimumab in utero is not recommended for 5 months following the mother's last adalimumab injection during pregnancy.
It is recommended that paediatric patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating adalimumab therapy.

Congestive heart failure.

In a clinical trial with another TNF antagonist worsening congestive heart failure and increased mortality due to congestive heart failure have been observed. Cases of worsening congestive heart failure have been reported in patients receiving adalimumab. Adalimumab should be used with caution in patients with mild heart failure (NYHA class I/II). Adalimumab is contraindicated in moderate or severe heart failure. Treatment with Hadlima must be discontinued in patients who develop new or worsening symptoms of congestive heart failure.

Malignancies.

In the controlled portions of clinical trials of TNF-antagonists, more cases of malignancies including lymphoma have been observed among patients receiving a TNF-antagonist, including adalimumab compared with control patients (see Section 4.8 Adverse Effects (Undesirable Effects), Malignancies). However, the occurrence was rare. Furthermore, there is an increased background lymphoma risk in rheumatoid arthritis patients with long-standing, highly active inflammatory disease, which complicates the risk estimation.
Very rare post-marketing reports of hepatosplenic T-cell lymphoma (HSTCL), a rare aggressive lymphoma that is often fatal, have been identified in patients treated with adalimumab. Most of the patients had prior infliximab therapy as well as concomitant azathioprine or 6-mercaptopurine use for inflammatory bowel disease.
The potential risk with the combination of azathioprine or 6-mercaptopurine and adalimumab should be carefully considered. The causal association of HSTCL with adalimumab is not clear.
With the current knowledge, a possible risk for the development of lymphomas or other malignancies in patients treated with a TNF-antagonist cannot be excluded.
Malignancies, some fatal, have been reported among children and adolescents who received treatment with TNF-blocking agents. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. The malignancies occurred after a median of 30 months of therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports.
No studies have been conducted that include patients with a history of malignancy or that continue treatment in patients who develop malignancy while receiving adalimumab. Thus, additional caution should be exercised in considering Hadlima treatment for these patients.
In an exploratory clinical trial evaluating the use of another anti-TNF agent, infliximab, in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in the lung or head and neck, were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking. Therefore, caution should be exercised when using any TNF-antagonist in COPD patients, as well as in patients with an increased risk for malignancy due to heavy smoking.
All patients, and in particular patients with a medical history of extensive immunosuppressant therapy or psoriasis patients with a history of PUVA treatment should be examined for the presence of non-melanoma skin cancer prior to and during treatment with adalimumab. Melanoma and Merkel cell carcinoma have also been reported in patients treated with TNF-antagonists including adalimumab (see Section 4.8 Adverse Effects (Undesirable Effects)).
Cases of acute and chronic leukaemia have been reported in association with postmarketing TNF blocker use in rheumatoid arthritis and other indications. Patients with rheumatoid arthritis may be at a higher risk (up to 2-fold) than the general population for the development of leukaemia, even in the absence of TNF-blocking therapy.
With current data it is not known if adalimumab treatment influences the risk for developing dysplasia or colon cancer. All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations.

Autoimmune processes.

Treatment with adalimumab may result in the formation of autoantibodies and rarely in the development of a lupus-like syndrome. The impact of long-term treatment with adalimumab on the development of autoimmune disease is unknown. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Hadlima, treatment should be discontinued (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions, Autoantibodies).

Concurrent administration of biologic DMARDS or TNF-antagonists.

Concurrent administration of etanercept and anakinra has been associated with an increased risk of serious infections, an increased risk of neutropaenia and no additional benefit compared to these medicinal products alone. Because of the nature of the adverse events seen with the combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNF-antagonists. Therefore, combination of adalimumab and anakinra is contraindicated.
Concomitant administration of adalimumab with other biologic DMARDS (e.g. anakinra and abatacept) or other TNF-antagonists is not recommended based upon the increased risk of infections including serious infections and other potential pharmacological interactions.

Use in psoriasis.

The safety and efficacy of adalimumab in combination with other systemic agents used in psoriasis or with phototherapy have not been studied. Adalimumab should not be used in combination with such agents.

Surgery.

There is limited safety experience of surgical procedures in patients treated with adalimumab. The long half-life of adalimumab should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on adalimumab should be closely monitored for infections, and appropriate actions should be taken. There is limited safety experience in patients undergoing arthroplasty while receiving adalimumab.

Use in hepatic impairment.

Adalimumab has not been studied in these patient populations. No dose recommendations can be made.

Use in renal impairment.

Adalimumab has not been studied in these patient populations. No dose recommendations can be made.

Use in the elderly.

Of the total number of subjects in clinical studies of adalimumab 10.4% were 65 years and over, while approximately 2.2% were 75 and over. A total of 519 RA patients 65 years of age and older, including 107 patients 75 years and older, received adalimumab in clinical RA studies I-IV. No overall difference in effectiveness was observed between these subjects and younger subjects. The frequency of serious infection and malignancy among adalimumab-treated subjects over age 65 was higher than for those under age 65. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly (see Section 4.2 Dose and Method of Administration).

Paediatric use.

The safety and efficacy of adalimumab has not been established in other forms of JIA such as systemic JIA or oligoarticular JIA. The long term effects of adalimumab on the growth and development of children have not been studied. Treatment with adalimumab should only be initiated in patients with paediatric Crohn's disease following diagnosis by a specialist gastroenterologist, where other diseases with potentially similar presentations (e.g. inflammatory bowel disease (IBD) associated with chronic granulomatous disease) have been ruled out. Adalimumab has not been studied in children with Crohn's disease aged less than 6 years.

Effects on laboratory tests.

There is no known interference between adalimumab and laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Adalimumab has been studied in RA patients taking concomitant methotrexate (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.1 Pharmacodynamic Properties, Steady-state). The data do not suggest the need for dose adjustment of either adalimumab or methotrexate. Interactions between adalimumab and drugs other than methotrexate have not been evaluated in formal pharmacokinetic studies. Concurrent administration of TNF-alpha inhibitors with anakinra or abatacept has been associated with an increased risk of serious infections (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of adalimumab on fertility has not been investigated.
(Category C)
Due to its inhibition of TNF-alpha, adalimumab administered during pregnancy could affect immune response in the in utero exposed newborn and infant. Data from eight infants exposed to adalimumab in utero suggest it crosses the placenta. Consequently, these infants may be at increased risk for infection. Administration of live vaccines to infants exposed to adalimumab in utero is not recommended for 5 months following the mother's last adalimumab injection during pregnancy.
There are no adequate and well-controlled studies in pregnant women and therefore adalimumab should only be used during pregnancy if clearly needed. Women of child bearing potential should consider the use of adequate contraception to prevent pregnancy and continue for at least 5 months after the last Hadlima treatment.
In a prospective cohort pregnancy exposure registry, 257 women with RA or CD treated with adalimumab at least during the first trimester and 120 women with RA or CD not treated with adalimumab were enrolled.
There were no significant differences in the overall rates for the primary endpoint of major birth defects (adjusted odds ratio 0.84, 95% confidence interval (CI) 0.34, 2.05) as well as the secondary endpoints which included minor birth defects, spontaneous abortion, preterm delivery, low birth weight, and serious or opportunistic infections. No stillbirths or malignancies were reported.
Although the registry has methodological limitations, including small sample size and non-randomised study design, the data show no increased risk of adverse pregnancy outcomes in women with RA or CD treated with adalimumab in comparison to women with RA or CD not treated with adalimumab. In addition, data from post-marketing surveillance does not establish the presence of a drug-associated risk.
Results obtained with a very high intravenous adalimumab dose (100 mg/kg/week) in an embryofetal toxicity study in cynomolgus monkeys were inconclusive. No developmental toxicity was observed with an intravenous dose of 30 mg/kg/week, which resulted in a serum drug concentration greater than 100-fold higher than the maximum value expected during therapy during 40 mg fortnightly. Parturition was unaffected by both doses.
 Limited information from three cases in the published literature indicates that adalimumab is excreted in breast milk at very low concentrations with the presence of adalimumab in human milk at concentrations of 0.1% to 1% of the maternal serum level. Published data suggest that the systemic exposure to a breastfed infant is expected to be low because adalimumab is a large molecule and is degraded in the gastrointestinal tract. However, the effects of local exposure in the gastrointestinal tract are unknown. There are no reports of adverse effects of adalimumab on the breastfed infant and no effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for adalimumab and any potential adverse effects on the breastfed child from adalimumab 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)

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 http://www.tga.gov.au/reporting-problems.

Clinical trials.

Adalimumab was studied in 9316 patients in controlled and open label trials. These trials included rheumatoid arthritis patients with short term and long standing disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis) as well as psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis, hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 5994 patients receiving adalimumab and 3704 patients receiving placebo or active comparator during the controlled period.
The proportion of patients who discontinued treatment due to adverse events during the double-blind, controlled portion of pivotal studies across all indications was 5.9% for patients taking adalimumab and 5.5% for control treated patients. The proportion of patients who discontinued treatment due to adverse events during the double-blind, placebo-controlled portion of RA Studies I, II, III and IV was 6.6% for patients taking adalimumab and 4.2% for placebo-treated patients.
Approximately 13% of patients can be expected to experience injection site reactions, based on the most common adverse event with adalimumab in controlled clinical studies.
Adverse events at least possibly causally-related to adalimumab for clinical studies, both clinical and laboratory, are displayed by system organ class and frequency (very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1000 to < 1/100); and rare ≥ 1/10,000 to < 1/1000 in Table 6.
The highest frequency seen among the various indications has been included.
Table 6 contains adverse drug reactions (ADRs), which in some cases represent groups of related preferred terms to represent a medical concept. The ADRs presented in the table were included based on criteria including statistical significance, doubling in rate in adalimumab treated patients compared to placebo treated patients, a rate greater than 1% for adalimumab treated patients and medical importance assessment.

Rheumatoid arthritis.

Table 7 contains adverse reactions reported in at least 1% of RA patients with higher incidence (≥ 1%) in patients treated with adalimumab compared to control in 4 placebo-controlled RA trials (RA study I-IV). In general, the adverse reactions across all indications were similar to those seen in RA patients.

Polyarticular juvenile idiopathic arthritis.

In general, the adverse events in paediatric patients were similar in frequency and type to those seen in adult patients.

Hidradenitis suppurativa.

The safety profile for patients with hidradenitis suppurativa treated with adalimumab weekly was consistent with the known safety profile of adalimumab.

Uveitis.

The safety profile for patients with non-infectious uveitis treated with adalimumab was consistent with the known safety profile of adalimumab.

Study V (DE013).

The safety profile for patients with rheumatoid arthritis treated with adalimumab for up to 10 years was consistent with the known safety profile of adalimumab. The following adverse events were observed in the study: RA (worsening of RA) in 32.6% patients (corresponding to 13.2 events per 100 patient years), arthralgia in 19.5% (5.9 E/100 PY), bronchitis in 16.2% (5.4 E/100 PY), diarrhoea in 15.1% (4.0 E/100 PY), fatigue in 14.1% (3.1 E/100 PY), pain in extremity in 10.6% (2.5 E/100 PY), osteoarthritis in 10.5% (3.1 E/100 PY), dizziness in 9.8% (2.4 E/100 PY), contusion in 7.3% (1.6 E/100 PY), fall in 6.7% (1.6 E/100 PY), cataract in 6% (1.5 E/100 PY), and tendonitis in 6% (1.5 E/100 PY). These events were not considered adverse drug reactions in that they were not observed in a statistically significantly higher percentage of patients in the adalimumab group than in the control (methotrexate) group.

Description of selected adverse reactions.

Injection site reactions. In the pivotal controlled trials in adults and children, 12.9% of patients treated with adalimumab developed injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared to 7.3% of patients receiving control treatments. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.
Infections. In pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in the adalimumab-treated patients and 1.46 per patient year in the control treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infections and sinusitis. Most patients continued on adalimumab after the infection resolved. The incidence of serious infections was 0.04 per patient year in adalimumab-treated patients and 0.03 per patient year in control treated patients.
In the controlled and open label adult and paediatric studies with adalimumab, serious infections (including fatal infections, which occurred rarely) have been reported, which include reports of tuberculosis (including miliary and extrapulmonary locations) and invasive opportunistic infections (e.g. disseminated histoplasmosis, Pneumocystis carinii pneumonia, aspergillosis and listeriosis). Most, but not all of the cases of tuberculosis occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease.
Malignancies. During the controlled portions of pivotal adalimumab trials in adults at least 12 weeks in duration in patients with moderately to severely active rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis, hidradenitis suppurativa and uveitis malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.9 (4.4, 10.6) per 1000 patients years among 5196 adalimumab-treated patients versus a rate of 6.4 (3.5, 11.9) per 1000 patient years among 3347 control patients (median duration of treatment was 4.0 months for adalimumab and 3.9 months for control-treated patients).
The rate (95% confidence interval) of non-melanoma (basal cell and squamous cell) skin cancers was 8.9 (6.1, 13.1) per 1000 patient years among adalimumab-treated patients and 3.2 (1.3, 7.7) per 1000 patient years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.5) per 1000 patient years among adalimumab-treated patients and 0.6 (0.1, 4.6) per 1000 patient years among control patients.
The rate (95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1000 patient years among adalimumab-treated patients and 0.6 (0.1, 4.6) per 1000 patient years among control patients.
When combining controlled portions of these trials and ongoing open label extension studies with a median duration of approximately 3.3 years including 6279 patients and over 26,045 patient years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma skin cancers is approximately 8.6 per 1000 patient years. The observed rate of non-melanoma skin cancers is approximately 9.8 per 1000 patient years and the observed rate of lymphomas is approximately 1.3 per 1000 patient years.
No malignancies were observed in 217 paediatric patients with an exposure of 610.4 patient years during adalimumab trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis).
In addition, no malignancies were observed in 192 paediatric patients with an exposure of 258.9 patient years during an adalimumab trial in paediatric patients with Crohn's disease.
No malignancies were observed in 77 paediatric patients with an exposure of 80.0 patient years during an adalimumab trial in paediatric patients with plaque psoriasis.
In post-marketing experience from January 2003 to December 2010, predominantly in patients with rheumatoid arthritis, the reported rate of malignancies is approximately 2.7 per 1000 patient years. The reported rates for non-melanoma skins cancers and lymphomas is approximately 0.3 per 1000 patient years.
Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab (see Section 4.4 Special Warnings and Precautions for Use).
Autoantibodies. Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis studies I-V. In these adequate and well-controlled trials, 11.9% of patients treated with adalimumab and 8.1% of placebo and active control treated patients that had negative baseline antinuclear antibody titres reported positive titres at Week 24. Two patients out of 3989 treated with adalimumab in all rheumatoid and psoriatic arthritis, and ankylosing spondylitis studies developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with adalimumab on the development of autoimmune diseases is unknown.
Psoriasis: new-onset and worsening. Cases of new onset psoriasis, including pustular psoriasis and palmoplantar psoriasis, and cases of worsening of pre-existing psoriasis have been reported with the use of TNF blockers, including adalimumab. Many of these patients were taking concomitant immunosuppressants (e.g. MTX, corticosteroids). Some of these patients required hospitalisation. Most patients had improvement of their psoriasis following discontinuation of their TNF blocker. Some patients have had recurrences of the psoriasis when they were re-challenged with a different TNF blocker. Discontinuation of adalimumab should be considered for severe cases and those that do not improve or that worsen despite topical treatments.
Liver enzyme elevations.

Rheumatoid arthritis and psoriatic arthritis (PsA) clinical trials.

In controlled Phase 3 trials of adalimumab (40 mg fortnightly), in patients with RA and PsA with a control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.7% of adalimumab-treated patients and 1.6% of control-treated patients. Since many of the patients in these trials were also taking medications that cause liver enzyme elevations (e.g. NSAIDS, MTX), the relationship between adalimumab and the liver enzyme elevations is not clear.

Juvenile idiopathic arthritis clinical trial.

In a controlled Phase 3 trial of adalimumab in patients with polyarticular JIA who were 4 to 17 years and enthesitis-related arthritis who were 6 to 17 years, ALT elevations ≥ 3 x ULN occurred in 6.1% of adalimumab-treated patients and 1.3% of control-treated patients. Most ALT elevations occurred with concomitant methotrexate use. No ALT elevations ≥ 3 x ULN occurred in the Phase 3 trial of adalimumab in patients with polyarticular JIA who were 2 to < 4 years or aged 4 years and above weighing < 15 kg.

Ankylosing spondylitis clinical trials.

In controlled Phase 3 trials of adalimumab (40 mg fortnightly), in patients with ankylosing spondylitis with a control period of 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 2.44% of adalimumab-treated patients and 0.66% of control-treated patients.

Hidradenitis suppurativa clinical trials.

In controlled trials of adalimumab (initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week 4), in patients with hidradenitis suppurativa with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of adalimumab-treated patients and 0.6% of control-treated patients.

Crohn's disease clinical trials.

In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on days 1 and 15, respectively, followed by 40 mg fortnightly), in patients with Crohn's disease with a control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of adalimumab-treated patients and 0.9% of control-treated patients.

Paediatric Crohn's disease clinical trial.

In the Phase 3 trial of adalimumab in patients with paediatric Crohn's disease which evaluated efficacy and safety of two body weight adjusted maintenance dose regimens following body weight adjusted induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 x ULN occurred in 2.6% (5/192) of patients of whom 4 were receiving concomitant immunosuppressants at baseline.

Ulcerative colitis clinical trials.

In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg on days 1 and 15 respectively, followed by 40 mg fortnightly), in patients with ulcerative colitis with a control period duration ranging from 1 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 1.5% of adalimumab-treated patients and 1.0% of control-treated patients.

Psoriasis clinical trials.

In controlled Phase 3 trials of adalimumab (initial dose of 80 mg then 40 mg fortnightly), in patients with plaque psoriasis with control a period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of adalimumab-treated patients and 1.8% of control-treated patients.

Paediatric patients with plaque psoriasis clinical trial.

No ALT elevations ≥ 3 x ULN occurred in the Phase 3 trial.

Uveitis clinical trials.

In controlled trials of adalimumab (initial doses of 80 mg at Week 0 followed by 40 mg fortnightly starting at Week 1) in patients with uveitis with an exposure of 165.4 patient years and 119.8 patient years in adalimumab-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of adalimumab-treated patients and 2.4% of control-treated patients.
In all indications, patients with raised ALT were asymptomatic and in most cases elevations were transient and resolved on continued treatment. However, there have been very rare postmarketing reports of severe hepatic reactions including liver failure in patients receiving TNF blockers, including adalimumab. The causal relationship to adalimumab treatment remains unclear.
Concurrent treatment with azathioprine/6-mercaptopurine. In adult Crohn's disease studies, higher incidences of malignant and serious infection-related adverse events were seen with the combination of adalimumab and azathioprine/6-mercaptopurine compared with adalimumab alone.
Polyarticular juvenile idiopathic arthritis clinical trials. In general, the adverse reactions in patients with polyarticular juvenile idiopathic arthritis (pJIA Studies I and II) were similar in frequency and type to those seen in adult patients. Important findings and differences from adults are discussed in the following paragraphs.
In pJIA Study I, adalimumab was studied in 171 patients, 4 to 17 years of age, with polyarticular juvenile idiopathic arthritis. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia and appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with adalimumab and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster.
In pJIA Study I, 45% of patients experienced an infection while receiving adalimumab with or without concomitant methotrexate in the first 16 weeks of treatment. The types of infections reported in polyarticular juvenile idiopathic arthritis (JIA) patients were generally similar to those commonly seen in outpatient polyarticular JIA populations. Upon initiation of treatment, the most common adverse reactions occurring in this patient population treated with adalimumab were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in patients receiving adalimumab was granuloma annulare which did not lead to discontinuation of adalimumab treatment.
In the first 48 weeks of treatment in pJIA Study I, non-serious hypersensitivity reactions were seen in approximately 6% of patients and included primarily localised allergic hypersensitivity reactions and allergic rash. Isolated mild to moderate elevations of liver aminotransferases (ALT more common than AST) were observed in patients with polyarticular JIA exposed to adalimumab alone; liver function tests (LFT) elevations were more frequent among those treated with the combination of adalimumab and methotrexate. In general, these elevations did not lead to discontinuation of adalimumab treatment.
In the pJIA Study I, 10% of patients treated with adalimumab who had negative baseline anti-dsDNA antibodies developed positive titres after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial.
Approximately 15% of patients treated with adalimumab developed mild-to-moderate elevations of creatine phosphokinase (CPK) in pJIA Study I. Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue adalimumab without interruption.
In pJIA Study II, adalimumab was studied in 32 patients who were 2 to < 4 years of age or 4 years of age and older weighing < 15 kg with polyarticular JIA. Thirty-one of 32 patients (97%) received the required minimum of 24 weeks of adalimumab treatment. Patients were able to continue up to a maximum of 120 weeks of treatment. The safety profile for this patient population was similar to the safety profile seen in patients 4 to 17 years of age with polyarticular JIA.
In pJIA Study II, 78% of patients experienced an infection while receiving adalimumab. These included nasopharyngitis, bronchitis, upper respiratory tract infection, otitis media, and were mostly mild to moderate in severity. Serious infections were observed in 9% of patients receiving adalimumab in the study and included dental caries, rotavirus gastroenteritis, and varicella.
In pJIA Study II, non-serious allergic reactions were observed in 6% of patients and included intermittent urticaria and rash, which were all mild in severity.

Additional adverse reactions from postmarketing surveillance or phase IV clinical trials.

Adverse events have been reported during post-approval use of adalimumab. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to adalimumab exposure (see Table 8).

Comparability of Hadlima 40 mg/0.8 mL (50 mg/mL) with Humira 40 mg/0.8 mL (50 mg/mL) - adverse effects.

During clinical studies with Hadlima, 63 healthy subjects were exposed to a single dose of Hadlima 40 mg/0.8 mL (50 mg/mL), and 268 patients with RA were exposed to Hadlima 40 mg/0.8 mL (50 mg/mL) every other week (EOW) up to Week 50 via subcutaneous injection (a total of 26 administrations of investigational product (IP)).
The incidence of treatment-emergent adverse events (TEAEs) up to Week 24 were 35.8% and 40.7% in the Hadlima treatment group and Humira treatment group, respectively.
Any TEAEs that occurred in at least 1% of all patients who received Hadlima or Humira up to Week 24 in Study SB5-G31-RA are outlined in Table 9.
At Week 24, of the 254 subjects receiving Humira, 125 patients were randomised to transition to Hadlima 40 mg (Humira/Hadlima) and 129 patients were randomised to continue on Humira 40 mg (Humira/Humira). The incidence of treatment-emergent adverse events (TEAEs) up to Week 52 were 52.2%, 56.4%, and 54.3% in the Hadlima, Humira overall, and Humira/Humira treatment groups, respectively. Up to Week 52, 3.4% of patients reported SAEs in the Hadlima group, and 5.9% and 4.7% of patients reported SAEs each in the Humira overall and the Humira/Humira treatment group among a total of 29 SAEs from 25 (4.6%) patients. After 24 weeks, the overall incidence of TEAEs reported were Hadlima/Hadlima (32.3%), Humira/Hadlima (37.6%) and Humira/Humira (33.1%). After Week 24 for SAF2, 2.4%, 3.2%, and 3.1% of patients reported SAEs accordingly in the Hadlima/Hadlima treatment group, in the Humira/Hadlima treatment group, and in the Humira/Humira treatment group.
Any TEAEs that occurred in at least 2% of all patients who received Hadlima or Humira up to Week 52 and after Week 24 in Study SB5-G31-RA are outlined in Table 10 and Table 11, respectively.
Abnormalities in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) for Hadlima observed in Study SB5-G31-RA are included in Table 9, Table 10 and Table 11.
Blood samples for determination of immunogenicity were collected at baseline and Weeks 4, 8, 16, 24, 32, 40 and 52.
The incidence of ADAs and NAbs to adalimumab for the safety set is presented in Table 12.

4.9 Overdose

The maximum tolerated dose of adalimumab has not been established in humans. No dose-limiting toxicities have been observed during clinical trials with Hadlima.
Multiple doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Tumour necrosis factor alpha (TNF-alpha) inhibitors.
ATC code: L04AB04.

Mechanism of action.

Adalimumab binds to TNF and neutralises the biological function of TNF by blocking its interaction with the p55 and p75 cell surface TNF receptors. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis (RA), including juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases.
Increased levels of TNF are also found in psoriasis (Ps) plaques, which contribute to the inflammatory response, to the proliferation and decreased maturation of keratinocytes and to the associated vascular damages that are characteristic of the disease.
Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M).

Pharmacodynamics.

After treatment with adalimumab, a rapid decrease in levels of acute phase reactants of inflammation (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) and serum cytokines (IL-6) was observed compared to baseline in patients with RA. In patients with Crohn's disease (CD), a decrease in CRP levels was observed by week 1.
After 12 weeks of treatment with adalimumab, subjects with CD had lower levels of expression of TNF-alpha and the inflammatory markers, human leucocyte antigen (HLA-DR) and myeloperoxidase (MPO) in the colon but not in the ileum, compared with subjects with CD given placebo. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodelling responsible for cartilage destruction were also decreased after adalimumab administration. Patients treated with adalimumab usually experienced improvement in haematological signs of chronic inflammation. A rapid decrease in CRP levels was also observed in patients with polyarticular juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis and hidradenitis suppurativa.
The serum adalimumab concentration-efficacy relationship as measured by the American College of Rheumatology response criteria (ACR20) appears to follow the Hill Emax equation as shown in Figure 1.
EC50 estimates ranging from 0.8 to 1.4 micrograms/mL were obtained through pharmacokinetic/pharmacodynamic modelling of swollen joint count, tender joint count and ACR20 response from patients participating in Phase II and III trials.

Steady-state.

Accumulation of adalimumab was predictable based on the half-life following SC administration of 40 mg of adalimumab fortnightly to patients with RA, with mean steady-state trough concentrations of approximately 5 micrograms/mL (without concomitant methotrexate (MTX)) and 8 to 9 micrograms/mL (with concomitant MTX), respectively. These trough concentration levels are well above the EC50 estimates of 0.8 to 1.4 micrograms/mL and consistent with those at which ACR20 responses appear to reach a maximum (Figure 1). The serum adalimumab trough levels at steady state increased approximately proportionally with dose following 20, 40 and 80 mg fortnightly and every week SC dosing. In long-term studies with dosing for more than two years, there was no evidence of changes in clearance over time.
In patients with psoriasis, the mean steady-state trough concentration was 5 micrograms/mL during adalimumab 40 mg fortnightly without concomitant methotrexate treatment (after an initial loading dose of 80 mg SC).
In adult patients with hidradenitis suppurativa, a dose of 160 mg adalimumab on Week 0, followed by 80 mg on Week 2, achieved serum adalimumab trough concentrations of approximately 7 to 8 micrograms/mL at Week 2 and Week 4. The mean steady-state trough concentrations at Week 12 through Week 36 were approximately 8 to 10 micrograms/mL during adalimumab 40 mg every week treatment.
In patients with Crohn's disease, the loading dose of 160 mg adalimumab on Week 0 followed by 80 mg adalimumab on Week 2 achieves serum adalimumab trough concentrations of approximately 12 micrograms/mL at Weeks 2 and 4. The mean steady state trough concentration at Weeks 24 and 56 were 6.6 micrograms/mL and 7.2 micrograms/mL respectively. The range of trough concentrations in patients who received a maintenance dose of 40 mg adalimumab every fortnight was 0-21.7 micrograms/mL.
In patients with ulcerative colitis, a loading dose of 160 mg adalimumab on Week 0 followed by 80 mg adalimumab on Week 2 achieves serum adalimumab trough concentrations of approximately 12 micrograms/mL during the induction period. Mean steady-state trough levels of approximately 8 micrograms/mL were observed in ulcerative colitis patients who received a maintenance dose of 40 mg adalimumab fortnightly in a 52-week study.
In patients with uveitis, a loading dose of 80 mg adalimumab on Week 0 followed by 40 mg adalimumab fortnightly starting at Week 1, resulted in mean steady-state concentrations of approximately 8 to 10 micrograms/mL.
Population pharmacokinetic and pharmacokinetic/pharmacodynamics modelling and simulation predicted comparable adalimumab exposure and efficacy in patients treated with 80 mg fortnightly when compared with 40 mg weekly (including adult patients with RA, HS, UC, CD or Ps, adolescent patients with HS and paediatric patients ≥ 40 kg with CD).
Population pharmacokinetic analyses with data from over 1200 RA patients revealed a trend toward higher apparent clearance of adalimumab with increasing body weight and in patients who developed the presence of anti-adalimumab antibodies.
Minor increases in apparent clearance were predicted in RA patients receiving doses lower than the recommended dose, and in RA patients with high rheumatoid factor or CRP concentrations. These factors are not likely to be clinically important. However, there is a significant difference in mean apparent clearance in patients with Crohn's disease studied short term (4 weeks-13.1 mL/hr) vs. long term (56 weeks-16.8 mL/hr).

Comparability of Hadlima with Humira - pharmacodynamic properties.

The comparability assessments of pharmacodynamic in vitro studies including binding and cell-based assays, as well as an in vivo efficacy study using a Tg197 transgenic mouse model of arthritis demonstrated similar pharmacological activity between Hadlima and Humira.
Results from in vitro assays including binding assays on TNF-α, C1q and Fc receptors (FcγRIa, FcγRIIa, FcγRIIb, FcγRIIIa and FcRn), and other cell-based assays such as apoptosis, antibody dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) assays demonstrated similarity between Hadlima and Humira.
An in vivo study using a Tg197 transgenic mouse model of arthritis was performed to assess drug efficacy in animals. The in vivo study results showed a similar inhibition level of arthritic and histopathologic scores between Hadlima, and US Humira, which demonstrated a similar in vivo behaviour, especially in relation to the mechanism of action of adalimumab. A repeated dose toxicity study was performed to evaluate and demonstrate similarity in toxicological profiles between Hadlima and US Humira in cynomolgus monkeys. The results showed that Hadlima and US Humira were similarly well tolerated.

Clinical trials with Humira.

Clinical trials for rheumatoid arthritis.

Description of clinical trials.

Adalimumab was evaluated in over 3000 patients in all rheumatoid arthritis clinical trials. Some patients were treated for greater than 60 months duration. The efficacy and safety of adalimumab were assessed in five randomised, double-blind and well-controlled studies.
The primary endpoint in the efficacy studies was ACR20 response, equating to an at least 20% improvement from baseline in tender joint count, swollen joint count, and at least 3 of the 5 remaining ACR core set measures: patient assessment of pain, patient global assessment of disease activity, physician global assessment of disease activity, patient self-assessed disability (HAQ), and erythrocyte sedimentation rate or CRP.
RA study I (DE009) evaluated 271 patients with moderately to severely active RA who were ≥ 18 years old, had failed therapy with at least one but no more than four disease-modifying anti-rheumatic drugs (DMARDs) and had insufficient efficacy with methotrexate at doses of 12.5 to 25 mg (10 mg if methotrexate-intolerant) every week and whose methotrexate dose remained constant at 10 to 25 mg every week. Patients had ≥ 6 swollen joints and ≥ 9 tender joints and RA diagnosed according to ACR criteria. Doses of 20, 40 or 80 mg of adalimumab or placebo were given fortnightly for 24 weeks.
RA study II (DE011) evaluated 544 patients with moderately to severely active RA who were ≥ 18 years old and had failed therapy with at least one DMARD. Patients, who were not permitted methotrexate or other DMARDs during the study, had ≥ 10 swollen joints and ≥ 12 tender joints and were also diagnosed according to ACR criteria. Doses of 20 or 40 mg of adalimumab were given by subcutaneous injection fortnightly with placebo on alternative weeks or every week for 26 weeks; placebo was given every week for the same duration.
RA study III (DE019) evaluated 619 patients with moderately to severely active RA who were ≥ 18 years old, had insufficient efficacy to methotrexate at doses of 12.5 to 25 mg (10 mg if methotrexate-intolerant) every week and whose methotrexate dose remained constant at 12.5 to 25 mg every week. Patients had 6 swollen joints and ≥ 9 tender joints and RA diagnosed according to ACR criteria. There were three groups in this study. The first received placebo injections every week for 52 weeks. The second received 20 mg of adalimumab every week for 52 weeks. The third group received 40 mg of adalimumab fortnightly with placebo injections on alternate weeks. Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of adalimumab/MTX was administered fortnightly, for up to 5 years. The objectives of this open-label extension were to evaluate the long-term safety and maintenance of efficacy of adalimumab in subjects with RA receiving concurrent MTX. The maintenance of efficacy was assessed by evaluating the effect of adalimumab on the signs and symptoms of RA, physical function, structural damage, rates of clinical remission and patient-reported outcomes. Of the 457 patients who entered the open-label extension, 53/457 (11.6%) subjects discontinued the study due to adverse events, and 16/457 (3.5%) subjects discontinued because of a lack of efficacy/disease progression.
RA study IV (DE031) primarily assessed safety in 636 patients with moderately to severely active RA who were ≥ 18 years old. These patients met the ACR criteria for diagnosis of RA for at least three months and had at least 6 swollen joints and 9 tender joints. Patients were permitted to be either DMARD naïve or to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. Patients were randomised to 40 mg of adalimumab or placebo fortnightly for 24 weeks.
RA study V (DE013) was an active comparator trial of 2 years duration, which randomised 799 adult methotrexate (MTX)-naïve patients with early RA (mean disease duration less than 9 months) to treatment with adalimumab 40 mg fortnightly alone, methotrexate up to 20 mg/week alone, or the combination of the two, for 104 weeks.
Upon completion of the first 104 weeks, 497 patients enrolled in an open-label extension phase in which 40 mg of adalimumab was administered fortnightly for up to 10 years. 31.5% of patients in the MTX group, 33.2% in the adalimumab group, and 32.5% in the combination group had taken previous DMARDs. The mean duration of RA was 0.8 years, 0.7 years, and 0.7 years in the MTX alone, adalimumab alone, and combination groups, respectively. The mean tender joint count (TJC 68) at baseline was 32.3, 31.8 and 30.7 for the three groups, and the Erosion Score was 13.6, 11.3 and 11.0, respectively.
Results of RA study I-V were expressed in percentage of patients with improvement in RA using ACR response criteria. The primary endpoint in RA Studies I, II and III and the secondary endpoint in RA Study IV was the percent of patients who achieved an ACR20 response at Week 24 or 26. The primary endpoint in RA Study V was the percent of patients who achieved an ACR50 response at Week 52. RA Studies III and V had an additional primary endpoint at 52 weeks of retardation of disease progression (as detected by X-ray results). RA Study III also had a primary endpoint of changes in quality of life. The primary endpoint in RA studies VI and VII was injection site pain immediately after injection as measured by a 0-10 cm VAS.

Clinical response: RA studies I, II and III.

The percent of adalimumab-treated patients achieving ACR20, 50 and 70 responses was consistent across all three trials. The results for the 40 mg fortnightly dose are summarised in Table 13.
Patients receiving adalimumab 40 mg every week in RA Study II also achieved statistically significant ACR20, 50 and 70 response rates of 53.4%, 35.0% and 18.4%, respectively, at six months (see Figure 2).
The results of the components of the ACR response criteria for RA Study III are shown in Table 14. ACR response rates and improvement in all ACR response criteria were maintained to Week 104. Over the 2 years in RA Study III, 20% of adalimumab patients achieved a major clinical response, defined as maintenance of an ACR70 response over a > 6 month period.
In RA Study III, 84.7% of patients with ACR20 responses at Week 24 maintained the response at 52 weeks. Clinical responses were maintained for up to 5 years in the open-label portion of RA Study III. ACR responses observed at Week 52 were maintained or increased through 5 years of continuous treatment with 22% (115/534) of patients achieving major clinical response. A total of 372 (67.8%) subjects had no change in their methotrexate dose during the study, 141 (25.7%) subjects had a dose reduction and 36 (6.6%) subjects required a dose increase. A total of 149 (55.6%) subjects had no change in their corticosteroid dose during the study, 80 (29.9%) subjects had a dose reduction and 39 (14.6%) subjects required a dose increase. Figure 3 illustrates the durability of ACR20 responses to adalimumab in RA Studies III and II.

RA study IV.

The ACR20 response of patients treated with adalimumab plus standard of care was statistically significantly better than patients treated with placebo plus standard of care (p < 0.001).
In RA studies I-IV, adalimumab-treated patients achieved statistically significant ACR20 and 50 responses compared to placebo as early as 1-2 weeks after initiation of treatment.

RA study V.

In RA Study V for early rheumatoid arthritis patients who were methotrexate naı̈ve, combination therapy with adalimumab plus methotrexate led to significantly greater ACR responses than methotrexate monotherapy at Week 52 and responses were sustained at Week 104 (see Table 15).
At Week 52, all individual components of the ACR response criteria improved with adalimumab/methotrexate therapy and improvements were maintained to Week 104.
Over the two-year study, 48.5% patients who received adalimumab/methotrexate combination therapy achieved a major clinical response (ACR70 for > six continuous months) compared to 27.2% of patients who received methotrexate monotherapy (p < 0.001).
In the open-label extension for RA study V, ACR responses were maintained when followed for up to 10 years. However, no statistical hypothesis was tested in the OLE period. Of 542 patients who were randomised to adalimumab 40 mg fortnightly, 170 patients continued on adalimumab 40 mg fortnightly for 10 years. Among those, 154 patients (90.6%) had ACR20 responses; 127 patients (74.7%) had ACR50 responses and 102 patients (60.0%) had ACR70 responses.
In RA Study V, adalimumab/methotrexate combination therapy was superior to methotrexate monotherapy in achieving clinical remission defined as disease activity score (DAS28) (CRP) < 2.6 at Week 52 (see Table 16).
Of the 342 subjects originally randomised to adalimumab monotherapy or adalimumab/methotrexate combination therapy who entered the open-label extension study, 171 subjects completed 10 years of adalimumab treatment. Among those, 109 subjects (63.7%) were reported to be in remission at 10 years.
Radiographic response. In RA Study III, adalimumab-treated patients had a mean duration of rheumatoid arthritis for approximately 11 years and a mean ± standard deviation baseline modified total sharp score for the 40 mg fortnightly group of 72.1 ± 60.7 and placebo group of 66.4 ± 47.4. Structural joint damage was assessed radiographically and expressed as change in modified total sharp score (TSS) and its components, erosion score and joint space narrowing score (JSN) at month 12 compared to baseline.
Adalimumab/methotrexate-treated patients demonstrated less radiographic progression than patients receiving placebo/methotrexate (see Table 17).
In the open-label extension of RA Study III, 77% of the original patients treated with any dose of adalimumab were evaluated radiographically at 2 years. Patients maintained inhibition of structural damage, as measured by the TSS; 54% had no progression of structural damage as defined by a change in the TSS of zero or less.
Fifty-five percent (113/207) of patients originally treated with 40 mg adalimumab fortnightly have been evaluated radiographically at 5 years. Patients had continued inhibition of structural damage with approximately 50% (57/113) showing no progression of structural damage defined by a change in the TSS of zero or less.
In RA study V, adalimumab-treated patients had a mean duration of rheumatoid arthritis of less than 9 months and had not previously received methotrexate.
Structural joint damage was assessed radiographically and expressed as change in modified total sharp score. The Week 52 results are shown in Table 18. A statistically significant difference for change in modified total sharp score and the erosion score was observed at Week 52 and maintained at Week 104.
In the open-label extension of RA study V, the mean change from baseline at Year 10 in the modified total sharp score was 10.8, 9.2 and 3.9 in patients originally randomised to methotrexate monotherapy, adalimumab monotherapy and adalimumab/methotrexate combination therapy, respectively. The corresponding proportions of patients with no radiographic progression were 31.3%, 23.7% and 36.7% respectively.
Physical function. Health-related quality of life and physical function was assessed using the disability index of the Stanford Health Assessment Questionnaire (HAQ), which was a pre-specified primary endpoint at Week 52 in RA study III.
The HAQ was developed as a disease-specific outcome measure for rheumatoid arthritis and has been extensively studied in RA. HAQ has been shown to correlate with mortality, work disability, functional limitations, pain, fatigue and psychological relief. The score is based on 8 questions and normalised to a scale of 0 to 3, where higher scores indicate more disability, and lower scores indicate less disability. Studies have shown that a change in HAQ score of 0.22 or greater represents an improvement in disability that is perceptible and meaningful to the patient. All doses/schedules of adalimumab in RA study III showed statistically significantly greater improvement in the disability index of the HAQ from baseline to Month 6 compared to placebo and the same was seen at Week 52.
There were 619 patients enrolled in RA study III also known as the DE019 study. The patients were divided into three groups. The first group received placebo injections every week for 52 weeks. The second group received 20 mg of adalimumab every week for 52 weeks. The third group received 40 mg of adalimumab fortnightly with placebo injections on alternate weeks. Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase (DE019 OLE) in which 40 mg of adalimumab/MTX was administered fortnightly. Maintenance of physical function was defined as maintaining a reduction in HAQ of -0.5 over the second year of active treatment.

Results.

In RA Study III, the mean (95% CI) improvement in HAQ from baseline at Week 52 was -0.60 (-0.65, 0.55) for the adalimumab patients and -0.25 (-0.33, -0.17) for the placebo/MTX (p < 0.001) patients. At Week 104, the mean improvement in HAQ from baseline was -0.70 (-0.8, -0.6) for the adalimumab patients (see Table 19).
At Year 2, 94/207 (45.4%) of patients who originally entered the study achieved a -0.5 reduction in HAQ. 79.5% (115/195) of the patients who achieved a reduction in HAQ of -0.5 at the end of one year of adalimumab treatment maintained this response over 5 years of active treatment.
Quality of life. Results from the short form health survey (SF-36) for all doses/schedules of adalimumab in all four studies support these findings, with statistically significant Physical Component Summary (PCS) scores, as well as statistically significant pain and vitality domain scores for the 40 mg fortnightly dose. A statistically significant decrease in fatigue as measured by Functional Assessment of Chronic Illness Therapy (FACIT) scores was seen in all three studies in which it was assessed (RA studies I, III, IV).
Improvement in SF-36 was measured up to Week 156 (3 years) and improvement was maintained through this time.
In RA study V, the active-comparator controlled study in early rheumatoid arthritis, the improvement in the HAQ disability index and the physical component of the SF-36 showed greater improvement (p < 0.001) for adalimumab/methotrexate combination therapy versus methotrexate monotherapy at Week 52, which was maintained through Week 104. Among the 250 subjects who completed the open-label extension study, improvements in physical function (measured by HAQ-DI response) were maintained through 10 years of treatment. No statistical hypothesis was tested in the OLE phase.

Clinical trials for juvenile idiopathic arthritis.

Polyarticular juvenile idiopathic arthritis (pJIA). The safety and efficacy of adalimumab was assessed in two clinical studies (pJIA studies I and II) in patients with active polyarticular or polyarticular-course juvenile idiopathic arthritis, who had a variety of JIA onset types (most frequently rheumatoid-factor negative polyarthritis, rheumatoid-factor positive polyarthritis or extended oligoarthritis).

pJIA study I.

The safety and efficacy of adalimumab were assessed in a multi-centre, randomised, withdrawal, double blind, parallel-group study in 171 patients (4 to 17 years of age) with polyarticular juvenile idiopathic arthritis (JIA). In the study, the patients were stratified into two groups: MTX-treated or non-MTX-treated. All patients had to show signs of active moderate or severe disease despite previous treatment with NSAIDs, analgesics, corticosteroids, or DMARDs. Patients who received prior treatment with any biologic DMARDs were excluded from the study.
The study included four phases: an open-label lead in phase (OL-LI; 16 weeks), a double-blind randomised withdrawal phase (DB; 32 weeks), an open-label extension phase (OLE-BSA; up to 136 weeks), and an open-label fixed dose phase (OLE-FD; 16 weeks). In the first three phases of the study, adalimumab was administered based on body surface area at a dose of 24 mg/m2 up to a maximum total body dose of 40 mg subcutaneously (SC) fortnightly. In the OLE-FD phase, the patients were treated with 20 mg of adalimumab SC fortnightly if their weight was less than 30 kg and with 40 mg of adalimumab SC fortnightly if their weight was 30 kg or greater. Patients remained on stable doses of NSAIDs and or prednisone (≤ 0.2 mg/kg/day or 10 mg/day maximum).
Patients demonstrating a paediatric ACR 30 response at the end of OL-LI phase were randomised into the double blind (DB) phase of the study and received either adalimumab or placebo fortnightly for 32 weeks or until disease flare. Disease flare was defined as a worsening of ≥ 30% from baseline in ≥ 3 of 6 paediatric ACR core criteria, ≥ 2 active joints, and improvement of > 30% in no more than 1 of the 6 criteria. After 32 weeks or at the time of disease flare during the DB phase, patients were treated in the open-label extension phase based on the BSA regimen (OLE-BSA), before converting to a fixed dose regimen based on body weight (OLE-FD phase).

pJIA study I clinical response.

At the end of the 16-week OL-LI phase, 94% of the patients in the MTX stratum and 74% of the patients in the non-MTX stratum were paediatric ACR 30 responders. In the DB phase significantly fewer patients who received adalimumab experienced disease flare compared to placebo, both without MTX (43% vs. 71%) and with MTX (37% vs. 65%). More patients treated with adalimumab continued to show paediatric ACR 30/50/70 responses at Week 48 compared to patients treated with placebo. Overall responses were generally better and, fewer patients developed antibodies when treated with the combination of adalimumab and MTX compared to adalimumab alone.
Paediatric ACR responses were maintained for up to six years in the OLE phase in patients who received adalimumab throughout the study. Overall 19 patients were treated for 6 years or longer, with 11 of the 19 patients in the 4 to 12 year age group, and 8 of the 19 patients being between 13 and 17 years of age.

pJIA study II.

The safety and efficacy of adalimumab was assessed in an open-label, multi-centre, uncontrolled study in 32 patients (2 to < 4 years old or aged 4 years and above weighing < 15 kg) with moderately to severely active polyarticular or polyarticular-course JIA. The patients received 24 mg/m2 body surface area (BSA) of adalimumab up to a maximum of 20 mg fortnightly as a single dose via SC injection for at least 24 weeks. During the study, most patients used concomitant MTX, with fewer reporting use of corticosteroids or NSAIDs.

pJIA study II clinical response.

At Week 12 and Week 24, paediatric ACR 30 response was 93.5% and 90.0%, respectively, using the observed data approach. The proportions of patients with paediatric ACR 50/70/90 at Week 12 and Week 24 were 90.3%/61.3%/38.7% and 83.3%/73.3%/36.7%, respectively. Amongst those who responded (paediatric ACR 30) at Week 24 (n=27 out of 30 patients), the paediatric ACR 30 responses were maintained for up to 60 weeks in patients who continued with adalimumab treatment throughout this time period. Overall, 20 patients were treated for 60 weeks or longer.
The long term effects of adalimumab on the growth and development of children have not been studied.
Enthesitis-related arthritis (ERA). The safety and efficacy of adalimumab were assessed in a multi-centre, randomised, double-blind study in 46 paediatric patients (6 to 17 years old) with enthesitis-related arthritis (M11-328). Subjects had to have a diagnosis of ERA prior to their sixteenth birthday, at least 3 active joints (swelling not due to deformity or joints with loss of motion plus pain and/or tenderness), evidence of past or present enthesitis in at least 1 location and an inadequate response or intolerance to at least 1 nonsteroidal anti-inflammatory drug (NSAID). In addition, subjects had to have an inadequate response or intolerance to at least 1 disease-modifying anti-rheumatic drug, either sulfasalazine or methotrexate.
Patients were randomised to receive either 24 mg/m2 body surface area (BSA) of adalimumab up to a maximum of 40 mg, or placebo fortnightly for 12 weeks. The double-blind period was followed by an open-label (OL) period, during which patients received 24 mg/m2 BSA of adalimumab up to a maximum of 40 mg fortnightly subcutaneously for up to an additional 192 weeks.
The primary endpoint was the percent change from Baseline to Week 12 in the number of active joints with arthritis (swelling not due to deformity or joints with loss of motion plus pain and/or tenderness), which was achieved (p=0.039) with mean percent decrease of -62.6% in patients in the adalimumab group compared to -11.6% in patients in the placebo group. Decreases in the mean percent change from baseline in the number of active joints with arthritis was maintained through Week 156 with a mean decrease from baseline of -88.3%. The majority of patients demonstrated clinical improvement in secondary endpoints such as number of sites of enthesitis, tender joint count, swollen joint count, paediatric ACR 30 response, paediatric ACR 50 response, and paediatric ACR 70 response, and maintained these results during the OL period through Week 156 of the study.

Clinical trials for psoriatic arthritis.

Adalimumab, 40 mg fortnightly, was studied in patients with moderately to severely active psoriatic arthritis in two placebo-controlled studies, PsA Studies I (M02-518) and II (M02-570). PsA study I with 24-week duration, treated 313 adult patients who had an inadequate response to non-steroidal anti-inflammatory drug therapy and of these, approximately 50% were taking methotrexate. PsA Study II with 12-week duration, treated 100 patients who had an inadequate response to DMARD therapy. Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which 40 mg adalimumab was administered fortnightly.

ACR and PASI response.

Adalimumab was superior to placebo in all measures of disease activity (p < 0.001) as shown in Table 20 and Table 21. Among patients with psoriatic arthritis who received adalimumab, the clinical responses were apparent at the time of the first visit (2 weeks), significant at 12 weeks and were maintained through 24 weeks of therapy.
Patients with a psoriasis involvement of at least 3% Body Surface Areas (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) response. In these patients the skin lesions of psoriasis were improved with adalimumab, relative to placebo, as measured by PASI. Responses were similar with and without concomitant methotrexate therapy. ACR responses were maintained in the open-label extension study for up to 136 weeks.

Radiographic response.

Radiographic changes were assessed in the psoriatic arthritis studies. Radiographs of hands, wrists and feet were obtained at baseline and Week 24 during the double-blind period when patients were on adalimumab or placebo and at Week 48 when all patients were on open-label adalimumab. A modified Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e. not identical to the TSS used for rheumatoid arthritis), was used by readers blinded to treatment group to assess the radiographs.
Adalimumab-treated patients demonstrated greater inhibition of radiographic progression compared to placebo-treated patients and this effect was maintained at 48 weeks (see Table 22).
In subjects treated with adalimumab with no radiographic progression from baseline to Week 48 (n=102), 84% continued to show no radiographic progression through 144 weeks of treatment.

Quality of life and physical function.

In PsA study VI, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the Short Form Health Survey (SF-36). Patients treated with 40 mg of adalimumab fortnightly showed greater improvement from baseline in the HAQ-DI score (mean decreases of 47% and 49% at Weeks 12 and 24 respectively) in comparison to placebo (mean decreases of 1% and 3% at Weeks 12 and 24 respectively).
Results from the Short Form Health Survey (SF-36) support these findings, with statistically significant Physical Component Summary (PCS) scores, as well as statistically significant pain and vitality domain scores. At Weeks 12 and 24, patients treated with adalimumab showed greater improvement from baseline in the SF-36 Physical Component Summary score compared to patients treated with placebo, and no worsening in the SF-36 Mental Component Summary score. Improvement in physical function and disability measures were maintained for up to 136 weeks through the open label portion of the study.

Clinical trials for ankylosing spondylitis.

The safety and efficacy of adalimumab 40 mg fortnightly was assessed in 393 adult patients in two randomised, 24-week double-blind, placebo-controlled studies in patients with active ankylosing spondylitis (AS). The larger study (AS Study I or M03-607) enrolled 315 adult patients with active AS (defined as fulfilling at least two of the following three criteria: (1) a Bath AS disease activity index (BASDAI) score ≥ 4 cm, (2) a visual analog score (VAS) for total back pain ≥ 40 mm, (3) morning stiffness ≥ 1 hour), who had an inadequate response to conventional therapy. Seventy-nine (20.1%) patients were treated concomitantly with disease modifying anti-rheumatic drugs, and 37 (9.4%) patients with glucocorticoids. The blinded period was followed by an open-label period. Subjects (N=215, 54.7%) who failed to achieve ASAS 20 at Weeks 12, or 16 or 20 received early escape open-label adalimumab 40 mg fortnightly SC and were subsequently treated as non-responders in double-blind statistical analyses.
Results showed statistically significant improvement of signs and symptoms of AS in patients treated with adalimumab compared to placebo. Significant improvement in measures of disease activity was first observed at Week 2 and maintained through 24 weeks as shown in Figure 4 and Table 23.
Patients with total spinal ankylosis were included in the larger study (n=11). Responses of these patients were similar to those without total ankylosis.
A low level of disease activity (defined as a value < 20 [on a scale of 0-100 mm] in each of the four ASAS response parameters) was achieved at 24 weeks in 22% of adalimumab-treated patients vs. 6% in placebo-treated patients (p < 0.001). See Table 24.
Results of this study were similar to those seen in the second randomised trial (AS Study II or M03-606), a multicenter, double-blind, placebo-controlled study of 82 patients with ankylosing spondylitis. Patient Reported Outcomes were assessed in both ankylosing spondylitis studies using the generic health status questionnaire SF-36 and the disease specific Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL). The adalimumab-treated patients had significantly greater improvement in SF-36 Physical Component Score (mean change: 6.93) compared to placebo-treated patients (mean change: 1.55; p < 0.001) at Week 12, which was maintained through Week 24.
Results from the ASQoL support these findings demonstrating improvement in overall quality of life. The adalimumab-treated patients had statistically significant improvement (mean change:-3.15) compared to placebo-treated patients (mean change:-0.95; p < 0.001) at Week 12, which was maintained through Week 24.

Clinical trials for Crohn's disease.

Adults. The safety and efficacy of multiple doses of adalimumab were assessed in over 1500 patients with moderately to severely active Crohn's disease (Crohn's Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in randomised, double-blind, placebo controlled studies. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted and 80% of patients continued to receive at least one of these medications.
Induction of clinical remission (defined as CDAI < 150) was evaluated in two studies, CD Study I (M02-403) and CD Study II (M04-691). In CD Study I, 299 TNF-antagonist naïve patients were randomised to one of four treatment groups; the placebo group received placebo at Weeks 0 to 2, the 160/80 group received 160 mg adalimumab at Week 0 and 80 mg at Week 2, the 80/40 group received 80 mg at Week 0 and 40 mg at Week 2, and the 40/20 group received 40 mg at Week 0 and 20 mg at Week 2. In CD Study II, 325 patients who had lost response or were intolerant to infliximab were randomised to receive either 160 mg adalimumab at Week 0 and 80 mg at Week 2, or placebo at Weeks 0 and 2.
Maintenance of clinical remission was evaluated in a third study, CD Study III (M02-404). In CD Study III, 854 patients received open-label 80 mg adalimumab at Week 0 and 40 mg adalimumab at Week 2. Patients were then randomised at Week 4 to 40 mg adalimumab fortnightly, 40 mg adalimumab every week or placebo with a total study duration of 56 weeks. Patients in clinical response (decrease in CDAI ≥ 70) at Week 4 were stratified and analysed separately from those not in clinical response at Week 4. Corticosteroid taper was permitted after Week 8. Fistula healing was an important pre-determined secondary endpoint for this study.
Clinical results.

CD study I/ CD study II.

A statistically significantly greater percentage of the groups treated with 160/80 mg adalimumab achieved induction of clinical remission versus placebo at Week 4 regardless of whether the patients were TNF antagonist naïve (CD Study I) or had been previously exposed to infliximab (CD Study II) (see Table 25).

CD study III (M02-404).

At Week 4, 58% (499/854) patients were in clinical response (decrease in CDAI ≥ 70 points) and were assessed in the primary analysis. Of those in clinical response at Week 4, 48% had been previously exposed to other anti-TNF therapy. At Weeks 26 and 56, statistically significantly greater proportions of patients who were in clinical response at Week 4 achieved clinical remission in the adalimumab maintenance groups compared to patients in the placebo maintenance group. Additionally, statistically significantly greater proportions of patients receiving concomitant corticosteroids at baseline were in clinical remission and were able to discontinue corticosteroid use for at least 90 days in the adalimumab maintenance groups compared to patients in the placebo maintenance group at Weeks 26 and 56 (see Table 27).
Disease-related hospitalisations and surgeries were statistically significantly reduced with adalimumab compared with placebo at Week 56 (see Table 26).
Clinical remission results presented in Table 27 remained relatively constant irrespective of previous TNF antagonist exposure.
Of those in response at Week 4 who attained remission during the study, patients in adalimumab maintenance groups maintained remission for a significantly longer time than patients in the placebo maintenance group (see Figure 5). Among patients who were not in response by Week 12, therapy continued beyond 12 weeks did not result in significantly more responses. The group that received adalimumab every week did not show significantly higher remission rates than the group that received adalimumab fortnightly.
117/854 patients had draining fistulas both at screening and at baseline. For the assessment of fistula healing, the data for both doses of adalimumab used in the study were pooled. The proportion of subjects (ITT population) with fistula healing at Week 26 was statistically significantly greater in patients treated with adalimumab [21/70 (30.0%)] compared to placebo [6/47 (12.8%)]. Complete fistula healing was maintained through Week 56 in 23/70 (32.9%) and 6/47 (12.8%) patients (ITT population) in the adalimumab and placebo groups, respectively.
117/276 patients from CD study I and 272/777 patients from CD studies II and III were followed through at least 3 years of open-label adalimumab therapy. 88 (75.2%) and 189 (69.5%) patients, respectively, continued to be in clinical remission. Clinical response (CR-100) was maintained in 102 (87.2%) and 233 (85.7%) patients, respectively.
An endoscopy study (n=135) assessed rates of mucosal healing in patients with moderate to severe Crohn's disease given either adalimumab or placebo. After 8 weeks of randomised treatment (Week 12 of study) there was a trend towards higher levels of mucosal healing in subjects given adalimumab compared with subjects given placebo but the differences were not statistically significant (healing in 27.4% (17/62) adalimumab vs 13.1% (8/61) given placebo; p = 0.056). Subjects who continued randomised adalimumab for 52 weeks (n=135) were more likely to experience mucosal healing relative to placebo (healing in 24.2% [15/62] adalimumab vs 0% [0/61] given placebo; p < 0.001).

Patient reported outcomes.

In CD study I and CD study II, statistically significant improvement in disease-specific inflammatory bowel disease questionnaire (IBDQ) total score was achieved at Week 4 in patients randomised to adalimumab 160/80 mg compared to placebo. Statistically significant improvement from baseline in IBDQ scores was seen at Weeks 26 and 56 in CD Study III among the adalimumab treatment groups compared to the placebo group.
Children and adolescents. Adalimumab was assessed in a multi-centre, randomised, double-blind clinical trial designed to evaluate the efficacy and safety of induction and maintenance treatment with doses dependent on body weight (< 40 kg or ≥ 40 kg) in 192 paediatric subjects between the ages of 6 and 17 (inclusive) years, with moderate to severe Crohn's disease (CD) defined as Paediatric Crohn's Disease Activity Index (PCDAI) score > 30. Subjects had to have failed conventional therapy (including a corticosteroid and/or an immunomodulator) for CD. Subjects may also have previously lost response or been intolerant to infliximab.
All subjects received open-label induction therapy at a dose based on their Baseline body weight: 160 mg at Week 0 and 80 mg at Week 2 for subjects ≥ 40 kg, and 80 mg and 40 mg, respectively, for subjects < 40 kg.
At Week 4, subjects were randomised 1:1 based on their body weight at the time to either the Low Dose or Standard Dose maintenance regimens as shown in Table 28.

Efficacy results.

The primary endpoint of the study was clinical remission at Week 26, defined as PCDAI score ≤ 10.
Clinical remission and clinical response (defined as reduction in PCDAI score of at least 15 points from baseline) rates are presented in Table 29 and Table 30.
Statistically significant increases (improvement) from baseline to Week 26 and 52 in body mass index and height velocity were observed for both treatment groups.
Statistically and clinically significant improvements from Baseline were also observed in both treatment groups for quality of life parameters (including IMPACT III).

Clinical trials for ulcerative colitis.

The safety and efficacy of adalimumab was assessed in adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12 with endoscopy sub score of 2 to 3) in randomised, double-blind, placebo-controlled studies. Enrolled patients received concurrent or prior treatment with immunosuppressants such as corticosteroids, azathioprine, or 6-MP.
In study UC-I, 576 TNF-antagonist naïve patients were randomised to receive either placebo at Weeks 0 and 2, 160 mg adalimumab at Week 0 followed by 80 mg at Week 2, or 80 mg adalimumab at Week 0 followed by 40 mg at Week 2. After Week 2, patients in both adalimumab arms received 40 mg fortnightly. Clinical remission (defined as Mayo score ≤ 2 with no sub score > 1) was assessed at Week 8. The primary endpoint was evaluated based on the 390 patients recruited after the 80/40 induction group was added by protocol amendment.
In study UC-II, 248 patients received 160 mg of adalimumab at Week 0, 80 mg at Week 2 and 40 mg fortnightly thereafter, and 246 patients received placebo. Clinical results were assessed for induction of remission at Week 8 and for maintenance of remission at Week 52.
Subjects induced with 160/80 mg adalimumab achieved clinical remission versus placebo at Week 8 in statistically significantly greater percentages in study UC-I (18% vs. 9% respectively, p=0.031) and Study UC-II (17% vs. 9% respectively, p=0.019). In Study UC-II, among those treated with adalimumab who were in clinical remission at Week 8, 21/41 (51%) were in clinical remission at Week 52. The percentage of subjects induced with 80/40 mg adalimumab in Study UC-I who achieved clinical remission at Week 8 was not statistically significantly different versus placebo.
Results from the overall UC-II study population are shown in Table 31.
Hadlima should be discontinued in patients who do not achieve a clinical response during the first 8 weeks of therapy because very few patients will achieve clinical remission with continuing treatment. In UC-1 and UC-2, of patients given adalimumab 160/80 mg at baseline who did not achieve a clinical response at Week 8, 5.2%, and 17.0% went on to be in remission and response, respectively at Week 52 (see Table 32).
Statistically significant reductions of both all-cause and UC-related rates of hospitalisation were observed in a pooled analysis of Studies UC I and II.
Approximately 40% of patients in study UC-II had failed prior anti-TNF treatment with infliximab. The efficacy of adalimumab in those patients was reduced compared to that in anti-TNF naïve patients.
The effectiveness of adalimumab in patients who have lost response to infliximab has not been established, statistically significant differences for Week 8 clinical remission and Week 8 clinical response were not observed for adalimumab versus placebo in those patients. However, at Week 52, clinical remission and clinical response were achieved in a statistically significantly greater number of patients on adalimumab versus placebo in patients who had failed prior anti-TNF treatment (i.e. remission: 3% on placebo versus 10% on adalimumab, and response: 10% on placebo versus 20% on adalimumab).
Patients who completed 52 weeks in UC study I and II continued in an open, uncontrolled extension study (UC-III). Of the 588 patients who entered in the open-label study, 299 (51%) were in remission at year 3 and 273 (46%) were in remission at year 4.
Patients, who lose response may benefit from an increase of dosing frequency to 40 mg weekly. 17% of patients initially responding to treatment with adalimumab required an increase in dosing frequency to 40 mg adalimumab every week.

Quality of life.

In UC Study II, improvement in the disease-specific inflammatory bowel disease questionnaire (IBDQ) total score was achieved at Week 52 in patients randomised to adalimumab 160/80 mg compared to placebo (p = 0.007).

Clinical trials for psoriasis.

Adults. The safety and efficacy of adalimumab were assessed in over 1600 patients 18 years of age or older with moderate to severe chronic plaque psoriasis who were candidates for systemic therapy or phototherapy in randomised, double-blind, well-controlled studies. The safety and efficacy of adalimumab were also studied in adult patients with moderate to severe plaque psoriasis with concomitant hand and/or foot psoriasis who were candidates for systemic therapy.
Ps study I (M03-656) evaluated 1212 patients with chronic plaque psoriasis with ≥ 10% BSA involvement and Psoriasis Area and Severity Index (PASI) ≥ 12 within three treatment periods. In period A, patients received placebo or adalimumab subcutaneously at an initial dose of 80 mg at Week 0 followed by a dose of 40 mg fortnightly starting at Week 1. After 16 weeks of therapy, patients who achieved at least a PASI 75 response at Week 16, defined as a PASI score improvement of at least 75% relative to baseline, entered period B and received open label 40 mg adalimumab fortnightly. After 17 weeks of open label therapy, patients who maintained at least a PASI 75 response at Week 33 and were originally randomised to active therapy in Period A were re-randomised in period C to receive 40 mg adalimumab fortnightly or placebo for an additional 19 weeks. Across all treatment groups the mean baseline PASI score was 18.9 and the baseline Physician's Global Assessment (PGA) score ranged from "moderate" (52.6%) to "severe" (41.3%) to "very severe" (6.1%).
Ps study II (M04-716) compared the efficacy and safety of adalimumab versus methotrexate and placebo in 271 patients with 10% BSA involvement and PASI ≥ 10. Patients received placebo, an initial dose of MTX 7.5 mg and thereafter dose increases up to Week 12, with a maximum dose of 25 mg or an initial dose of 80 mg adalimumab followed by 40 mg fortnightly (starting one week after the initial dose) for 16 weeks. There are no data available comparing adalimumab and MTX beyond 16 weeks of therapy. Patients receiving MTX who achieved a ≥ PASI 50 response at Week 8 and/or 12 did not receive further dose increases. Across all treatment groups, the mean baseline PASI score was 19.7 and the baseline PGA score ranged from "mild" (< 1%) to "moderate" (48%) to "severe" (46%) to "very severe" (6%).
Ps study III (M02-528) evaluated 148 patients with chronic plaque psoriasis with ≥ 5% BSA involvement for at least 1 year. Patients received placebo or adalimumab subcutaneously at a dose of 40 mg fortnightly starting at Week 1 after an initial dose of 80 mg at Week 0 or adalimumab at an initial dose of 80 mg at Week 0 followed by a dose of 40 mg weekly.
Patients participating in all Phase 2 and Phase 3 psoriasis studies were eligible to enrol into an open-label extension trial (M03-658) where adalimumab was given for at least an additional 108 weeks at 40 mg fortnightly, with the option to dose-escalate to 40 mg weekly if response was sub-optimal.

Clinical results.

In Ps studies I, II and III, the primary endpoint was the proportion of patients who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline at Week 16 for Ps studies I and II and Week 12 for Ps study III. Other evaluated outcomes in Ps studies I, II, and III included the PGA and other PASI measures. Ps study I had an additional primary endpoint of loss of adequate response after Week 33 and on or before Week 52. Loss of adequate response is defined as a PASI score after Week 33 and on or before Week 52 that resulted in a < PASI 50 response relative to baseline with a minimum of a 6-point increase in PASI score relative to Week 33. In Ps studies I and II, more patients randomised to adalimumab than to placebo achieved at least a 75% reduction from baseline of PASI score at Week 16. Other relevant clinical parameters including PASI 100 (i.e. complete clearance of psoriasis skin signs) and PGA of "clear or minimal" were also improved over placebo. Patients with ≥ PASI 75 response continued to Week 33. In Ps study I, patients who were PASI 75 responders and were re-randomised to continue adalimumab therapy at Week 33 were less likely to experience a loss of adequate response on or before Week 52 than the PASI 75 responders who were re-randomised to placebo at Week 33 (4.9% versus 28.4%, p < 0.001). In Ps Study II, superior results were achieved for PASI 75, PASI 100 and PGA of "clear or minimal" in patients randomised to the adalimumab treatment group versus those randomised to receive methotrexate (see Table 33 and Table 34).
Two of the continuous treatment populations entering trial M03-658 were those from Period C of study I and those from study II.
250 subjects in the adalimumab group in Period C of study I achieved PASI 75 at Weeks 16 and 33 and received continuous adalimumab therapy at 40 mg fortnightly for up to 52 weeks. Of these, 233 entered the extension trial M03-658 and the proportion of patients with PGA of "clear or minimal" response was 70.0% at entry to the extension trial (52 weeks adalimumab treatment), 73.4% after 76 weeks treatment, and 59.0% after 160 weeks treatment. The corresponding percentages for PASI 75 were 83.7% at entry, 86.5% after 76 weeks treatment, and 74.7% after 160 weeks treatment.
108 subjects in the adalimumab group of study II received continuous adalimumab therapy at 40 mg fortnightly for 16 weeks. Of these, 94 entered the extension trial M03-658, and the proportion of these patients with PGA of "clear or minimal" response was 68.1% at entry to the extension trial (16 weeks adalimumab treatment) and 46.2% after 124 weeks treatment. The corresponding percentages for PASI 75 were 74.5% at entry and 58.1% after 124 weeks treatment.
There was a withdrawal and retreatment evaluation in the extension trial (M03-658) after subjects had received at least 2 years of treatment with adalimumab. A pre-specified evaluable population of stable responders to adalimumab was assessed after withdrawal of adalimumab. This population consisted of subjects with stable psoriasis defined as PGA clear or minimal at the last 2 visits at least 12 weeks apart and receiving adalimumab 40 mg fortnightly during the last 12 weeks. If subjects relapsed (PGA became moderate or worse) during the withdrawal period, adalimumab was recommenced at an initial dose of 80 mg and then, from the following week, at 40 mg fortnightly. After 178 subjects had relapsed and recommenced adalimumab, the remaining subjects who had not relapsed were also eligible for retreatment with adalimumab.
Of 347 stable responders withdrawn from adalimumab, 339 had at least one post-baseline evaluation. Approximately half (55.5%) of these subjects relapsed. The median time to relapse was approximately 5 months. None of the subjects experienced rebound of disease (PASI ≥ 125% or new generalised erythrodermic or pustular psoriasis within 3 months of withdrawal of adalimumab). The number of retreated subjects was 285, of whom 178 had relapsed during the withdrawal period. At week 16 of retreatment, PGA "clear or minimal" increased from 0% to 69.1% in relapsed subjects and from 59.8% to 88.8% in non-relapsed subjects. Therefore, after withdrawal of adalimumab and relapse, most subjects responded to retreatment within 16 weeks.
In the open-label extension trial (M03-658), patients who dose escalated from 40 mg fortnightly to 40 mg every week due to a PASI response below 50%, 26.4% (92/349) and 37.8% (132/349) of patients achieved PASI 75 response at Week 12 and 24, respectively.
An additional Ps study (M10-405) compared the efficacy and safety of adalimumab versus placebo in 72 patients with moderate to severe chronic plaque psoriasis and hand and/or foot psoriasis. Patients received an initial dose of 80 mg of adalimumab, followed by 40 mg fortnightly (starting one week after the initial dose), or placebo for 16 weeks. At Week 16, a statistically significantly greater proportion of patients who received adalimumab achieved a PGA score of "clear" or "almost clear" for the hands and/or feet compared to patients who received placebo (30.6% versus 4.3%, respectively [P = 0.014]).
Psoriasis study IV (M13-674) compared efficacy and safety of adalimumab versus placebo in 217 adult patients with moderate to severe nail psoriasis. Patients received an initial dose of 80 mg adalimumab followed by 40 mg fortnightly (starting one week after the initial dose) or placebo for 26 weeks followed by open-label adalimumab treatment for an additional 26 weeks.
This study evaluated the proportion of subjects who achieved at least a 75% improvement from baseline in the Modified Nail Psoriasis Severity Index (mNAPSI 75) and the proportion of subjects who achieved "clear" or "minimal" assessment with at least a 2-grade improvement on the PGA-F scale at week 26 (see Table 35). The mNAPSI is a numeric index for the evaluation of nail psoriasis. The index assessed each nail abnormality for each of a subject's fingernails. Pitting, onycholysis and oil-drop dyschromia and crumbling of each fingernail were graded on a scale from 0 to 3.
Leukonychia, splinter hemmorrhages, hyperkeratosis and red spots in the lunula were graded as either present (scored as 1) or absent (scored as 0) for each fingernail. The mean (± SD) severity of mNAPSI at baseline was 58.11 ± 21.550 and 57.59 ± 20.159 in the placebo and adalimumab treatment group, respectively.
Of those who continued to receive adalimumab treatment until Week 52, 65.0% achieved mNAPSI 75 response and 61.3% achieved PGA-F response.
The percent improvement in NAPSI was also statistically significantly greater in adalimumab patients compared with placebo at Week 16 (44.2% vs 7.8%).

Quality of life.

Patient Reported Outcomes (PRO) were evaluated by several measures. Quality of Life was assessed using the disease-specific Dermatology Life Quality Index (DLQI) in Ps Study I and Ps Study II. In Ps Study I, patients receiving adalimumab demonstrated clinically meaningful improvement in the DLQI total score, disease severity, pain, and pruritus compared to the placebo group at both Weeks 4 and 16. The DLQI result was maintained at Week 52. In Ps Study II, patients receiving adalimumab demonstrated clinically meaningful improvement in the DLQI total score, disease severity, and pruritus compared to the placebo and methotrexate groups at Week 16, and clinically meaningful improvement in pain compared to the placebo group at Week 16.
The Short Form Health Survey (SF-36) was used to assess general health-related quality of life in Ps Study I. The adalimumab-treated patients had significantly greater improvement in the SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores.
In Ps Study IV, patients receiving adalimumab showed clinically meaningful improvements at Week 26 from baseline compared with placebo in the DLQI.
Children and adolescents. The efficacy of adalimumab was assessed in a randomised, double-blind, controlled study of 114 paediatric patients from 4 years of age with severe chronic plaque psoriasis (as defined by a PGA ≥ 4 or > 20% BSA involvement or > 10% BSA involvement with very thick lesions or PASI ≥ 20 or ≥ 10 with clinically relevant facial, genital, or hand/ foot involvement) who were inadequately controlled with topical therapy and heliotherapy or phototherapy.
Patients received adalimumab 0.8 mg/kg fortnightly (up to 40 mg), 0.4 mg/kg fortnightly (up to 20 mg), or methotrexate 0.1-0.4 mg/kg weekly (up to 25 mg). At week 16, more patients randomised to adalimumab 0.8 mg/kg had positive efficacy responses (e.g. PASI 75) than those randomised to MTX (see Table 36).
Patients who achieved PASI 75 and PGA clear or minimal were withdrawn from treatment for up to 36 weeks and monitored for loss of disease control (loss of PGA response). Patients were then re-treated with adalimumab 0.8 mg/kg fortnightly for an additional 16 weeks. Among patients who were responders to the initial 16 weeks of treatment but who relapsed upon withdrawal and were retreated, PASI 75 response of 78.9% (15 of 19 subjects) and PGA clear or minimal of 52.6% (10 of 19 subjects) was observed.
In the open label period of the study, PASI 75 and PGA clear or minimal responses were maintained for up to an additional 52 weeks with no new safety findings. A total of 91 subjects received only adalimumab 0.8 mg/kg in period D, the mean duration of treatment with adalimumab 0.8 mg/kg in period D was 315.0 days (range 42 to 380 days). Of the 91 subjects who only received adalimumab 0.8 mg/kg in period D, the PASI 75 response rate and PGA clear/minimal response rate at week 52 were 69.2% and 59.3%, respectively.

Clinical trials for hidradenitis suppurativa.

Adults.

The safety and efficacy of adalimumab were assessed in randomised, double-blind, placebo-controlled studies and an open-label extension study in adult patients with moderate to severe hidradenitis suppurativa (HS) who were intolerant, had a contraindication or an inadequate response to at least a 3-month trial of systemic antibiotic therapy. The patients in Studies HS-I and HS-II had Hurley Stage II or III disease with at least 3 abscesses or inflammatory nodules.
Study HS-I (M11-313) evaluated 307 patients with 2 treatment periods. In Period A, patients received placebo or adalimumab at an initial dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every week starting at Week 4 to Week 11. Concomitant antibiotic use was not allowed during the study. After 12 weeks of therapy, patients who had received adalimumab in Period A were re-randomised in Period B to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab 40 mg fortnightly, or placebo from Week 12 to Week 35). Patients who had been randomised to placebo in Period A were assigned to receive adalimumab 40 mg every week in Period B.
Study HS-II (M11-810) evaluated 326 patients with 2 treatment periods. In Period A, patients received placebo or adalimumab at an initial dose of 160 mg at Week 0 and 80 mg at Week 2 and 40 mg every week starting at Week 4 to Week 11. 19.3% of patients had continued baseline oral antibiotic therapy during the study. After 12 weeks of therapy, patients who had received adalimumab in Period A were re-randomised in Period B to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab 40 mg fortnightly, or placebo from Week 12 to Week 35). Patients who had been randomised to placebo in Period A were assigned to receive placebo in Period B.
Patients participating in Studies HS-I and HS-II were eligible to enrol into an open-label extension study in which adalimumab 40 mg was administered every week. Mean exposure in all adalimumab population was 762 days (standard deviation: 397 days).
Throughout all 3 studies patients used topical antiseptic wash daily.

Clinical response.

Reduction of inflammatory lesions and prevention of worsening of abscesses and draining fistulas was assessed using Hidradenitis Suppurativa Clinical Response (HiSCR; at least a 50% reduction in total abscess and inflammatory nodule count with no increase in abscess count and no increase in draining fistula count relative to Baseline). Reduction in HS-related skin pain was assessed using a Numeric Rating Scale in patients who entered the study with an initial baseline score of 3 or greater on an 11 point scale.
At Week 12, a significantly higher proportion of patients treated with adalimumab versus placebo achieved HiSCR. At Week 12, a significantly higher proportion of patients in Study HS II experienced a clinically relevant decrease in HS-related skin pain (see Table 37). Patients treated with adalimumab had reduced risk of disease flare during the initial 12 weeks of treatment.
There is a statistically significantly higher HiSCR rate at Week 36 in patients who continued to receive weekly adalimumab compared to those who stopped adalimumab at Week 12.
At Week 36 HiSCR was achieved by 43% of the patients receiving ongoing weekly adalimumab and 28% of the patients who were withdrawn from adalimumab treatment after Week 12 (p < 0.05), in the pooled Study HS-I and Study HS-II population.
Of the 88 patients randomised to adalimumab continuous weekly dosing who were at least partial responders at Week 12 and subsequently entered the open-label extension study, 81 and 53 patients had observed efficacy assessments at Week 48 and Week 96, respectively. The overall HiSCR response rate at Week 12 was maintained through Week 96.
Greater improvements at Week 12 from baseline compared to placebo were demonstrated in skin-specific health-related quality of life, as measured by the Dermatology Life Quality Index (DLQI; Study HS-II), and patient global satisfaction with medication treatment as measured by the Treatment Satisfaction Questionnaire medication (TSQM; Study HS-II).

Adolescents.

There are no clinical trials in adolescent patients with hidradenitis suppurativa (HS). Efficacy of adalimumab for the treatment of adolescent patients from 12 years of age with HS is predicted based on the demonstrated efficacy and exposure-response relationship in adult HS patients and the likelihood that the disease course, pathophysiology, and drug effects are substantially similar to that of adults at the same exposure levels. (See Section 5.2 Pharmacokinetic Properties.)

Clinical trials for uveitis.

The safety and efficacy of adalimumab were assessed in adult patients with non-infectious intermediate, posterior, and panuveitis (also known as "non-infectious uveitis affecting the posterior segment"), excluding patients with isolated anterior uveitis, in two randomised, double-masked, placebo-controlled studies (UV I and II). Patients received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg fortnightly starting one week after the initial dose. Concomitant stable doses of non-biologic immuno-suppressants were permitted. The primary efficacy endpoint in both studies was 'time to treatment failure'. Following initial control of disease, a prolongation in time to treatment failure will result in reduced risk of disease flares, inflammation and vision loss.
Treatment failure was defined by a multi-component outcome based on inflammatory chorioretinal and/or inflammatory retinal vascular lesions, anterior chamber (AC) cell grade, vitreous haze (VH) grade and best corrected visual acuity (BCVA).
Study UV I evaluated 217 patients with active uveitis despite treatment with corticosteroids (oral prednisone at a dose of 10 to 60 mg/day). A majority of the 217 patients were female and Caucasian with mean age of 42.7 years. There was no statistically significant demographic difference between the placebo and adalimumab groups. All patients received a standardised dose of prednisone 60 mg/day at study entry followed by a mandatory taper schedule, with complete corticosteroid discontinuation by Week 15.
Study UV II evaluated 226 patients with inactive uveitis requiring chronic corticosteroid treatment (oral prednisone 10 to 35 mg/day) at baseline to control their disease. A majority of the 226 patients were female and Caucasian with mean age of 42.5 years. There was no statistically significant demographic difference between the placebo and adalimumab groups. Patients subsequently underwent a mandatory taper schedule, with complete corticosteroid discontinuation by Week 19.

Clinical results.

Results from both studies demonstrated statistically significant reduction of the risk of treatment failure in patients treated with adalimumab versus patients receiving placebo (see Table 38). Both studies demonstrated an early and sustained effect of adalimumab on the treatment failure rate versus placebo (see Figures 6 and 7).
In both studies, all components of the primary endpoint contributed cumulatively to the overall difference between adalimumab and placebo groups (Table 39).
Additionally, in study UV I, statistically significant differences in favour of adalimumab versus placebo were observed for the secondary endpoints changes in AC cell grade, vitreous haze grade, and log MAR BCVA (mean change from best state prior to Week 6 to the final visit; P Values: 0.011, < 0.001 and 0.003, respectively).
In the long-term extension of studies UV I and UV II, 276 of 371 eligible patients reached 78 weeks of open-label adalimumab treatment. Of these, 222 (80.4%) were quiescence (no active inflammatory lesions, AC cell grade ≤ 0.5+, VH grade ≤ 0.5+) with a concomitant steroid dose ≤ 7.5 mg per day, and 184 (66.7%) were in steroid-free quiescence. BCVA was either improved or maintained (< 5 letters deterioration) in 88.4% of the eyes at week 78.

Quality of life.

In Study UV 1, treatment with adalimumab resulted in maintenance of vision-related functioning and health-related quality of life, as measured by the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25).

Comparability of Hadlima 40 mg/0.8 mL (50 mg/mL) with Humira 40 mg/0.8 mL (50 mg/mL) - clinical trials.

The comparability of Hadlima 40 mg/0.8 mL (50 mg/mL) and EU Humira 40 mg/0.8 mL (50 mg/mL) was assessed in a randomised, double-blind, parallel group, multicentre, clinical Phase III study in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy (Study SB5-G31-RA).
This study evaluated 544 patients who were 18-75 years old with moderate to severe active disease despite MTX therapy. At Week 0, 544 patients were randomised in 1:1 ratio to receive either Hadlima 40 mg or Humira 40 mg every other week via subcutaneous injection. Up to Week 24, 271 patients and 273 patients were exposed to at least one dose of Hadlima and Humira, respectively. In addition to adalimumab, each patient also took a stable dose of oral or parenteral MTX (10-25 mg weekly) and was required to take folic acid (5-15 mg weekly) while taking MTX.
The primary objective of the study was to demonstrate therapeutic equivalence of Hadlima to EU Humira at Week 24, in terms of ACR20 response. The two treatment groups were considered equivalent if the 95% CI of the difference of the two proportions was entirely contained within the pre-justified margin of [-15%, 15%].
Other efficacy endpoints included the ACR50 response, the ACR70 response, individual components of the ACR improvement criteria, DAS28, major clinical response, and the European League Against Rheumatism (EULAR) response (good response, moderate or no response).
The demographic characteristics were comparable between the Hadlima and EU Humira treatment groups, however, there was a statistically significant difference in age between the groups (49.8 vs. 52.5 years, p-value = 0.010). The proportion of patients aged at least 65 years was 10.7% in the SB5 treatment group, and 14.7% in the EU Humira treatment group. The majority of patients were female (81.1%) and white (99.3%).
The baseline disease characteristics were comparable, with no statistically significant differences between the Hadlima treatment group and the EU Humira treatment group. The mean disease duration of RA at baseline was 5.44 years in the Hadlima treatment group and 5.46 years in the EU Humira treatment group.
Furthermore, the overall mTSS score at baseline in the Hadlima treatment group and the EU Humira treatment group were 29.51 and 31.39, respectively. The mean weekly dose of MTX at baseline was 15.13 mg in the Hadlima treatment group and 15.35 mg in the EU Humira treatment group.
The primary efficacy endpoint, ACR20 response rate at Week 24 was equivalent in Hadlima treatment group and Humira treatment group in the per-protocol set 1 (PPS1) (see Table 40). The proportion of patients achieving ACR20 response at Week 24 was 72.4% (173/239) and 72.2% (171/237) in the Hadlima and EU Humira treatment groups, respectively. The adjusted treatment difference in ACR20 response rate at Week 24 was 0.1% and the 95% confidence interval (CI) of the adjusted treatment difference was [-7.83%, 8.13%] which was completely contained within the pre-defined equivalence margin of [-15%, 15%]. Furthermore, with non-responder imputation, the ACR20 response rates of Hadlima and EU Humira were equivalent at Week 24 for the full analysis set; 68.0% of the Hadlima patients and 67.4% of the EU Humira patients achieved the ACR20 response rates at Week 24.
The secondary efficacy endpoints of ACR50, ACR70, DAS28, EULAR response at Week 24 were comparable between Hadlima and EU Humira.
The analysis of ACR 20, ACR50, ACR70 response rate at Week 24 are shown in Table 40.
At Week 24, 254 patients receiving Humira were randomised again to either continue on Humira 40 mg (Humira/Humira) or be transitioned to Hadlima 40 mg (Humira/Hadlima) every other week up to Week 50. Patients receiving Hadlima 40 mg continued to receive Hadlima 40 mg (Hadlima/Hadlima) up to Week 50. 129 patients were continued to be exposed to at least one dose of Humira and 125 patients were exposed to at least one dose of Hadlima following the transition from Humira treatment.
The analysis of ACR20, ACR50, ACR70 response rate at Week 52 are shown in Table 41.
During the study, the efficacy by anti-drug antibody (ADA) status was assessed as a subgroup analysis. In ADA positive patients, the ACR20 response rate at Week 24 was lower in the Hadlima treatment group than in the Humira treatment group (57.5% and 71.2%, respectively), while the ACR50 response rates were 28.8% and 35.6%, and the ACR 70 response rates were 19.2% and 16.4% in the Hadlima and the Humira treatment groups, respectively. The ACR20 response rates at Week 52 in ADA positive patients were 67.1%, 82.1%, and 76.2% in the Hadlima, Humira/Hadlima, and Humira/Humira treatment groups, respectively. Due to the small subgroup analyses, these results have a limitation to draw a definite conclusion.

Immunogenicity of Humira.

Patients in rheumatoid arthritis studies I, II, and III were tested at multiple time points for anti-adalimumab antibodies during the 6 to 12-month period.
Approximately 5.5% (58 of 1,062) of adult rheumatoid arthritis patients receiving adalimumab developed low-titre antibodies to adalimumab at least once during treatment, which were neutralising in vitro. Patients treated with concomitant MTX had a lower rate of antibody development than patients on adalimumab monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse events was observed. With monotherapy, patients receiving fortnightly dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg fortnightly as monotherapy, the ACR20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of adalimumab is unknown.
In pJIA study I a greater percentage of patients developed antibodies to adalimumab compared to adult rheumatoid arthritis patients. Antibody formation was lower when adalimumab was given together with methotrexate in comparison with use as monotherapy. There was no apparent correlation between the presence of antibodies and adverse events. Anti-adalimumab antibodies were identified in 15.8% (27/171) of patients treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 25.6% (22/86), compared to 5.9% (5/85) when adalimumab was used as an add-on to methotrexate.
In pJIA Study II anti-adalimumab antibodies were identified in 7% (1/15) of patients, and the one patient was receiving concomitant methotrexate.
In patients with enthesitis-related arthritis, anti-adalimumab antibodies were identified in 11% (5/46) of patients treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 14% (3/22), compared to 8% (2/24) when adalimumab was used as an add-on to methotrexate.
In paediatric patients with moderately to severely active Crohn's disease, the rate of antibody development in patients receiving adalimumab was 3.3%.
In patients with ankylosing spondylitis, the rate of development of anti-adalimumab antibodies in adalimumab-treated patients was comparable to patients with rheumatoid arthritis. In patients with psoriatic arthritis, the rate of antibody development in patients receiving adalimumab monotherapy was comparable to patients with rheumatoid arthritis; however, in patients receiving concomitant methotrexate the rate was 7% compared to 1% in rheumatoid arthritis. The immunogenicity rate was 8% for psoriasis patients who were treated with adalimumab monotherapy.
In patients with Crohn's disease, anti-adalimumab antibodies were identified in 2.6% (7/269) of patients treated with adalimumab.
In patients with ulcerative colitis, anti-adalimumab antibodies were identified in 3.9% (19/487) of patients treated with adalimumab. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 micrograms/mL. Among the patients whose serum adalimumab levels were < 2 micrograms/mL (approximately 25% of total patients studied), the immunogenicity rate was 20.7%.
In plaque psoriasis patients on long term adalimumab without concomitant methotrexate who participated in a withdrawal and retreatment study, the rate of anti-adalimumab antibodies after retreatment was similar to the rate observed prior to withdrawal.
In patients with paediatric psoriasis, anti-adalimumab antibodies were identified in 13% (5/38) of subjects treated with 0.8 mg/kg adalimumab monotherapy. 37 of the 38 subjects completed the initial double blind period (16 weeks) of study M04-717, and one subject entered the long term follow up period after Week 4.
In patients with moderate to severe hidradenitis suppurativa, anti-adalimumab antibodies were identified in 10/99 subjects (10.1%) treated with adalimumab.
In patients with non-infectious uveitis, anti-adalimumab antibodies were identified in 4.8% (12/249) of patients treated with adalimumab.
The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. For these reasons, comparison of the incidence of antibodies to adalimumab with the incidence of antibodies to other products may be misleading.

Immunogenicity of Hadlima.

See Section 4.8 Adverse Effects (Undesirable Effects), Comparability of Hadlima with Humira - adverse effects; Section 5.1 Pharmacodynamic Properties, Comparability of Hadlima with Humira - clinical trials for information on the immunogenicity of Hadlima.

5.2 Pharmacokinetic Properties

Pharmacokinetics.

Absorption.

Following a single 40 mg subcutaneous (SC) administration of adalimumab to 59 healthy adult subjects, absorption of adalimumab was slow, with mean peak serum concentration being reached about five days after administration. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. The pharmacokinetics of adalimumab was linear over the dose range of 0.5 to 10 mg/kg following a single intravenous dose.

Distribution and elimination.

The single dose pharmacokinetics of adalimumab in rheumatoid arthritis (RA) patients was determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The distribution volume (Vss) ranged from 4.7 to 6.0 L. Adalimumab is slowly eliminated, with clearances typically under 12 mL/h. The mean terminal phase half-life was approximately two weeks, ranging from 10 to 20 days across studies.
Adalimumab concentrations in the synovial fluid from several RA patients ranged from 31 to 96% of those in serum.

Specific populations.

Pharmacokinetics in special populations were investigated using population pharmacokinetic analyses.

Race/ethnicity.

No differences in immunoglobulin clearance would be expected among races. From limited data in non-Caucasians, no important kinetic differences were observed for adalimumab.

Gender/weight.

No gender-related pharmacokinetic differences were observed after correction for a patient's body weight.

Paediatric patients.

In pJIA Study I for patients with polyarticular juvenile idiopathic arthritis (4 to 17 years of age), the mean steady-state trough serum adalimumab concentrations for patients weighing < 30 kg receiving 20 mg adalimumab subcutaneously fortnightly without concomitant methotrexate or with concomitant methotrexate were 6.8 micrograms/mL and 10.9 micrograms/mL, respectively. The mean steady-state trough serum adalimumab concentrations for patients weighing ≥ 30 kg receiving 40 mg adalimumab subcutaneously fortnightly without concomitant methotrexate, or with concomitant methotrexate, were 6.6 micrograms/mL and 8.1 micrograms/mL, respectively. In pJIA Study II for patients with polyarticular juvenile idiopathic arthritis who were 2 to < 4 years old, or aged 4 years and above weighing < 15 kg, the mean steady-state trough serum adalimumab concentrations for patients receiving adalimumab subcutaneously fortnightly were 6.0 ± 6.1 micrograms/mL (101% CV) for adalimumab without concomitant methotrexate, and 7.9 ± 5.6 micrograms/mL (71.2% CV) with concomitant methotrexate (see Table 42).
Following the administration of 24 mg/m2 (up to a maximum of 40 mg) subcutaneously fortnightly to patients with enthesitis-related arthritis, the mean trough steady-state (values measured at Week 24) serum adalimumab concentrations were 8.8 ± 6.6 micrograms/mL for adalimumab without concomitant methotrexate and 11.8 ± 4.3 micrograms/mL with concomitant methotrexate. Based on a population pharmacokinetic (PK) modelling approach, simulated steady-state adalimumab serum trough concentrations for a weight-based dosing regimen (20 mg adalimumab fortnightly for body weight < 30 kg and 40 mg adalimumab fortnightly for body weight ≥ 30 kg) were comparable to the simulated trough concentrations for the body surface area-based regimen.
In paediatric patients with moderately to severely active Crohn's disease, the open-label adalimumab induction dose was 160/80 mg or 80/40 mg at Weeks 0 and 2, respectively, dependent on a body weight cut-off of 40 kg. At Week 4, subjects were randomised 1:1 to either the Standard Dose (40/20 mg fortnightly) or Low Dose (20/10 mg fortnightly) maintenance treatment groups based on their body weight. The mean (± SD) serum adalimumab trough concentrations achieved at Week 4 were 15.7 ± 6.6 micrograms/mL for patients ≥ 40 kg (160/80 mg) and 10.6 ± 6.1 micrograms/mL for patients < 40 kg (80/40 mg).
For subjects who stayed on their randomised therapy, the mean (± SD) adalimumab trough concentrations at Week 52 were 9.5 ± 5.6 micrograms/mL for the Standard Dose group and 3.5 ± 2.2 micrograms/mL for the Low Dose group. The mean trough concentrations were maintained in subjects who continued to receive adalimumab treatment fortnightly for 52 weeks. For subjects who dose escalated from fortnightly to weekly regimen, the mean (± SD) serum concentrations of adalimumab at Week 52 were 15.3 ± 11.4 micrograms/mL (40/20 mg, weekly) and 6.7 ± 3.5 micrograms/mL (20/10 mg, weekly).
Following the administration of 0.8 mg/kg (up to a maximum of 40 mg) subcutaneously fortnightly to paediatric patients with chronic plaque psoriasis, the mean ± SD steady-state adalimumab trough concentration (measured at Week 11) was approximately 7.4 ± 5.8 micrograms/mL (79% CV). Serum adalimumab concentrations after 40 mg fortnightly in adult psoriasis patients are comparable to those following 0.8 mg/kg fortnightly in paediatric psoriasis patients in study M04-717 (range 7-11 micrograms/mL).
Adalimumab exposure in adolescent hidradenitis suppurativa (HS) patients was predicted using population pharmacokinetic modelling and simulation based on cross-indication pharmacokinetics in other paediatric patients (paediatric psoriasis, juvenile idiopathic arthritis, paediatric Crohn's disease, and enthesitis-related arthritis). The recommended adolescent HS dosing schedule of 40 mg fortnightly is predicted to provide serum adalimumab exposure and efficacy similar to that observed in adult HS patients receiving the recommended adult dose of 40 mg every week.

Geriatric patients.

Adalimumab's apparent clearance decreases slightly with increasing age. From the population analyses, the mean weight-adjusted clearances in patients 40 to 65 years (n=850) and ≥ 65 years (n=287) were 0.33 and 0.30 mL/h/kg, respectively.

Hepatic and renal insufficiency.

No pharmacokinetic data are available in patients with hepatic or renal impairment.

Disease states.

Healthy volunteers and patients with RA displayed similar adalimumab pharmacokinetics.

Drug interactions, methotrexate.

When adalimumab was administered to 21 RA patients on stable methotrexate therapy, there were no statistically significant changes in the serum methotrexate concentration profiles. In contrast, after single and multiple dosing, methotrexate reduced adalimumab's apparent clearances by 29% and 44% respectively (see Section 4.4 Special Warnings and Precautions for Use). This is consistent with the higher trough concentrations of adalimumab found in patients treated with concomitant methotrexate (see Section 5.1 Pharmacodynamic Properties, Steady-state).

Comparability of Hadlima 40 mg/0.8 mL (50 mg/mL) with Humira 40 mg/0.8 mL (50 mg/mL) - pharmacokinetic properties.

The pharmacokinetic profiles of Hadlima 40 mg/0.8 mL and Humira 40 mg/0.8 mL were comparable in a randomised, single-blind, three-arm, parallel group clinical Phase I study in healthy subjects following a single SC injection of either Hadlima, EU Humira or US Humira (40 mg) (study SB5-G11-NHV). The PK parameters, AUCinf, AUClast and Cmax, were compared between Hadlima and Humira. The summary of the pharmacokinetic profiles of Hadlima and EU Humira in healthy volunteers are listed in Table 43.
In addition, to provide supportive evidence of PK similarity between Hadlima and EU Humira in patients with RA, pharmacokinetic profiles were evaluated in a subset of RA patients receiving either 40 mg of Hadlima (n=178) or 40 mg of EU Humira (n=178) in a randomised, double-blind, parallel group clinical Phase III study (Study SB5-G31-RA). The levels of Ctrough from Week 4 to Week 24 were comparable between Hadlima and EU Humira, ranging from 3.850 to 6.761 micrograms/mL for Hadlima and 3.892 to 6.773 micrograms/mL for EU Humira.

Comparability of Hadlima 40 mg/0.4 mL (100 mg/mL) with Hadlima 40 mg/0.8 mL (50 mg/mL) - pharmacokinetic properties.

The pharmacokinetic profiles of Hadlima 40 mg/0.4 mL (100 mg/mL) and Hadlima 40 mg/0.8 mL (50 mg/mL) were comparable in a randomised, single-blind, two-arm, parallel-group, phase I clinical study in healthy male subjects following a single SC injection of either Hadlima 40 mg/0.4 mL or Hadlima 40 mg/0.8 mL (study SB5-1003). The summary of the pharmacokinetic profiles of Hadlima 40 mg/0.4 mL and Hadlima 40 mg/0.8 mL in healthy male subjects are listed in Table 44.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity was observed in an in vitro test for bacterial gene mutation or in an in vivo mouse micronucleus test for clastogenicity.

Carcinogenicity.

Long-term animal studies have not been conducted to evaluate the carcinogenic potential of adalimumab.

6 Pharmaceutical Particulars

6.1 List of Excipients

Hadlima 40 mg/0.8 mL (50 mg/mL).

Inactive ingredients include: 1.6 mg sodium citrate dihydrate, 0.544 mg citric acid monohydrate, 0.96 mg histidine, 8.64 mg histidine hydrochloride monohydrate, 20.0 mg sorbitol, 0.64 mg polysorbate 20 and water for injections.

Hadlima 40 mg/0.4 mL (100 mg/mL).

Inactive ingredients include: 0.376 mg histidine, 4.436 mg histidine hydrochloride monohydrate, 12.00 mg mannitol, 0.32 mg polysorbate 20, 0.008 mg dibasic sodium phosphate heptahydrate, 0.14 mg monobasic sodium phosphate monohydrate and 0.196 mg sodium succinate, 0.096 mg succinic acid and water for injections.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store at 2°C to 8°C (in a refrigerator) and store the syringe and PushTouch auto-injector in the outer carton to protect from light. Do not freeze.
Do not use beyond the expiration date.
When required (for example, when travelling), a single Hadlima pre-filled syringe or PushTouch auto-injector 40 mg /0.8 mL (50 mg/mL) may be stored below 25°C (room temperature) for a maximum period of 28 days, but must be protected from light. Once removed from the refrigerator for room temperature storage, the syringe or PushTouch auto-injector must be used within 28 days or discarded, even if it is returned to the refrigerator.
Hadlima pre-filled syringe or PushTouch auto-injector 40 mg/0.4 mL (100 mg/mL) may be stored below 25°C (room temperature) for a maximum period of 31 days. Once removed from the refrigerator for room temperature storage, the syringe or PushTouch auto-injector must be used within 31 days or discarded even if it is returned to the refrigerator.
The date of removal from the refrigerator should be recorded on the syringe label, to allow the syringe to be discarded after the maximum 28 days for 40 mg/0.8 mL and maximum 31 days for 40 mg/0.4 mL if not used.

6.5 Nature and Contents of Container

Hadlima (adalimumab) solution for injection is supplied as a sterile solution of 40 mg adalimumab dissolved in 0.8 mL or 0.4 mL sterile solution for subcutaneous administration in the following packaging configurations:

Hadlima 40 mg solution for injection in single-use pre-filled syringe (for patient use).

0.8 mL or 0.4 mL solution for injection in single-use pre-filled syringe (type I glass) with a stainless steel needle, a rigid needle shield, a rubber plunger (chlorobutyl), a plunger rod, a safe-shield body and a finger flange.
Carton containing 2 pre-filled syringes.

Hadlima 40 mg solution for injection in single-use PushTouch auto-injector (for patient use).

0.8 mL or 0.4 mL solution for injection in single-use pre-filled pen for patient use containing a pre-filled syringe. The syringe inside the pen is made from type I glass with a stainless steel needle, a rigid needle shield, a rubber plunger (chlorobutyl).
Carton containing 2 PushTouch auto-injectors.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.
Hadlima contains no antimicrobial agent. Hadlima is for single use in one patient only. Discard any residue.

6.7 Physicochemical Properties

CAS number.

CAS Registry Number: 331731-18-1.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes