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نشرة الممارس الصحي	نشرة معلومات المريض بالعربية	نشرة معلومات المريض بالانجليزية	صور الدواء	بيانات الدواء

رقم التسجيل

1910222761

سنة التسجيل

2022

الاسم التجاري

SIMLANDI 40MG/0.4ML SOLUTION FOR INJECTION PFS

الاسم العلمي

ADALIMUMAB

التركيز

وحدة التركيز

طريقة الإستعمال

Subcutaneous use

الشكل الصيدلاني

Solution for injection

الحجم

وحدة الحجم

حجم العبوة

انواع العبوات

Pre-filled pen

طريقة الصرف

Prescription

حالة المراقبة

Uncontrolled

نوع الدواء

Biological

مدة الصلاحية بالأشهر

شروط التخزين

Store in a refrigerator (2°C – 8°C), do not freeze

سعر الجمهور بالريال ( السعر )

1889.10

المصنع

Alvotech hf

الوكيل

Tabuk Pharmaceutical Manufacturing Company

الشركة المسوقة

Tabuk Pharmaceutical Manufacturing Company

كود الكيمياء العلاجية التشريحية 1

QL04AB04

كود الكيمياء العلاجية التشريحية 2

لم يتم إدخال بيانات نشرة معلومات المريض لهذا الدواء حتى الآن

Read this leaflet carefully before you start using this product as it contains important information for you

1. NAME OF THE MEDICINAL PRODUCT

SIMLANDI 40 mg solution for injection in pre-filled syringe SIMLANDI 40 mg solution for injection in pre-filled pen

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

SIMLANDI 40 mg solution for injection in pre-filled syringe Each 0.4 ml single dose pre-filled syringe contains 40 mg adalimumab. SIMLANDI 40 mg solution for injection in pre-filled pen Each 0.4 ml single dose pre-filled pen contains 40 mg adalimumab. Adalimumab is a recombinant human monoclonal antibody produced in Chinese Hamster Ovary cells. For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection. Clear and colourless solution for injection.

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

Rheumatoid arthritis
SIMLANDI in combination with methotrexate, is indicated for:
 the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the
response to disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate has
been inadequate.
 the treatment of severe, active and progressive rheumatoid arthritis in adults not previously
treated with methotrexate.
SIMLANDI can be given as monotherapy in case of intolerance to methotrexate or when continued
treatment with methotrexate is inappropriate.
Adalimumab has been shown to reduce the rate of progression of joint damage as measured by X-ray
and to improve physical function, when given in combination with methotrexate.
Juvenile idiopathic arthritis
Polyarticular juvenile idiopathic arthritis
SIMLANDI in combination with methotrexate is indicated for the treatment of active polyarticular
juvenile idiopathic arthritis, in patients from the age of 2 years who have had an inadequate response
to one or more DMARD. SIMLANDI can be given as monotherapy in case of intolerance to
methotrexate or when continued treatment with methotrexate is inappropriate (for the efficacy in
monotherapy see section 5.1). Adalimumab has not been studied in patients aged less than 2 years.
Enthesitis-related arthritis
SIMLANDI is indicated for the treatment of active enthesitis-related arthritis in patients, ≥ 6 years of
age, who have had an inadequate response to, or who are intolerant of, conventional therapy (see
section 5.1).
Axial spondyloarthritis
Ankylosing spondylitis (AS)
SIMLANDI is indicated for the treatment of adults with severe active ankylosing spondylitis who have
had an inadequate response to conventional therapy.
Axial spondyloarthritis without radiographic evidence of AS
SIMLANDI is indicated for the treatment of adults with severe axial spondyloarthritis without
radiographic evidence of AS but with objective signs of inflammation by elevated CRP and/or MRI,
who have had an inadequate response to, or are intolerant to nonsteroidal anti-inflammatory drugs
(NSAIDs).
Psoriatic arthritis
SIMLANDI is indicated for the treatment of active and progressive psoriatic arthritis in adults when
the response to previous DMARD therapy has been inadequate. Adalimumab has been shown to
reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with
polyarticular symmetrical subtypes of the disease (see section 5.1) and to improve physical function.
Psoriasis
SIMLANDI is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult
patients who are candidates for systemic therapy.
Paediatric plaque psoriasis
SIMLANDI is indicated for the treatment of severe chronic plaque psoriasis in children and
adolescents from 4 years of age who have had an inadequate response to or are inappropriate
candidates for topical therapy and phototherapies.
Hidradenitis suppurativa (HS)
SIMLANDI is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne
inversa) in adults and adolescents from 12 years of age with an inadequate response to conventional
systemic HS therapy (see sections 5.1 and 5.2).
Crohn’s disease
SIMLANDI is indicated for treatment of moderately to severely active Crohn’s disease, in adult
patients who have not responded despite a full and adequate course of therapy with a corticosteroid
and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such
therapies.
Paediatric Crohn's disease
SIMLANDI is indicated for the treatment of moderately to severely active Crohn's disease in
paediatric patients (from 6 years of age) who have had an inadequate response to conventional therapy
including primary nutrition therapy and a corticosteroid and/or an immunomodulator, or who are
intolerant to or have contraindications for such therapies.
Ulcerative colitis
SIMLANDIis indicated for treatment of moderately to severely active ulcerative colitis in adult
patients who have had an inadequate response to conventional therapy including corticosteroids and 6-
mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical
contraindications for such therapies.
Uveitis
SIMLANDI is indicated for the treatment of non-infectious intermediate, posterior and panuveitis 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.
Paediatric uveitis
SIMLANDI is indicated for the treatment of paediatric chronic non-infectious anterior uveitis in
patients from 2 years of age who have had an inadequate response to or are intolerant to conventional
therapy, or in whom conventional therapy is inappropriate.

4.2 Posology And Method Administration

SIMLANDI treatment should be initiated and supervised by specialist physicians experienced in the
diagnosis and treatment of conditions for which SIMLANDI is indicated. Ophthalmologists are
advised to consult with an appropriate specialist before initiation of treatment with SIMLANDI (see
section 4.4). Patients treated with SIMLANDI should be given the Patient Reminder Card.
After proper training in injection technique, patients may self-inject with SIMLANDI if their
physician determines that it is appropriate and with medical follow-up as necessary.
During treatment with SIMLANDI, other concomitant therapies (e.g., corticosteroids and/or
immunomodulatory agents) should be optimised.
Posology
Adults
Rheumatoid arthritis
The recommended dose of SIMLANDI for adult patients with rheumatoid arthritis is 40 mg
adalimumab administered every other week as a single dose via subcutaneous injection. Methotrexate
should be continued during treatment with SIMLANDI.
Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, or analgesics can be continued
during treatment with SIMLANDI. Regarding combination with disease modifying anti-rheumatic
drugs other than methotrexate see sections 4.4 and 5.1.
In monotherapy, some patients who experience a decrease in their response to SIMLANDI 40 mg
every other week may benefit from an increase in dosage to 40 mg adalimumab every week or 80 mg
every other week.
Available data suggest that the clinical response is usually achieved within 12 weeks of treatment.
Continued therapy should be reconsidered in a patient not responding within this time period.
SIMLANDI may be available in other strengths and/or presentations depending on the individual
treatment needs. SIMLANDI is only available as 40 mg pre-filled syringe, 40 mg pre-filled pen and 80
mg pre-filled syringe. Thus, it is not possible to administer SIMLANDI to patients that require less
than a full 40 mg dose.
Dose interruption
There may be a need for dose interruption, for instance before surgery or if a serious infection occurs.
Available data suggest that re-introduction of adalimumab after discontinuation for 70 days or longer
resulted in the same magnitudes of clinical response and similar safety profile as before dose
interruption.
Ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS and psoriatic
arthritis
The recommended dose of SIMLANDI for patients with ankylosing spondylitis, axial
spondyloarthritis without radiographic evidence of AS and for patients with psoriatic arthritis is 40 mg
adalimumab administered every other week as a single dose via subcutaneous injection.
Available data suggest that the clinical response is usually achieved within 12 weeks of treatment.
Continued therapy should be reconsidered in a patient not responding within this time period.
Psoriasis
The recommended dose of SIMLANDI for adult patients is an initial dose of 80 mg administered
subcutaneously, followed by 40 mg subcutaneously given every other week 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 to SIMLANDI 40 mg every other week may
benefit from an increase in dosage to 40 mg every week or 80 mg every other week. The benefits and
risks of continued 40 mg weekly or 80 mg every other week therapy should be carefully reconsidered
in a patient with an inadequate response after the increase in dosage (see section 5.1). If adequate
response is achieved with 40 mg every week or 80 mg every other week, the dosage may subsequently
be reduced to 40 mg every other week.
SIMLANDI may be available in other strengths and/or presentations depending on the individual
treatment needs. SIMLANDI is only available as 40 mg pre-filled syringe, 40 mg pre-filled pen and 80
mg pre-filled syringe. Thus, it is not possible to administer SIMLANDI to patients that require less
than a full 40 mg dose.
Hidradenitis suppurativa
The recommended SIMLANDI 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 in one day). Two weeks later (Day 29) continue with a dose of 40 mg every week or 80 mg
every other week (given as two 40 mg injections in one day). Antibiotics may be continued during
treatment with SIMLANDI 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 SIMLANDI.
Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with no
improvement within this time period.
Should treatment be interrupted, SIMLANDI 40 mg every week or 80 mg every other week may be reintroduced (see section 5.1).
The benefit and risk of continued long-term treatment should be periodically evaluated (see section
5.1).
SIMLANDI may be available in other strengths and/or presentations depending on the individual
treatment needs. SIMLANDI is only available as 40 mg pre-filled syringe, 40 mg pre-filled pen and
80 mg pre-filled syringe. Thus, it is not possible to administer SIMLANDI to patients that require less
than a full 40 mg dose.
Crohn’s disease
The recommended SIMLANDI induction dose regimen for adult patients with moderately to severely
active Crohn’s disease is 80 mg at Week 0 followed by 40 mg at Week 2. In case there is a need for a
more rapid response to therapy, the regimen 160 mg at Week 0 (given as four 40 mg injections in one
day or as two 40 mg injections per day for two consecutive days), 80 mg at Week 2 (given as two
40 mg injections in one day), can be used with the awareness that the risk for adverse events is higher
during induction.
After induction treatment, the recommended dose is 40 mg every other week via subcutaneous
injection. Alternatively, if a patient has stopped SIMLANDI and signs and symptoms of disease recur,
SIMLANDI may be re-administered. There is little experience from re-administration after more than
8 weeks since the previous dose.
During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice
guidelines.
Some patients who experience decrease in their response to SIMLANDI 40 mg every other week may
benefit from an increase in dosage to 40 mg SIMLANDI every week or 80 mg every other week.
Some patients who have not responded by Week 4 may benefit from continued maintenance therapy
through Week 12. Continued therapy should be carefully reconsidered in a patient not responding
within this time period.
SIMLANDI may be available in other strengths and/or presentations depending on the individual
treatment needs. SIMLANDI is only available as 40 mg pre-filled syringe, 40 mg pre-filled pen and 80
mg pre-filled syringe. Thus, it is not possible to administer SIMLANDI to patients that require less
than a full 40 mg dose.
Ulcerative colitis
The recommended SIMLANDI induction dose regimen for adult patients with moderate to severe
ulcerative colitis is 160 mg at Week 0 (given as four 40 mg injections in one day or as two 40 mg
injections per day for two consecutive days) and 80 mg at Week 2 (given as two 40 mg injections in
one day). After induction treatment, the recommended dose is 40 mg every other week via
subcutaneous injection.
During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice
guidelines.
Some patients who experience decrease in their response to 40 mg every other week may benefit from
an increase in dosage to 40 mg SIMLANDI every week or 80 mg every other week.
Available data suggest that clinical response is usually achieved within 2-8 weeks of treatment.
SIMLANDI therapy should not be continued in patients failing to respond within this time period.
SIMLANDI may be available in other strengths and/or presentations depending on the individual
treatment needs. SIMLANDI is only available as 40 mg pre-filled syringe, 40 mg pre-filled pen and 80
mg pre-filled syringe. Thus, it is not possible to administer SIMLANDI to patients that require less
than a full 40 mg dose.
Uveitis
The recommended dose of SIMLANDI for adult patients with uveitis is an initial dose of 80 mg,
followed by 40 mg given every other week starting one week after the initial dose. There is limited
experience in the initiation of treatment with adalimumab alone. Treatment with SIMLANDI can be
initiated in combination with corticosteroids and/or with other non-biologic immunomodulatory
agents. Concomitant corticosteroids may be tapered in accordance with clinical practice starting two
weeks after initiating treatment with SIMLANDI.
It is recommended that the benefit and risk of continued long-term treatment should be evaluated on a
yearly basis (see section 5.1).
SIMLANDI may be available in other strengths and/or presentations depending on the individual
treatment needs. SIMLANDI is only available as 40 mg pre-filled syringe, 40 mg pre-filled pen and
80 mg pre-filled syringe. Thus, it is not possible to administer SIMLANDI to patients that require less
than a full 40 mg dose.
Special populations
Elderly
No dose adjustment is required.
Renal and/or hepatic impairment
Adalimumab has not been studied in these patient populations. No dose recommendations can be
made.
Paediatric population
Juvenile idiopathic arthritis
Polyarticular juvenile idiopathic arthritis from 2 years of age
The recommended dose of SIMLANDI for patients with polyarticular juvenile idiopathic arthritis from
2 years of age is based on body weight (Table 1). SIMLANDI is administered every other week via
subcutaneous injection.

Available data suggest that 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.
There is no relevant use of adalimumab in patients aged less than 2 years for this indication.
SIMLANDI is available as 40 mg pre-filled syringe and 40 mg pre-filled pen as the lowest dose. Thus,
it is not possible to administer SIMLANDI to patients that require less than a full 40 mg dose.
SIMLANDI is only available as 40 mg pre-filled syringe, 40 mg pre-filled pen and 80 mg pre-filled
syringe. Thus, it is not possible to administer SIMLANDI to patients that require less than a full 40 mg
dose.
Enthesitis-related arthritis
The recommended dose of SIMLANDI for patients with enthesitis-related arthritis from 6 years of age
is based on body weight (Table 2). SIMLANDI is administered every other week via subcutaneous
injection.

Adalimumab has not been studied in patients with enthesitis-related arthritis aged less than 6 years.
SIMLANDI is available as 40 mg pre-filled syringe and 40 mg pre-filled pen as the lowest dose. Thus,
it is not possible to administer SIMLANDI to patients that require less than a full 40 mg dose.
SIMLANDI is only available as 40 mg pre-filled syringe, 40 mg pre-filled pen and 80 mg pre-filled
syringe. Thus, it is not possible to administer SIMLANDI to patients that require less than a full 40 mg
dose.
Paediatric plaque psoriasis
The recommended SIMLANDI dose for patients with plaque psoriasis from 4 to 17 years of age is
based on body weight (Table 3). SIMLANDI is administered via subcutaneous injection.

Continued therapy beyond 16 weeks should be carefully considered in a patient not responding within
this time period.
If retreatment with adalimumab is indicated, the above guidance on dose and treatment duration
should be followed.
The safety of adalimumab in paediatric patients with plaque psoriasis has been assessed for a mean of
13 months.
There is no relevant use of adalimumab in children aged less than 4 years for this indication.
SIMLANDI is available as 40 mg pre-filled syringe and 40 mg pre-filled pen as the lowest dose. Thus,
it is not possible to administer SIMLANDI to patients that require less than a full 40 mg dose.
SIMLANDI is only available as 40 mg pre-filled syringe, 40 mg pre-filled pen and 80 mg pre-filled
syringe. Thus, it is not possible to administer SIMLANDI to patients that require less than a full 40 mg
dose.
Adolescent hidradenitis suppurativa (from 12 years of age, weighing at least 30 kg)
There are no clinical trials with adalimumab in adolescent patients with HS. The posology of
adalimumab in these patients has been determined from pharmacokinetic modelling and simulation
(see section 5.2).
The recommended SIMLANDI dose is 80 mg at Week 0 followed by 40 mg every other week starting
at Week 1 via subcutaneous injection.
In adolescent patients with inadequate response to SIMLANDI 40 mg every other week, an increase in
dosage to 40 mg every week or 80 mg every other week may be considered.
Antibiotics may be continued during treatment with SIMLANDI 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 SIMLANDI.
Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with no
improvement within this time period.
Should treatment be interrupted, SIMLANDI may be re-introduced as appropriate.
The benefit and risk of continued long-term treatment should be periodically evaluated (see adult data
in section 5.1).
There is no relevant use of adalimumab in children aged less than 12 years in this indication.
SIMLANDI may be available in other strengths and/or presentations depending on the individual
treatment needs. SIMLANDI is only available as 40 mg pre-filled syringe, 40 mg pre-filled pen and
80 mg pre-filled syringe. Thus, it is not possible to administer SIMLANDI to patients that require less
than a full 40 mg dose.
Paediatric Crohn's disease
The recommended dose of SIMLANDI for patients with Crohn’s disease from 6 to 17 years of age is
based on body weight (Table 4). SIMLANDI is administered via subcutaneous injection.

Patients who experience insufficient response may benefit from an increase in dosage:
• < 40 kg: 20 mg every week
• ≥ 40 kg: 40 mg every week or 80 mg every other week
Continued therapy should be carefully considered in a subject not responding by Week 12.
There is no relevant use of adalimumab in children aged less than 6 years for this indication.
SIMLANDI is available as 40 mg pre-filled syringe and 40 mg pre-filled pen as the lowest dose. Thus,
it is not possible to administer SIMLANDI to patients that require less than a full 40 mg dose.
SIMLANDI is only available as 40 mg pre-filled syringe, 40 mg pre-filled pen and 80 mg pre-filled
syringe. Thus, it is not possible to administer SIMLANDI to patients that require less than a full 40 mg
dose.
Paediatric uveitis
The recommended dose of SIMLANDI for paediatric patients with uveitis from 2 years of age is based
on body weight (Table 5). SIMLANDI is administered via subcutaneous injection.
In paediatric uveitis, there is no experience in the treatment with adalimumab without concomitant
treatment with methotrexate.

When SIMLANDI therapy is initiated, a loading dose of 40 mg for patients < 30 kg or 80 mg for
patients ≥ 30 kg may be administered one week prior to the start of maintenance therapy. No clinical
data are available on the use of an adalimumab loading dose in children < 6 years of age (see section
5.2).
There is no relevant use of adalimumab in children aged less than 2 years in this indication.
It is recommended that the benefit and risk of continued long-term treatment should be evaluated on a
yearly basis (see section 5.1).
SIMLANDI is available as 40 mg pre-filled syringe and 40 mg pre-filled pen as the lowest dose. Thus,
it is not possible to administer SIMLANDI to patients that require less than a full 40 mg dose.
SIMLANDI is only available as 40 mg pre-filled syringe, 40 mg pre-filled pen and 80 mg pre-filled
syringe. Thus, it is not possible to administer SIMLANDI to patients that require less than a full 40 mg
dose.
Paediatric ulcerative colitis
The safety and efficacy of adalimumab in children aged 4-17 years have not yet been established. No
data are available.
There is no relevant use of adalimumab in children aged less than 4 years for this indication.
Psoriatic arthritis and axial spondyloarthritis including ankylosing spondylitis
There is no relevant use of adalimumab in the paediatric population for the indications of ankylosing
spondylitis and psoriatic arthritis.
Method of administration
SIMLANDI is administered by subcutaneous injection. Full instructions for use are provided in the
package leaflet.
SIMLANDI is available as 40 mg pre-filled syringe and 40 mg pre-filled pen or as 80 mg pre-filled
syringe.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Active tuberculosis or other severe infections such as sepsis, and opportunistic infections (see section 4.4). - Moderate to severe heart failure (NYHA class III/IV) (see section 4.4).

4.4. Special warnings and precautions for use

Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number
of the administered product should be clearly recorded.
Infections
Patients taking TNF-antagonists are more susceptible to serious infections. Impaired lung function
may increase the risk for developing infections. Patients must therefore be monitored closely for
infections, including tuberculosis, before, during and after treatment with SIMLANDI. Because the
elimination of adalimumab may take up to four months, monitoring should be continued throughout
this period.
Treatment with SIMLANDI 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
SIMLANDI should be considered prior to initiating therapy (see “Other opportunistic infections”).
Patients who develop a new infection while undergoing treatment with SIMLANDI should be
monitored closely and undergo a complete diagnostic evaluation. Administration of SIMLANDI
should be discontinued if a patient develops a new serious infection or sepsis, and appropriate
antimicrobial or antifungal therapy should be initiated until the infection is controlled. 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, including the use
of concomitant immunosuppressive medications.
Serious infections
Serious infections, including sepsis, due to bacterial, mycobacterial, invasive fungal, parasitic, viral, or
other opportunistic infections such as listeriosis, legionellosis and pneumocystis have been reported in
patients receiving 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.
Tuberculosis
Tuberculosis, including reactivation and new onset of tuberculosis, has been reported in patients
receiving adalimumab. Reports included cases of pulmonary and extra-pulmonary (i.e. disseminated)
tuberculosis.
Before initiation of therapy with SIMLANDI, all patients must be evaluated for both active or 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 (i.e. tuberculin skin
test and chest X-ray) should be performed in all patients (local recommendations may apply). It is
recommended that the conduct and results of these tests are recorded in the Patient Reminder Card.
Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients
who are severely ill or immunocompromised.
If active tuberculosis is diagnosed, SIMLANDI therapy must not be initiated (see section 4.3).
In all situations described below, the benefit/risk balance of therapy should be very carefully
considered.
If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be
consulted.
If latent tuberculosis is diagnosed, appropriate treatment must be started with anti-tuberculosis
prophylaxis treatment before the initiation of SIMLANDI, and in accordance with local
recommendations.
Use of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of
SIMLANDI 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.
Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in
patients treated with adalimumab. Some patients who have been successfully treated for active
tuberculosis have redeveloped tuberculosis while being treated with adalimumab.
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, listlessness) occur during or
after therapy with SIMLANDI.
Other opportunistic infections
Opportunistic infections, including invasive fungal infections have been observed in patients receiving
adalimumab. These infections have not consistently been recognised in patients taking TNFantagonists and this has resulted in delays in appropriate treatment, sometimes resulting in fatal
outcomes.
For patients who develop the signs and symptoms such as fever, malaise, weight loss, sweats, cough,
dyspnoea, and/or pulmonary infiltrates or other serious systemic illness with or without concomitant
shock an invasive fungal infection should be suspected and administration of SIMLANDI should be
promptly discontinued. Diagnosis and administration of empiric antifungal therapy in these patients
should be made in consultation with a physician with expertise in the care of patients with invasive
fungal infections.
Hepatitis B reactivation
Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including adalimumab,
who are chronic carriers of this virus (i.e. surface antigen positive). Some cases have had a fatal
outcome. Patients should be tested for HBV infection before initiating treatment with SIMLANDI. For
patients who test positive for hepatitis B infection, consultation with a physician with expertise in the
treatment of hepatitis B is recommended.
Carriers of HBV who require treatment with SIMLANDI should be closely monitored for signs and
symptoms of active HBV infection throughout therapy and for several months following termination
of therapy. Adequate data from treating patients who are carriers of HBV with anti-viral therapy in
conjunction with TNF-antagonist therapy to prevent HBV reactivation are not available. In patients
who develop HBV reactivation, SIMLANDI should be stopped and effective anti-viral therapy with
appropriate supportive treatment should be initiated.
Neurological events
TNF-antagonists including adalimumab have been associated in rare instances 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 SIMLANDI in patients with pre-existing or recent-onset central or peripheral nervous system
demyelinating disorders; discontinuation of SIMLANDI 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 SIMLANDI therapy and regularly during treatment to assess for preexisting or developing central demyelinating disorders.
Allergic reactions
Serious allergic reactions associated with adalimumab were rare during clinical trials. Non-serious
allergic reactions associated with adalimumab were uncommon during clinical trials. 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
SIMLANDI should be discontinued immediately and appropriate therapy initiated.
Immunosuppression
In a study of 64 patients with rheumatoid arthritis that were treated with adalimumab, there was no
evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or
change in enumeration of effector T-, B-, NK-cells, monocyte / macrophages, and neutrophils.
Malignancies and lymphoproliferative disorders
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 compared with control
patients. However, the occurrence was rare. In the post-marketing setting, cases of leukaemia have
been reported in patients treated with a TNF-antagonist. There is an increased background risk for
lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active,
inflammatory disease, which complicates the risk estimation. With the current knowledge, a possible
risk for the development of lymphomas, leukaemia, and other malignancies in patients treated with a
TNF-antagonist cannot be excluded.
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to
22 years of age) treated with TNF-antagonists (initiation of therapy ≤ 18 years of age), including
adalimumab in the post-marketing setting. Approximately half the cases were lymphomas. The other
cases represented a variety of different malignancies and included rare malignancies usually associated
with immunosuppression. A risk for the development of malignancies in children and adolescents
treated with TNF-antagonists cannot be excluded.
Rare post-marketing cases of hepatosplenic T-cell lymphoma have been identified in patients treated
with adalimumab. This rare type of T-cell lymphoma has a very aggressive disease course and is
usually fatal. Some of these hepatosplenic T-cell lymphomas with adalimumab have occurred in
young adult patients on concomitant treatment with azathioprine or 6-mercaptopurine used for
inflammatory bowel disease. The potential risk with the combination of azathioprine or 6-
mercaptopurine and SIMLANDI should be carefully considered. A risk for the development of
hepatosplenic T-cell lymphoma in patients treated with SIMLANDI cannot be excluded (see section
4.8).
No studies have been conducted that include patients with a history of malignancy or in whom
treatment with adalimumab is continued following development of malignancy. Thus additional
caution should be exercised in considering SIMLANDI treatment of these patients (see section 4.8).
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 nonmelanoma skin cancer prior to and during treatment with SIMLANDI. Melanoma and Merkel cell
carcinoma have also been reported in patients treated with TNF-antagonists including adalimumab
(see section 4.8).
In an exploratory clinical trial evaluating the use of another TNF-antagonist, 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 increased risk for malignancy due to
heavy smoking.
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.
Haematologic reactions
Rare reports of pancytopenia including aplastic anaemia have been reported with TNF-antagonists.
Adverse events of the haematologic system, including medically significant cytopenia (e.g.
thrombocytopenia, leukopenia) have been reported with adalimumab. All patients should be advised to
seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias
(e.g. persistent fever, bruising, bleeding, pallor) while on SIMLANDI. Discontinuation of SIMLANDI
therapy should be considered in patients with confirmed significant haematologic abnormalities.
Vaccinations
Similar antibody responses to the standard 23-valent pneumococcal vaccine and the influenza trivalent
virus vaccination were observed in a study in 226 adult subjects with rheumatoid arthritis who were
treated with adalimumab or placebo. No data are available on the secondary transmission of infection
by live vaccines in patients receiving adalimumab.
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 SIMLANDI therapy.
Patients on SIMLANDI may receive concurrent vaccinations, except for live vaccines. Administration
of live vaccines (e.g., BCG vaccine) to infants exposed to adalimumab in utero is not recommended
for 5 months following the mother’s last adalimumab injection during pregnancy.
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 also been reported in patients receiving adalimumab. SIMLANDI should be used with
caution in patients with mild heart failure (NYHA class I/II). SIMLANDI is contraindicated in
moderate to severe heart failure (see section 4.3). Treatment with SIMLANDI must be discontinued in
patients who develop new or worsening symptoms of congestive heart failure.
Autoimmune processes
Treatment with SIMLANDI may result in the formation of autoimmune antibodies. The impact of
long-term treatment with adalimumab on the development of autoimmune diseases is unknown. If a
patient develops symptoms suggestive of a lupus-like syndrome following treatment with SIMLANDI
and is positive for antibodies against double-stranded DNA, further treatment with SIMLANDI should
not be given (see section 4.8).
Concurrent administration of biologic DMARDS or TNF-antagonists
Serious infections were seen in clinical studies with concurrent use of anakinra and another TNFantagonist, etanercept, with no added clinical benefit compared to etanercept 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, the
combination of adalimumab and anakinra is not recommended (see section 4.5).
Concomitant administration of adalimumab with other biologic DMARDS (e.g, anakinra and
abatacept) or other TNF-antagonists is not recommended based upon the possible increased risk for
infections, including serious infections and other potential pharmacological interactions (see section
4.5).
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 SIMLANDI should be closely monitored for infections, and
appropriate actions should be taken. There is limited safety experience in patients undergoing
arthroplasty while receiving adalimumab.
Small bowel obstruction
Failure to respond to treatment for Crohn’s disease may indicate the presence of fixed fibrotic stricture
that may require surgical treatment. Available data suggest that adalimumab does not worsen or cause
strictures.
Elderly
The frequency of serious infections among adalimumab-treated subjects over 65 years of age (3.7%)
was higher than for those under 65 years of age (1.5%). Some of those had a fatal outcome. Particular
attention regarding the risk for infection should be paid when treating the elderly.
Paediatric population
See “Vaccinations” above.
Excipients
This medicine contains less than 1 mmol sodium (23 mg) per 0.4 ml, that is to say essentially ‘sodiumfree’.

4.5. Interactions with other medicinal products

Adalimumab has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and
psoriatic arthritis patients taking adalimumab as monotherapy and those taking concomitant
methotrexate. Antibody formation was lower when adalimumab was given together with methotrexate
in comparison with use as monotherapy. Administration of adalimumab without methotrexate resulted
in increased formation of antibodies, increased clearance and reduced efficacy of adalimumab (see
section 5.1).
The combination of adalimumab and anakinra is not recommended (see section 4.4 “Concurrent
administration of biologic DMARDS or TNF-antagonists”).
The combination of adalimumab and abatacept is not recommended (see section 4.4 “Concurrent
administration of biologic DMARDS or TNF-antagonists”).

4.6. Fertility, pregnancy and lactation

pregnancy category: Category B.
Women of child bearing potential
Women of childbearing potential should consider the use of adequate contraception to prevent
pregnancy and continue its use for at least five months after the last SIMLANDI treatment.
Pregnancy
A large number (approximately 2,100) of prospectively collected pregnancies exposed to adalimumab
resulting in live birth with known outcomes, including more than 1,500 exposed during the first
trimester, does not indicate an increase in the rate of malformation in the newborn.
In a prospective cohort registry, 257 women with rheumatoid arthritis (RA) or Crohn’s disease (CD)
treated with adalimumab at least during the first trimester and 120 women with RA or CD not treated
with adalimumab were enrolled. The primary endpoint was the birth prevalence of major birth defects.
The rate of pregnancies ending with at least one live born infant with a major birth defect was 6/69
(8.7%) in the adalimumab-treated women with RA and 5/74 (6.8%) in the untreated women with RA
(unadjusted OR 1.31, 95% CI 0.38-4.52) and 16/152 (10.5%) in the adalimumab-treated women with
CD and 3/32 (9.4%) in the untreated women with CD (unadjusted OR 1.14, 95% CI 0.31-4.16). The
adjusted OR (accounting for baseline differences) was 1.10 (95% CI 0.45-2.73) with RA and CD
combined. There were no distinct differences between adalimumab-treated and untreated women for
the secondary endpoints spontaneous abortions, minor birth defects, preterm delivery, birth size and
serious or opportunistic infections and no stillbirths or malignancies were reported. The interpretation
of data may be impacted due to methodological limitations of the study, including small sample size
and non-randomised design.
In a developmental toxicity study conducted in monkeys, there was no indication of maternal toxicity,
embryotoxicity or teratogenicity. Preclinical data on postnatal toxicity of adalimumab are not available
(see section 5.3).
Due to its inhibition of TNFα, adalimumab administered during pregnancy could affect normal
immune responses in the newborn. Adalimumab should only be used during pregnancy if clearly
needed.
Adalimumab may cross the placenta into the serum of infants born to women treated with adalimumab
during pregnancy. Consequently, these infants may be at increased risk for infection. Administration
of live vaccines (e.g., BCG vaccine) to infants exposed to adalimumab in utero is not recommended
for 5 months following the mother’s last adalimumab injection during pregnancy.
Breast-feeding
Limited information from 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. Given orally, immunoglobulin G proteins undergo intestinal
proteolysis and have poor bioavailability. No effects on the breast-fed newborns/infants are
anticipated. Consequently, SIMLANDI can be used during breast-feeding.
Fertility
Preclinical data on fertility effects of adalimumab are not available.

4.7. Effects on ability to drive and use machines

SIMLANDI may have a minor influence on the ability to drive and use machines. Vertigo and visual
impairment may occur following administration of SIMLANDI (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile
Adalimumab was studied in 9,506 patients in pivotal controlled and open-label trials for up to 60
months or more. 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 axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis without
radiographic evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis,
hidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients
receiving adalimumab and 3,801 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 was 5.9% for patients taking adalimumab and 5.4% for control
treated patients.
The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper
respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain
or swelling), headache and musculoskeletal pain.
Serious adverse reactions have been reported for adalimumab. TNF-antagonists, such as adalimumab
affect the immune system and their use may affect the body’s defence against infection and cancer.
Fatal and life-threatening infections (including sepsis, opportunistic infections and TB), HBV
reactivation and various malignancies (including leukaemia, lymphoma and HSTCL) have also been
reported with use of adalimumab.
Serious haematological, neurological and autoimmune reactions have also been reported. These
include rare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events
and reports of lupus, lupus-related conditions and Stevens-Johnson syndrome.
Paediatric population
In general, the adverse events in paediatric patients were similar in frequency and type to those seen in
adult patients.
Tabulated list of adverse reactions
The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience and are displayed by system organ class and frequency in Table 6 below: very
common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to
<1/1,000); and not known (cannot be estimated from the available data). Within each frequency
grouping, undesirable effects are presented in order of decreasing seriousness. The highest frequency
seen among the various indications has been included. An asterisk (*) appears in the SOC column if
further information is found elsewhere in sections 4.3, 4.4 and 4.8.

Hidradenitis suppurativa
The safety profile for patients with HS treated with adalimumab weekly was consistent with the
known safety profile of adalimumab.
Uveitis
The safety profile for patients with uveitis treated with adalimumab every other week was consistent
with the known safety profile of adalimumab.
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 7.2% of patients receiving placebo or active control. Injection site reactions generally did not
necessitate discontinuation of the medicinal product.
Infections
In the 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 placebo and active control-treated
patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, 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 placebo and active control - treated patients.
In 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 extra-pulmonary locations) and invasive opportunistic infections
(e.g. disseminated or extrapulmonary histoplasmosis, blastomycosis, coccidioidomycosis,
pneumocystis, candidiasis, aspergillosis and listeriosis). Most of the cases of tuberculosis occurred
within the first eight months after initiation of therapy and may reflect recrudescence of latent disease.
Malignancies and lymphoproliferative disorders
No malignancies were observed in 249 paediatric patients with an exposure of 655.6 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 498.1 patient years during adalimumab trials in paediatric patients with
Crohn’s disease. No malignancies were observed in 77 paediatric patients with an exposure of 80.0
patient years during adalimumab trial in paediatric patients with chronic plaque psoriasis. No
malignancies were observed in 60 paediatric patients with an exposure of 58.4 patient years during a
adalimumab trial in paediatric patients with uveitis.
During the controlled portions of pivotal adalimumab trials in adults of at least 12 weeks in duration in
patients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axial
spondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitis
suppurativa, Crohn’s disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and
non-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per
1,000 patient-years among 5,291 adalimumab-treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000
patient-years among 3,444 control patients (median duration of treatment was 4.0 months for
adalimumab and 3.8 months for control-treated patients). The rate (95% confidence interval) of nonmelanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among adalimumab-treated patients
and 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell
carcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among
adalimumab-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate
(95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among
adalimumab-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients.
When combining controlled portions of these trials and ongoing and completed open label extension
studies with a median duration of approximately 3.3 years including 6,427 patients and over 26,439
patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma
skin cancers is approximately 8.5 per 1,000 patient years. The observed rate of non-melanoma skin
cancers is approximately 9.6 per 1,000 patient years, and the observed rate of lymphomas is
approximately 1.3 per 1,000 patient years.
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 1,000 patient treatment
years. The reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and
0.3 per 1,000 patient treatment years, respectively (see section 4.4).
Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated
with adalimumab (see section 4.4).
Autoantibodies
Patients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis
studies I - V. In these trials, 11.9% of patients treated with adalimumab and 8.1% of placebo and
active control - treated patients that had negative baseline anti-nuclear antibody titres reported
positive titres at Week 24. Two patients out of 3,441 treated with adalimumab in all rheumatoid
arthritis and psoriatic arthritis 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.
Hepatobiliary events
In controlled Phase 3 trials of adalimumab in patients with rheumatoid arthritis and psoriatic arthritis
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.
In controlled Phase 3 trials of adalimumab in patients with polyarticular juvenile idiopathic arthritis
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 juvenile idiopathic arthritis
who were 2 to < 4 years.
In controlled Phase 3 trials of adalimumab in patients with Crohn’s disease and ulcerative colitis with
a control period ranging from 4 to 52 weeks. ALT elevations ≥ 3 x ULN occurred in 0.9% of
adalimumab-treated patients and 0.9% of controlled-treated patients.
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.
In controlled Phase 3 trials of adalimumab in patients with plaque psoriasis with a control period
duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of adalimumabtreated patients and 1.8% of control-treated patients.
No ALT elevations ≥ 3 x ULN occurred in the Phase 3 trial of adalimumab in paediatric patients with
plaque psoriasis.
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.
In controlled trials of adalimumab (initial doses of 80 mg at Week 0 followed by 40 mg every other
week starting at Week 1) in adult patients with uveitis up to 80 weeks with a median exposure of 166.5
days and 105.0 days 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.
Across all indications in clinical trials patients with raised ALT were asymptomatic and in most cases
elevations were transient and resolved on continued treatment. However, there have also been postmarketing reports of liver failure as well as less severe liver disorders that may precede liver failure,
such as hepatitis including autoimmune hepatitis in patients receiving adalimumab.
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.
Reporting of suspected adverse reactions
• Saudi Arabia
- The National Pharmacovigilance Centre (NPC):
- SFDA Call Center: 19999
- E-mail: npc.drug@sfda.gov.sa
- Website: https://ade.sfda.gov.sa
• Other GCC states /other countries
-Please contact the relevant competent authority.
Special Population
Special populations
Elderly
No dose adjustment is required.
Renal and/or hepatic impairment
Adalimumab has not been studied in these patient populations. No dose recommendations can be
made.
Paediatric population
Juvenile idiopathic arthritis
Polyarticular juvenile idiopathic arthritis from 2 years of age
The recommended dose of SIMLANDI for patients with polyarticular juvenile idiopathic arthritis from
2 years of age is based on body weight (Table 1). SIMLANDI is administered every other week via
subcutaneous injection.

4.9. Overdoes

No dose-limiting toxicity was observed during clinical trials. The highest dose level evaluated has
been multiple intravenous doses of 10 mg/kg, which is approximately 15 times the recommended
dose.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

Pharmacotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha (TNF-α) inhibitors,
ATC code: L04AB04
SIMLANDI is a biosimilar medicinal product. Detailed information is available on the website of the
European Medicines Agency http://www.ema.europa.eu.
Mechanism of action
Adalimumab binds specifically to TNF and neutralises the biological function of TNF by blocking its
interaction with the p55 and p75 cell surface TNF receptors.
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 of0.1-0.2 nM).
Pharmacodynamic effects
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 rheumatoid arthritis. 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 after treatment with
adalimumab. In patients with Crohn’s disease, a reduction of the number of cells expressing
inflammatory markers in the colon including a significant reduction of expression of TNFα was seen.
Endoscopic studies in intestinal mucosa have shown evidence of mucosal healing in adalimumab
treated patients.
Clinical efficacy and safety
Rheumatoid arthritis
Adalimumab was evaluated in over 3,000 patients in all rheumatoid arthritis clinical trials. The
efficacy and safety of adalimumab were assessed in five randomised, double-blind and well-controlled
studies. Some patients were treated for up to 120 months duration. Injection site pain of adalimumab
40 mg/0.4 ml was assessed in two randomised, active control, single-blind, two-period crossover
studies.
RA study I evaluated 271 patients with moderately to severely active rheumatoid arthritis who were
≥ 18 years old, had failed therapy with at least one disease-modifying, anti-rheumatic drug 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. Doses of 20,
40 or 80 mg of adalimumab or placebo were given every other week for 24 weeks.
RA study II evaluated 544 patients with moderately to severely active rheumatoid arthritis who were
≥ 18 years old and had failed therapy with at least one disease-modifying, anti-rheumatic drugs. Doses
of 20 mg or 40 mg of adalimumab were given by subcutaneous injection every other week with
placebo on alternative weeks or every week for 26 weeks; placebo was given every week for the same
duration. No other disease-modifying anti-rheumatic drugs were allowed.
RA study III evaluated 619 patients with moderately to severely active rheumatoid arthritis who were
≥ 18 years old, and who had an ineffective response to methotrexate at doses of 12.5 to 25 mg or have
been intolerant to 10 mg of methotrexate every week. 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 every other week 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 every other
week up to 10 years.
RA study IV primarily assessed safety in 636 patients with moderately to severely active rheumatoid
arthritis who were ≥18 years old. Patients were permitted to be either disease-modifying, antirheumatic drug-naïve or to remain on their pre-existing rheumatologic therapy provided that therapy
was stable for a minimum of 28 days. These therapies include methotrexate, leflunomide,
hydroxychloroquine, sulfasalazine and/or gold salts. Patients were randomised to 40 mg of
adalimumab or placebo every other week for 24 weeks.
RA study V evaluated 799 methotrexate-naïve, adult patients with moderate to severely active early
rheumatoid arthritis (mean disease duration less than 9 months). This study evaluated the efficacy of
adalimumab 40 mg every other week/methotrexate combination therapy, adalimumab 40 mg every
other week monotherapy and methotrexate monotherapy in reducing the signs and symptoms and rate
of progression of joint damage in rheumatoid arthritis 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 every other week up to 10 years.
RA studies VI and VII each evaluated 60 patients with moderately to severely active rheumatoid
arthritis who were ≥ 18 years old. Enrolled patients were either current users of adalimumab
40 mg/0.8 ml and rated their average injection site pain as at least 3 cm (on a 0-10 cm VAS) or were
biologic-naïve subjects who were starting adalimumab 40 mg/0.8 ml. Patients were randomised to
receive a single dose of adalimumab 40 mg/0.8 ml or adalimumab 40 mg/0.4 ml, followed by a single
injection of the opposite treatment at their next dose.
The primary end point in RA studies I, II and III and the secondary endpoint in RA study IV was the
percent of patients who achieved an ACR 20 response at Week 24 or 26. The primary endpoint in RA\
study V was the percent of patients who achieved an ACR 50 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.
ACR response
The percent of adalimumab-treated patients achieving ACR 20, 50 and 70 responses was consistent
across RA studies I, II and III. The results for the 40 mg every other week dose are summarised in
Table 7.

In RA studies I-IV, all individual components of the ACR response criteria (number of tender and
swollen joints, physician and patient assessment of disease activity and pain, disability index (HAQ)
scores and CRP (mg/dl) values) improved at 24 or 26 weeks compared to placebo. In RA study III,
these improvements were maintained throughout 52 weeks.
In the open-label extension for RA study III, most patients who were ACR responders maintained
response when followed for up to 10 years. Of 207 patients who were randomised to adalimumab
40 mg every other week, 114 patients continued on adalimumab 40 mg every other week for 5 years.
Among those, 86 patients (75.4%) had ACR 20 responses; 72 patients (63.2%) had ACR 50 responses;
and 41 patients (36%) had ACR 70 responses. Of 207 patients, 81 patients continued on adalimumab
40 mg every other week for 10 years. Among those, 64 patients (79.0%) had ACR 20 responses; 56
patients (69.1%) had ACR 50 responses; and 43 patients (53.1%) had ACR 70 responses.
In RA study IV, the ACR 20 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 ACR 20 and 50
responses compared to placebo as early as one to two weeks after initiation of treatment.
In RA study V with early rheumatoid arthritis patients who were methotrexate naïve, combination
therapy with adalimumab and methotrexate led to faster and significantly greater ACR responses than
methotrexate monotherapy and adalimumab monotherapy at Week 52 and responses were sustained at
Week 104 (see Table 8).

In the open-label extension for RA study V, ACR response rates were maintained when followed for
up to 10 years. Of 542 patients who were randomised to adalimumab 40 mg every other week, 170
patients continued on adalimumab 40 mg every other week for 10 years. Among those, 154 patients
(90.6%) had ACR 20 responses; 127 patients (74.7%) had ACR 50 responses; and 102 patients
(60.0%) had ACR 70 responses.
At Week 52, 42.9% of patients who received adalimumab/methotrexate combination therapy achieved
clinical remission (DAS28 (CRP) < 2.6) compared to 20.6% of patients receiving methotrexate
monotherapy and 23.4% of patients receiving adalimumab monotherapy. Adalimumab/methotrexate
combination therapy was clinically and statistically superior to methotrexate (p < 0.001) and
adalimumab monotherapy (p < 0.001) in achieving a low disease state in patients with recently
diagnosed moderate to severe rheumatoid arthritis. The response for the two monotherapy arms was
similar (p = 0.447). Of 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, where adalimumab-treated patients had a mean duration of rheumatoid arthritis of
approximately 11 years, structural joint damage was assessed radiographically and expressed as
change in modified Total Sharp Score (TSS) and its components, the erosion score and joint space
narrowing score. Adalimumab/methotrexate patients demonstrated significantly less radiographic
progression than patients receiving methotrexate alone at 6 and 12 months (see Table 9).
In the open-label extension of RA Study III, the reduction in rate of progression of structural damage
is maintained for 8 and 10 years in a subset of patients. At 8 years, 81 of 207 patients originally treated
with 40 mg adalimumab every other week were evaluated radiographically. Among those, 48 patients
showed no progression of structural damage defined by a change from baseline in the mTSS of 0.5 or
less. At 10 years, 79 of 207 patients originally treated with 40 mg adalimumab every other week were
evaluated radiographically. Among those, 40 patients showed no progression of structural damage
defined by a change from baseline in the mTSS of 0.5 or less.

In RA study V, structural joint damage was assessed radiographically and expressed as change in
modified Total Sharp Score (see Table 10)

Following 52 weeks and 104 weeks of treatment, the percentage of patients without progression
(change from baseline in modified Total Sharp Score ≤ 0.5) was significantly higher with
adalimumab/methotrexate combination therapy (63.8% and 61.2% respectively) compared to
methotrexate monotherapy (37.4% and 33.5% respectively, p < 0.001) and adalimumab monotherapy
(50.7%, p < 0.002 and 44.5%, p < 0.001 respectively).
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.
Quality of life and physical function
Health-related quality of life and physical function were assessed using the disability index of the
Health Assessment Questionnaire (HAQ) in the four original adequate and well-controlled trials,
which was a pre-specified primary endpoint at Week 52 in RA study III. All doses/schedules of
adalimumab in all four studies showed statistically significantly greater improvement in the disability
index of the HAQ from baseline to Month 6 compared to placebo and in RA study III the same was
seen at Week 52. 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 every other week 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).
In RA study III, most subjects who achieved improvement in physical function and continued
treatment maintained improvement through Week 520 (120 months) of open-label treatment.
Improvement in quality of life was measured up to Week 156 (36 months) and improvement was
maintained through that time.
In RA study V, 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 and adalimumab 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 were maintained through 10 years of treatment.
Injection site pain
For the pooled crossover RA studies VI and VII, a statistically significant difference for injection site
pain immediately after dosing was observed between 40 mg/0.8 ml adalimumab and 40 mg/0.4 ml
adalimumab (mean VAS of 3.7 cm versus 1.2 cm, scale of 0-10 cm, p < 0.001). This represented an
84% median reduction in injection site pain.
Juvenile idiopathic arthritis (JIA)
Polyarticular juvenile idiopathic arthritis (pJIA)
The safety and efficacy of adalimumab was assessed in two studies (pJIA I and II) in children with
active polyarticular or polyarticular course juvenile idiopathic arthritis, who had a variety of JIA onset
types (most frequently rheumatoid-factor negative or positive polyarthritis and extended
oligoarthritis).
pJIA I
The safety and efficacy of adalimumab were assessed in a multicentre, randomised, double-blind,
parallel - group study in 171 children (4-17 years old) with polyarticular JIA. In the open-label lead in
phase (OL LI) patients were stratified into two groups, MTX (methotrexate)-treated or non-MTXtreated. Patients who were in the non-MTX stratum were either naïve to or had been withdrawn from
MTX at least two weeks prior to study drug administration. Patients remained on stable doses of
NSAIDs and or prednisone (≤ 0.2 mg/kg/day or 10 mg/day maximum). In the OL LI phase all patients
received 24 mg/m2 up to a maximum of 40 mg adalimumab every other week for 16 weeks. The
distribution of patients by age and minimum, median and maximum dose received during the OL LI
phase is presented in Table 11.

Patients demonstrating a Paediatric ACR 30 response at Week 16 were eligible to be randomised into
the double-blind (DB) phase and received either 24 mg/m2 adalimumab up to a maximum of 40 mg, or
placebo every other week for an additional 32 weeks or until disease flare. Disease flare criteria were
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 disease
flare, patients were eligible to enroll into the open label extension phase.

Amongst those who responded at Week 16 (n=144), the Paediatric ACR 30/50/70/90 responses were
maintained for up to six years in the OLE phase in patients who received adalimumab throughout the
study. Over all 19 subjects, of which 11 of the baseline age group 4 to 12 and 8 of the baseline age
group 13 to 17 years were treated 6 years or longer.
Overall responses were generally better and, fewer patients developed antibodies when treated with
the combination of adalimumab and MTX compared to adalimumab alone. Taking these results into
consideration, adalimumab is recommended for use in combination with MTX and for use as
monotherapy in patients for whom MTX use is not appropriate (see section 4.2).
pJIA II
The safety and efficacy of adalimumab was assessed in an open-label, multicentre study in 32 children
(2 - < 4 years old or aged 4 and above weighing < 15 kg) with moderately to severely active
polyarticular JIA. The patients received 24 mg/m2 body surface area (BSA) of adalimumab up to a
maximum of 20 mg every other week as a single dose via SC injection for at least 24 weeks. During
the study, most subjects used concomitant MTX, with fewer reporting use of corticosteroids or
NSAIDs.
At Week 12 and Week 24, PedACR30 response was 93.5% and 90.0%, respectively, using the
observed data approach. The proportions of subjects with PedACR50/70/90 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 the OLE phase in patients who received adalimumab throughout this
time period. Overall, 20 subjects were treated for 60 weeks or longer.
Enthesitis-related arthritis
The safety and efficacy of adalimumab were assessed in a multicentre, randomised, double-blind study
in 46 paediatric patients (6 to 17 years old) with moderate enthesitis-related arthritis. Patients were
randomised to receive either 24 mg/m2 body surface area (BSA) of adalimumab up to a maximum of
40 mg, or placebo every other week for 12 weeks. The double-blind period is followed by an openlabel (OL) period during which patients received 24 mg/m2 BSA of adalimumab up to a maximum of
40 mg every other week 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 with
mean percent decrease of -62.6% (median percent change -88.9%) in patients in the adalimumab
group compared to -11.6% (median percent change -50.0%) in patients in the placebo group.
Improvement in number of active joints with arthritis was maintained during the OL period through
Week 156 for the 26 of 31 (84%) patients in the adalimumab group who remained in the study.
Although not statistically significant, the majority of patients demonstrated clinical improvement in
secondary endpoints such as number of sites of enthesitis, tender joint count (TJC), swollen joint count
(SJC), Paediatric ACR 50 response, and Paediatric ACR 70 response.
Axial spondyloarthritis
Ankylosing spondylitis (AS)
Adalimumab 40 mg every other week was assessed in 393 patients in two randomised, 24 week
double-blind, placebo-controlled studies in patients with active ankylosing spondylitis (mean baseline
score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.3 in
all groups) who have 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 during which
patients received 40 mg adalimumab every other week subcutaneously for up to an additional 28
weeks. Subjects (n=215, 54.7%) who failed to achieve ASAS 20 at Weeks 12, or 16 or 20 received
early escape open-label 40 mg adalimumab every other week subcutaneously and were subsequently
treated as non-responders in the double-blind statistical analyses.
In the larger AS study I with 315 patients, results showed statistically significant improvement of the
signs and symptoms of ankylosing spondylitis in patients treated with adalimumab compared to
placebo. Significant response was first observed at Week 2 and maintained through 24 weeks (Table
13).

Adalimumab treated patients had significantly greater improvement at Week 12 which was maintained
through Week 24 in both the SF36 and Ankylosing Spondylitis Quality of Life Questionnaire
(ASQoL).
Similar trends (not all statistically significant) were seen in the smaller randomised, double-blind,
placebo controlled AS study II of 82 adult patients with active ankylosing spondylitis.
Axial spondyloarthritis without radiographic evidence of AS
The safety and efficacy of adalimumab were assessed in two randomised, double-blind placebocontrolled studies in patients with non-radiographic axial spondyloarthritis (nr-axSpA). Study nraxSpA I evaluated patients with active nr-axSpA. Study nr-axSpA II was a treatment withdrawal study
in active nr-axSpA patients who achieved remission during open-label treatment with adalimumab.
34
Study nr-axSpA I
In Study nr-axSpA I, adalimumab 40 mg every other week was assessed in 185 patients in a
randomised, 12 week double-blind, placebo-controlled study in patients with active nr-axSpA (mean
baseline score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)]
was 6.4 for patients treated with adalimumab and 6.5 for those on placebo) who have had an
inadequate response to or intolerance to ≥ 1 NSAIDs, or a contraindication for NSAIDs.
Thirty-three (18%) patients were treated concomitantly with disease modifying anti-rheumatic drugs,
and 146 (79%) patients with NSAIDs at baseline. The double-blind period was followed by an openlabel period during which patients receive adalimumab 40 mg every other week subcutaneously for up
to an additional 144 weeks. Week 12 results showed statistically significant improvement of the signs
and symptoms of active nr-axSpA in patients treated with adalimumab compared to placebo (Table
14).

In the open-label extension, improvement in the signs and symptoms was maintained with
adalimumab therapy through Week 156.
Inhibition of inflammation
Significant improvement of signs of inflammation as measured by hs-CRP and MRI of both Sacroiliac
Joints and the Spine was maintained in adalimumab-treated patients through Week 156 and Week 104,
respectively.
Quality of life and physical function
Health-related quality of life and physical function were assessed using the HAQ-S and the SF-36
questionnaires. Adalimumab showed statistically significantly greater improvement in the HAQ-S
total score and the SF-36 Physical Component Score (PCS) from baseline to Week 12 compared to
placebo. Improvement in health-related quality of life and physical function was maintained during the
open-label extension through Week 156.
Study nr-axSpA II
673 patients with active nr-axSpA (mean baseline disease activity [BASDAI] was 7.0) who had an
inadequate response to ≥ 2 NSAIDs, or an intolerance to or a contraindication for NSAIDs enrolled
into the open-label period of Study nr-axSpA II during which they received 40 mg adalimumab every
other week for 28 weeks.
These patients also had objective evidence of inflammation in the sacroiliac joints or spine on MRI or
elevated hs-CRP. Patients who achieved sustained remission for at least 12 weeks (N=305) (ASDAS
< 1.3 at Weeks 16, 20, 24, and 28) during the open-label period were then randomised to receive either
continued treatment with 40 mg adalimumab every other week (N=152) or placebo (N=153) for an
additional 40 weeks in a double-blind, placebo-controlled period (total study duration 68 weeks).
Subjects who flared during the double-blind period were allowed 40 mg adalimumab every other week
rescue therapy for at least 12 weeks.
The primary efficacy endpoint was the proportion of patients with no flare by Week 68 of the study.
Flare was defined as ASDAS ≥ 2.1 at two consecutive visits four weeks apart. A greater proportion of
patients on adalimumab had no disease flare during the double-blind period, when compared with
those on placebo (70.4% vs. 47.1%, p < 0.001) (Figure 1).

Note: P = Placebo (Number at Risk (flared)); A = (Number at Risk (flared)).
Among the 68 patients who flared in the group allocated to treatment withdrawal, 65 completed 12
weeks of rescue therapy with adalimumab, out of which 37 (56.9%) had regained remission
(ASDAS < 1.3) after 12 weeks of restarting the open-label treatment.
By Week 68, patients receiving continuous adalimumab treatment showed statistically significant
greater improvement of the signs and symptoms of active nr-axSpA as compared to patients allocated
to treatment withdrawal during the double-blind period of the study (Table 15).

Psoriatic arthritis
Adalimumab, 40 mg every other week, was studied in patients with moderately to severely active
psoriatic arthritis in two placebo-controlled studies, PsA studies I and II. 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 every other week.
There is insufficient evidence of the efficacy of adalimumab in patients with ankylosing spondylitislike psoriatic arthropathy due to the small number of patients studied.

ACR responses in PsA study I were similar with and without concomitant methotrexate therapy. ACR
responses were maintained in the open-label extension study for up to 136 weeks.
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.
Adalimumab treatment reduced the rate of progression of peripheral joint damage compared with
placebo treatment as measured by change from baseline in mTSS (mean ± SD) 0.8 ± 2.5 in the placebo
group (at Week 24) compared with 0.0 ± 1.9; (p < 0.001) in the adalimumab group (at Week 48).
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.
Adalimumab treated patients demonstrated statistically significant improvement in physical function
as assessed by HAQ and Short Form Health Survey (SF 36) compared to placebo at Week 24.
Improved physical function continued during the open label extension up to Week 136.
Psoriasis
The safety and efficacy of adalimumab were studied in adult patients with chronic plaque psoriasis
(≥ 10% BSA involvement and Psoriasis Area and Severity Index (PASI) ≥ 12 or ≥ 10) who were
candidates for systemic therapy or phototherapy in randomised, double-blind studies. 73% of patients
enrolled in Psoriasis Studies I and II had received prior systemic therapy or phototherapy. The safety
and efficacy of adalimumab were also studied in adult patients with moderate to severe chronic plaque
psoriasis with concomitant hand and/or foot psoriasis who were candidates for systemic therapy in a
randomised double-blind study (Psoriasis Study III).
Psoriasis Study I (REVEAL) evaluated 1,212 patients within three treatment periods. In period A,
patients received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every other
week starting one week after the initial dose. After 16 weeks of therapy, patients who achieved at least
a PASI 75 response (PASI score improvement of at least 75% relative to baseline), entered period B
and received open-label 40 mg adalimumab every other week. Patients who maintained ≥ PASI 75
response at Week 33 and were originally randomised to active therapy in Period A, were rerandomised in period C to receive 40 mg adalimumab every other week 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” (53% of subjects included) to
“severe” (41%) to “very severe” (6%).
Psoriasis Study II (CHAMPION) compared the efficacy and safety of adalimumab versus
methotrexate and placebo in 271 patients. 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 every other week (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%).
Patients participating in all Phase 2 and Phase 3 psoriasis studies were eligible to enroll into an openlabel extension trial, where adalimumab was given for at least an additional 108 weeks.
In Psoriasis Studies I and II, a primary endpoint was the proportion of patients who achieved a PASI
75 response from baseline at Week 16 (see Tables 17 and 18).

In Psoriasis Study I, 28% of patients who were PASI 75 responders and were re-randomised to
placebo at Week 33 compared to 5% continuing on adalimumab, p < 0.001, experienced “loss of
adequate response” (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).
Of the patients who lost adequate response after re-randomisation to placebo who then enrolled into
the open-label extension trial, 38% (25/66) and 55% (36/66) regained PASI 75 response after 12 and
24 weeks of re-treatment, respectively.
A total of 233 PASI 75 responders at Week 16 and Week 33 received continuous adalimumab therapy
for 52 weeks in Psoriasis Study I, and continued adalimumab in the open-label extension trial. PASI
75 and PGA of clear or minimal response rates in these patients were 74.7% and 59.0%, respectively,
after an additional 108 weeks of open-label therapy (total of 160 weeks). In an analysis in which all
patients who dropped out of the study for adverse events or lack of efficacy, or who dose-escalated,
were considered non-responders, PASI 75 and PGA of clear or minimal response rates in these
patients were 69.6% and 55.7%, respectively, after an additional 108 weeks of open-label therapy
(total of 160 weeks).
A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an openlabel extension study. During the withdrawal period, symptoms of psoriasis returned over time with a
median time to relapse (decline to PGA “moderate” or worse) of approximately 5 months. None of
these patients experienced rebound during the withdrawal period. A total of 76.5% (218/285) of
patients who entered the retreatment period had a response of PGA “clear” or “minimal” after 16
weeks of retreatment, irrespective of whether they relapsed during withdrawal (69.1%[123/178] and
88.8% [95/107] for patients who relapsed and who did not relapse during the withdrawal period,
respectively). A similar safety profile was observed during retreatment as before withdrawal.
Significant improvements at Week 16 from baseline compared to placebo (Studies I and II) and MTX
(Study II) were demonstrated in the DLQI (Dermatology Life Quality Index). In Study I,
improvements in the physical and mental component summary scores of the SF-36 were also
significant compared to placebo.
In an open-label extension study, for patients who dose escalated from 40 mg every other week to
40 mg weekly 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.
Psoriasis Study III (REACH) 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 adalimumab followed by 40 mg every other week (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 PGA 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 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 every other week (starting one week after the initial dose) or placebo for 26 weeks followed
by open-label adalimumab treatment for an additional 26 weeks. Nail psoriasis assessments included
the Modified Nail Psoriasis Severity Index (mNAPSI), the Physician’s Global Assessment of
Fingernail Psoriasis (PGA-F) and the Nail Psoriasis Severity Index (NAPSI) (see Table 19).
Adalimumab demonstrated a treatment benefit in nail psoriasis patients with different extents of skin
involvement (BSA ≥ 10% (60% of patients) and BSA < 10% and ≥ 5% (40% of patients)).

Adalimumab-treated patients showed statistically significant improvements at Week 26 compared with
placebo in the DLQI.
Paediatric plaque psoriasis
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 eow (up to 40 mg), 0.4 mg/kg eow (up to 20 mg), or
methotrexate 0.1- 0.4 mg/kg weekly (up to 25 mg). At Week 16, more patients randomised to
0.8 mg/kg adalimumab had positive efficacy responses (e.g., PASI 75) than those randomised to
0.4 mg/kg eow or MTX.

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 (i.e. a worsening of PGA by at least 2 grades).
Patients were then re-treated with adalimumab 0.8 mg/kg eow for an additional 16 weeks and response
rates observed during retreatment were similar to the previous double-blind period: PASI 75 response
of 78.9% (15 of 19 subjects) and PGA clear or minimal of 52.6% (10 of 19 subjects).
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.
Hidradenitis suppurativa
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 HS-I and HS-II had Hurley Stage II or III
disease with at least 3 abscesses or inflammatory nodules.
40
Study HS-I (PIONEER I) 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 rerandomised in Period B to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab
40 mg every other week, 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 (PIONEER II) 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 every other week, 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 enroll into an open-label extension
study in which adalimumab 40mg was administered every week. Mean exposure in all adalimumab
population was 762 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 a 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 21). Patients treated with adalimumab
had significantly reduced risk of disease flare during the initial 12 weeks of treatment.

Treatment with adalimumab 40 mg every week significantly reduced the risk of worsening of
abscesses and draining fistulas. Approximately twice the proportion of patients in the placebo group in
the first 12 weeks of Studies HS-I and HS-II, compared with those in the adalimumab group
experienced worsening of abscesses (23.0% vs 11.4%, respectively) and draining fistulas (30.0% vs
13.9%, respectively).
Greater improvements at Week 12 from baseline compared to placebo were demonstrated in skinspecific health-related quality of life, as measured by the Dermatology Life Quality Index (DLQI;
Studies HS-I and HS-II), patient global satisfaction with medication treatment as measured by the
41
Treatment Satisfaction Questionnaire - medication (TSQM; Studies HS-I and HS-II), and physical
health as measured by the physical component summary score of the SF-36 (Study HS-I).
In patients with at least a partial response to adalimumab 40 mg weekly at Week 12, the HiSCR rate at
Week 36 was higher in patients who continued weekly adalimumab than in patients in whom dosing
frequency was reduced to every other week, or in whom treatment was withdrawn (see Table 22).

Among patients who were at least partial responders at Week 12, and who received continuous weekly
adalimumab therapy, the HiSCR rate at Week 48 was 68.3% and at Week 96 was 65.1%. Longer term
treatment with adalimumab 40 mg weekly for 96 weeks identified no new safety findings.
Among patients whose adalimumab treatment was withdrawn at Week 12 in Studies HS-I and HS-II,
the HiSCR rate 12 weeks after re-introduction of adalimumab 40 mg weekly returned to levels similar
to that observed before withdrawal (56.0 %).
Adolescent hidradenitis suppurativa
There are no clinical trials with adalimumab in adolescent patients with HS. Efficacy of adalimumab
for the treatment of adolescent patients 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. Safety of the recommended adalimumab dose in the adolescent HS population is based on
cross-indication safety profile of adalimumab in both adults and paediatric patients at similar or more
frequent doses (see section 5.2).
Crohn’s disease
The safety and efficacy of adalimumab were assessed in over 1,500 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
(CLASSIC I) and CD Study II (GAIN). In CD Study I, 299 TNF-antagonist naive patients were
randomised to one of four treatment groups; placebo at Weeks 0 and 2, 160 mg adalimumab at Week 0
and 80 mg at Week 2, 80 mg at Week 0 and 40 mg at Week 2, and 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. The primary non-responders were excluded from the studies and therefore these
patients were not further evaluated.
Maintenance of clinical remission was evaluated in CD study III (CHARM). In CD Study III, 854
patients received open-label 80 mg at Week 0 and 40 mg at Week 2. At Week 4 patients were
randomised to 40 mg every other week, 40 mg 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.
CD study I and CD study II induction of remission and response rates are presented in Table 23.

Similar remission rates were observed for the 160/80 mg and 80/40 mg induction regimens by Week 8
and adverse events were more frequently noted in the 160/80 mg group.
In CD Study III, at Week 4, 58% (499/854) of patients were in clinical response and were assessed in
the primary analysis. Of those in clinical response at Week 4, 48% had been previously exposed to
other TNF-antagonists. Maintenance of remission and response rates are presented in Table 24.
Clinical remission results remained relatively constant irrespective of previous TNF-antagonist
exposure.
Disease-related hospitalisations and surgeries were statistically significantly reduced with adalimumab
compared with placebo at Week 56.

Among patients who were not in response at Week 4, 43% of adalimumab maintenance patients
responded by Week 12 compared to 30% of placebo maintenance patients. These results suggest that
some patients who have not responded by Week 4 benefit from continued maintenance therapy
through Week 12. Therapy continued beyond 12 weeks did not result in significantly more responses
(see section 4.2).
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 and 189 patients, respectively,
continued to be in clinical remission. Clinical response (CR-100) was maintained in 102 and 233
patients, respectively.
Quality of life
In CD Study I and CD Study II, statistically significant improvement in the disease-specific
inflammatory bowel disease questionnaire (IBDQ) total score was achieved at Week 4 in patients
randomised to adalimumab 80/40 mg and 160/80 mg compared to placebo and was seen at Weeks 26
and 56 in CD Study III as well among the adalimumab treatment groups compared to the placebo
group.
Paediatric Crohn’s disease
Adalimumab was assessed in a multicentre, 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 25.

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).
One hundred patients (n=100) from the Paediatric CD Study continued in an open-label long-term
extension study. After 5 years of adalimumab therapy, 74.0% (37/50) of the 50 patients remaining in
the study continued to be in clinical remission, and 92.0% (46/50) of patients continued to be in
clinical response per PCDAI.
Ulcerative colitis
The safety and efficacy of multiple doses of adalimumab were assessed in adult patients with
moderately to severely active ulcerative colitis (Mayo score 6 to 12 with endoscopy subscore of 2 to 3)
in randomised, double-blind, placebo-controlled studies.
In study UC-I, 390 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 eow.
Clinical remission (defined as Mayo score ≤ 2 with no subscore > 1) was assessed at Week 8.
In study UC-II, 248 patients received 160 mg of adalimumab at Week 0, 80 mg at Week 2 and 40 mg
eow 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.
Patients 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 remission at Week 8, 21/41 (51%) were in remission at Week 52.
Results from the overall UC-II study population are shown in Table 28.

Of those patients who had a response at Week 8, 47% were in response, 29% were in remission, 41%
had mucosal healing, and 20% were in steroid-free remission for ≥ 90 days at Week 52.
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. Among patients who had failed prior anti-TNF treatment, Week 52 remission was achieved
by 3% on placebo and 10% on adalimumab.
Patients from studies UC-I and UC-II had the option to roll over into an open-label long-term
extension study (UC III). Following 3 years of adalimumab therapy, 75% (301/402) continued to be in
clinical remission per partial Mayo score.
Hospitalisation rates
During 52 weeks of studies UC-I and UC-II, lower rates of all-cause hospitalisations and UC-related
hospitalisations were observed for the adalimumab-treated arm compared to the placebo arm. The
number of all cause hospitalisations in the adalimumab treatment group was 0.18 per patient year vs.
0.26 per patient year in the placebo group and the corresponding figures for UC-related
hospitalisations were 0.12 per patient year vs. 0.22 per patient year.
Quality of life
In study UC-II, treatment with adalimumab resulted in improvements in the Inflammatory Bowel
Disease Questionnaire (IBDQ) score.
Uveitis
The safety and efficacy of adalimumab were assessed in adult patients with non-infectious
intermediate, posterior, and panuveitis, 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 every other week starting one week after
the initial dose. Concomitant stable doses of one non-biologic immunosuppressant were permitted.
Study UV I evaluated 217 patients with active uveitis despite treatment with corticosteroids (oral
prednisone at a dose of 10 to 60 mg/day). All patients received a 2-week 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. Patients subsequently underwent
a mandatory taper schedule, with complete corticosteroid discontinuation by Week 19.
The primary efficacy endpoint in both studies was ´time to treatment failure´. 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).
Patients who completed Studies UV I and UV II were eligible to enroll in an uncontrolled long-term
extension study with an originally planned duration of 78 weeks. Patients were allowed to continue on
study medication beyond Week 78 until they had access to adalimumab.
Clinical response
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 29). Both
studies demonstrated an early and sustained effect of adalimumab on the treatment failure rate versus
placebo (see Figure 2).

In Study UV I statistically significant differences in favour of adalimumab versus placebo were
observed for each component of treatment failure. In Study UV II, statistically significant differences
were observed for visual acuity only, but the other components were numerically in favour of
adalimumab.
Of the 424 subjects included in the uncontrolled long-term extension of Studies UV I and UV II, 60
subjects were regarded ineligible (e.g. due to deviations or due to complications secondary to diabetic
retinopathy, due to cataract surgery or vitrectomy) and were excluded from the primary analysis of
efficacy. Of the 364 remaining patients, 269 evaluable patients (74%) reached 78 weeks of open-label
adalimumab treatment. Based on the observed data approach, 216 (80.3%) were in 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 178 (66.2%) were in steroid-free quiescence. BCVA was either improved or
maintained (< 5 letters deterioration) in 88.6% of the eyes at week 78. Data beyond Week 78 were
generally consistent with these results but the number of enrolled subjects declined after this time.
Overall, among the patients who discontinued the study, 18% discontinued due to adverse events, and
8% due to insufficient response to adalimumab treatment.
Quality of life
Patient reported outcomes regarding vision-related functioning were measured in both clinical studies,
using the NEI VFQ-25. Adalimumab was numerically favoured for the majority of subscores with
statistically significant mean differences for general vision, ocular pain, near vision, mental health, and
total score in Study UV I, and for general vision and mental health in Study UV II. Vision related
effects were not numerically in favour of adalimumab for colour vision in Study UVI and for colour
vision, peripheral vision and near vision in Study UV II.
Paediatric uveitis
The safety and efficacy of adalimumab was assessed in a randomised, double-masked, controlled
study of 90 paediatric patients from 2 to < 18 years of age with active JIA-associated noninfectious
anterior uveitis who were refractory to at least 12 weeks of methotrexate treatment. Patients received
either placebo or 20 mg adalimumab (if < 30 kg) or 40 mg adalimumab (if ≥ 30 kg) every other week
in combination with their baseline dose of methotrexate.
The primary endpoint was ‘time to treatment failure’. The criteria determining treatment failure were
worsening or sustained non-improvement in ocular inflammation, partial improvement with
development of sustained ocular co-morbidities or worsening of ocular co-morbidities, non-permitted
use of concomitant medications, and suspension of treatment for an extended period of time.
Clinical response
Adalimumab significantly delayed the time to treatment failure, as compared to placebo (see Figure 3,
p < 0.0001 from log rank test).The median time to treatment failure was 24.1 weeks for subjects
treated with placebo, whereas the median time to treatment failure was not estimable for subjects
treated with adalimumab because less than one-half of these subjects experienced treatment failure.
Adalimumab significantly decreased the risk of treatment failure by 75% relative to placebo, as shown
by the hazard ratio (HR = 0.25 [95% CI: 0.12, 0.49]).

Immunogenicity
Anti-adalimumab antibodies may develop during adalimumab treatment. Formation of antiadalimumab antibodies is associated with increased clearance and reduced efficacy of adalimumab.
There is no apparent correlation between the presence of anti-adalimumab antibodies and the
occurrence of adverse events.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with the
reference medicinal product containing adalimumab in one or more subsets of the paediatric
population in ulcerative colitis (see section 4.2 for information on paediatric use).

5.2. Pharmacokinetic Properties

Absorption and distribution
After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab
was slow, with peak serum concentrations being reached about 5 days after administration. The
average absolute bioavailability of adalimumab estimated from three studies conducted with the
reference product following a single 40 mg subcutaneous dose was 64%. After single intravenous
doses ranging from 0.25 to 10 mg/kg, concentrations were dose proportional. After doses of 0.5 mg/kg
(~40 mg), clearances ranged from 11 to 15 ml/hour, the distribution volume (Vss) ranged from 5 to
6 litres and the mean terminal phase half-life was approximately two weeks. Adalimumab
concentrations in the synovial fluid from several rheumatoid arthritis patients ranged from 31-96% of
those in serum.
Following subcutaneous administration of 40 mg of adalimumab every other week in adult rheumatoid
arthritis (RA) patients the mean steady-state trough concentrations were approximately 5 μg/ml
(without concomitant methotrexate) and 8 to 9 μg/ml (with concomitant methotrexate), respectively.
The serum adalimumab trough levels at steady-state increased roughly proportionally with dose
following 20, 40 and 80 mg subcutaneous dosing every other week and every week.
Following the administration of 24 mg/m2 (up to a maximum of 40 mg) subcutaneously every other
week to patients with polyarticular juvenile idiopathic arthritis (JIA) who were 4 to 17 years the mean
trough steady-state (values measured from Week 20 to 48) serum adalimumab concentration was 5.6 ±
5.6 μg/ml (102% CV) for adalimumab without concomitant methotrexate and 10.9 ± 5.2 μg/ml (47.7%
CV) with concomitant methotrexate.
In patients with polyarticular JIA who were 2 to < 4 years old or aged 4 and above weighing < 15 kg
dosed with adalimumab 24 mg/m2 , the mean trough steady-state serum adalimumab concentrations
was 6.0 ± 6.1 μg/ml (101% CV) for adalimumab without concomitant methotrexate and 7.9 ±
5.6 μg/ml (71.2% CV) with concomitant methotrexate.
Following the administration of 24 mg/m2 (up to a maximum of 40 mg) subcutaneously every other
week to patients with enthesitis-related arthritis who were 6 to 17 years, the mean trough steady-state
(values measured at Week 24) serum adalimumab concentrations were 8.8 ± 6.6 μg/ml for
adalimumab without concomitant methotrexate and 11.8 ± 4.3 μg/ml with concomitant methotrexate.
Following subcutaneous administration of 40 mg of adalimumab every other week in adult nonradiographic axial spondyloarthritis patients, the mean (±SD) trough steady-state concentration at
Week 68 was 8.0 ± 4.6 μg/ml.
In adult patients with psoriasis, the mean steady-state trough concentration was 5 μg/ml during
adalimumab 40 mg every other week monotherapy treatment.
Following the administration of 0.8 mg/kg (up to a maximum of 40 mg) subcutaneously every other
week to paediatric patients with chronic plaque psoriasis, the mean ± SD steady-state adalimumab
trough concentration was approximately 7.4 ± 5.8 μg/ml (79% CV).
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 μg/ml at
Week 2 and Week 4. The mean steady-state trough concentration at Week 12 through Week 36 were
approximately 8 to 10 μg/ml during adalimumab 40 mg every week treatment.
Adalimumab exposure in adolescent 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 is 40 mg every other week. Since
exposure to adalimumab can be affected by body size, adolescents with higher body weight and
inadequate response may benefit from receiving the recommended adult dose of 40 mg every week.
In patients with Crohn’s disease, the loading dose of 80 mg adalimumab on Week 0 followed by
40 mg adalimumab on Week 2 achieves serum adalimumab trough concentrations of approximately
5.5 μg/ml during the induction period. 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 μg/ml during the induction period. Mean steady-state trough levels of approximately 7 μg/ml were
observed in Crohn’s disease patients who received a maintenance dose of 40 mg adalimumab every
other week.
In paediatric patients with moderate to severe CD, 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, patients were randomised 1:1 to either the standard dose (40/20 mg every other week) or
low dose (20/10 mg every other week) maintenance treatment groups based on their body weight. The
mean (±SD) serum adalimumab trough concentrations achieved at Week 4 were 15.7 ± 6.6 μg/ml for
patients ≥ 40 kg (160/80 mg) and 10.6 ± 6.1 μg/ml for patients < 40 kg (80/40 mg).
For patients who stayed on their randomised therapy, the mean (±SD) adalimumab trough
concentrations at Week 52 were 9.5 ± 5.6 μg/ml for the standard dose group and 3.5 ± 2.2 μg/ml for
the low dose group. The mean trough concentrations were maintained in patients who continued to
receive adalimumab treatment every other week for 52 weeks. For patients who dose escalated from
every other week to weekly regimen, the mean (±SD) serum concentrations of adalimumab at Week
52 were 15.3 ± 11.4 μg/ml (40/20 mg, weekly) and 6.7 ± 3.5 μg/ml (20/10 mg, weekly).
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 μg/ml during the induction period. Mean steady-state trough levels of approximately 8 μg/ml were
observed in ulcerative colitis patients who received a maintenance dose of 40 mg adalimumab every
other week.
In adult patients with uveitis, a loading dose of 80 mg adalimumab on Week 0 followed by 40 mg
adalimumab every other week starting at Week 1, resulted in mean steady-state concentrations of
approximately 8 to 10 μg/ml.
Adalimumab exposure in paediatric uveitis 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). No clinical exposure data are available on the use of a loading dose in children < 6 years.
The predicted exposures indicate that in the absence of methotrexate, a loading dose may lead to an
initial increase in systemic exposure.
Population pharmacokinetic and pharmacokinetic/pharmacodynamic modelling and simulation
predicted comparable adalimumab exposure and efficacy in patients treated with 80 mg every other
week when compared with 40 mg every week (including adult patients with RA, HS, UC, CD or Ps,
patients with adolescent HS, and paediatric patients ≥ 40 kg with CD).
Exposure-response relationship in paediatric population
On the basis of clinical trial data in patients with JIA (pJIA and ERA), an exposure-response
relationship was established between plasma concentrations and PedACR 50 response. The apparent
adalimumab plasma concentration that produces half the maximum probability of PedACR 50
response (EC50) was 3 μg/ml (95% CI: 1-6 μg/ml).
Exposure-response relationships between adalimumab concentration and efficacy in paediatric patients
with severe chronic plaque psoriasis were established for PASI 75 and PGA clear or minimal,
respectively. PASI 75 and PGA clear or minimal increased with increasing adalimumab
concentrations, both with a similar apparent EC50 of approximately 4.5 μg/mL (95% CI 0.4-47.6 and
1.9-10.5, respectively).
Elimination
Population pharmacokinetic analyses with data from over 1,300 RA patients revealed a trend toward
higher apparent clearance of adalimumab with increasing body weight. After adjustment for weight
differences, gender and age appeared to have a minimal effect on adalimumab clearance. The serum
levels of free adalimumab (not bound to anti-adalimumab antibodies, AAA) were observed to be
lower in patients with measurable AAA.
Hepatic or renal impairment
Adalimumab has not been studied in patients with hepatic or renal impairment.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on studies of single dose toxicity,
repeated dose toxicity, and genotoxicity.
An embryo-foetal developmental toxicity/perinatal developmental study has been performed in
cynomologous monkeys at 0, 30 and 100 mg/kg (9-17 monkeys/group) and has revealed no evidence
of harm to the foetuses due to adalimumab. Neither carcinogenicity studies, nor a standard assessment
of fertility and postnatal toxicity, were performed with adalimumab due to the lack of appropriate
models for an antibody with limited cross-reactivity to rodent TNF and to the development of
neutralising antibodies in rodents.

6. PHARMACEUTICAL PARTICULARS

6.1 Excipients List

Sodium chloride
Sucrose
Polysorbate 80
Water for injections
Hydrochloric acid (for pH adjustment)
Sodium hydroxide (for pH adjustment)

6.2. Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.

6.3. Shelf Life

2 years

6.4. Special precautions for storage

Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the pre-filled syringe or pre-filled pen in its
outer carton in order to protect from light.
A single pre-filled syringe or pre-filled pen may be stored at temperatures up to a maximum of 25°C
for a period of up to 14 days. The pre-filled syringe or the pre-filled pen must be discarded if not used
within the 14-day period.

6.5. Nature and contents of container

SIMLANDI 40 mg solution for injection in pre-filled syringe
0.4 ml preservative-free solution for injection in a pre-filled type I glass syringe with a fixed 29-gauge
(0.5 inch) needle stoppered with a fluoropolymer barrier film-coated (FluroTec) bromobutyl plunger
(latex-free).
Pack sizes: 2 pre-filled syringes each packed in a PVC/PE blister, with 2 alcohol pads.
SIMLANDI 40 mg solution for injection in pre-filled pen
0.4 ml preservative-free solution for injection in pre-filled needle-based injection system (autoinjector)
containing a pre-filled type I glass syringe a fixed 29-gauge (0.5 inch) needle stoppered with a
fluoropolymer barrier film-coated (FluroTec) bromobutyl plunger (latex-free). The pen is a single use,
disposable, handheld, mechanical injection device.
Pack sizes: 2 pre-filled pens, packed in a PVC/PE blister, with 2 alcohol pads.

6.6. Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.

7. MARKETING AUTHORISATION HOLDER

SAJA Pharmaceuticals- Jeddah – Saudi Arabia

8. DATE OF REVISION OF THE TEXT

12/2020

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