ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Humira 40 mg solution for injection.
2.
Each 0.8 ml single dose vial contains 40 mg of adalimumab.
Adalimumab is a recombinant human monoclonal antibody expressed in Chinese Hamster Ovary cells.
For a full list of excipients, see section 6.1.
3.
Clear solution for injection.
4.
Rheumatoid arthritis
Humira 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 including methotrexate has been
inadequate.
the treatment of severe, active and progressive rheumatoid arthritis in adults not previously
treated with methotrexate.
Humira can be given as monotherapy in case of intolerance to methotrexate or when continued
treatment with methotrexate is inappropriate.
Humira 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.
Polyarticular juvenile idiopathic arthritis
Humira in combination with methotrexate is indicated for the treatment of active polyarticular juvenile
idiopathic arthritis, in adolescents aged 13 to 17 years who have had an inadequate response to one or
more disease-modifying anti-rheumatic drugs (DMARDs). Humira can be given as monotherapy in
case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate
(see section 5.1).
Psoriatic arthritis
Humira is indicated for the treatment of active and progressive psoriatic arthritis in adults when the
response to previous disease-modifying anti-rheumatic drug therapy has been inadequate. Humira 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.
2
Ankylosing spondylitis
Humira is indicated for the treatment of adults with severe active ankylosing spondylitis who have had
an inadequate response to conventional therapy.
Crohn’s disease
Humira is indicated for treatment of severe, active Crohn’s disease, in 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.
Psoriasis
Humira is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients
who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy
including cyclosporine, methotrexate or PUVA.
Humira treatment should be initiated and supervised by specialist physicians experienced in the
diagnosis and treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic
arthritis, ankylosing spondylitis, Crohn’s disease or psoriasis. Patients treated with Humira should be
given the special alert card.
After proper training in injection technique, patients may self-inject with Humira if their physician
determines that it is appropriate and with medical follow-up as necessary.
During treatment with Humira, other concomitant therapies (e.g., corticosteroids and/or
immunomodulatory agents) should be optimised.
Adults
Rheumatoid arthritis
The recommended dose of Humira 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 Humira.
Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, or analgesics can be continued
during treatment with Humira. 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 may benefit from an
increase in dose intensity to 40 mg adalimumab every week.
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 Humira after discontinuation for 70 days or longer
resulted in the same magnitudes of clinical response and similar safety profile as before dose
interruption.
Psoriatic arthritis and ankylosing spondylitis
The recommended dose of Humira for patients with psoriatic arthritis or ankylosing spondylitis is
40 mg adalimumab administered every other week as a single dose via subcutaneous injection.
3
For all of the above indications, available data suggest that the 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.
Crohn’s disease
The recommended Humira induction dose regimen for adult patients with severe 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 (dose can be administered as four injections in one day or as
two injections per day for two consecutive days), 80 mg at Week 2, 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 Humira and signs and symptoms of disease recur,
Humira 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 may benefit from an increase in dose
intensity to 40 mg Humira every 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.
Psoriasis
The recommended dose of Humira 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.
Elderly patients
No dose adjustment is required.
Children and adolescents (aged 13 to 17 years)
Polyarticular Juvenile Idiopathic Arthritis
The recommended dose of Humira for patients with polyarticular juvenile idiopathic arthritis, aged 13
years and above is 40 mg adalimumab administered every other week as a single dose 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.
Impaired renal and/or hepatic function
Humira has not been studied in these patient populations. No dose recommendations can be made.
4
Hypersensitivity to the active substance or to any of the excipients.
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).
Infections
Patients taking TNF-blockers 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 Humira. Because the elimination of
adalimumab may take up to five months, monitoring should be continued throughout this period.
Treatment with Humira should not be initiated in patients with active infections including chronic or
localized 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 Humira
should be considered prior to initiating therapy (see
Opportunistic infections
).
Patients who develop a new infection while undergoing treatment with Humira, should be monitored
closely and undergo a complete diagnostic evaluation. Administration of Humira 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 Humira 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, and pneumocystis have been reported in patients
receiving Humira.
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:
There have been reports of tuberculosis in patients receiving Humira. It should be noted that in the
majority of those reports, tuberculosis was extra-pulmonary, i.e. disseminated.
Before initiation of therapy with Humira, all patients must be evaluated for both, active or inactive
(latent) tuberculosis infection. This evaluation should include a detailed medical history of patients
with a personal history of tuberculosis or possible previous exposure to patients 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 of these tests should be recorded in the patient alert 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, Humira therapy must not be initiated (see section 4.3).
5
If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be
consulted. In all situations described below, the benefit/risk balance of therapy should be very
carefully considered.
If inactive (‘latent’) tuberculosis is diagnosed, appropriate treatment for latent tuberculosis must be
started with anti-tuberculosis prophylaxis therapy before the initiation of Humira, and in accordance
with local recommendations.
In patients who have several or significant risk factors for tuberculosis and have a negative
test for latent tuberculosis, anti-tuberculosis therapy should also be considered before the
initiation of Humira.
Use of anti-tuberculosis therapy should also be considered before the initiation of Humira in patients
with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be
confirmed. Some patients who have previously received treatment for latent or active tuberculosis
have developed active tuberculosis while being treated with Humira.
Patients should be instructed to seek medical advice if signs/symptoms (e.g., persistent cough,
wasting/weight loss, low grade fever) suggestive of a tuberculosis infection occur during or after
therapy with Humira.
Other opportunistic infections:
Opportunistic infections, including invasive fungal infections have been observed in patients receiving
Humira. These infections have not consistently been recognised in patients taking TNF-blockers and
this 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,
dyspnea, and/or pulmonary infiltrates or other serious systemic illness with or without concomitant
shock an invasive fungal infection should be suspected and administration of Humira 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 who are chronic carriers of this virus when
receiving a TNF-antagonist including Humira. Some cases have had a fatal outcome. Patients at risk
for HBV infection should be evaluated for prior evidence of HBV infection before initiating Humira
therapy. Carriers of HBV who require treatment with Humira 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 the treatment of 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, Humira should be stopped and effective anti-
viral therapy with appropriate supportive treatment should be initiated.
Neurological events
TNF-antagonists including Humira have been associated in rare instances with new onset or
exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease including
multiple sclerosis. Prescribers should exercise caution in considering the use of Humira in patients
with pre-existing or recent-onset central nervous system demyelinating disorders.
6
Allergic reactions
Serious allergic adverse reactions have not been reported with subcutaneous administration of Humira
during clinical trials. Non-serious allergic reactions associated with Humira were uncommon during
clinical trials. In postmarketing, serious allergic reactions including anaphylaxis have been reported
very rarely following Humira administration. If an anaphylactic reaction or other serious allergic
reaction occurs, administration of Humira should be discontinued immediately and appropriate therapy
initiated.
The needle cover of the syringe contains natural rubber (latex). This may cause severe allergic
reactions in patients sensitive to latex.
Immunosuppression
In a study of 64 patients with rheumatoid arthritis that were treated with Humira, 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 leukemia have been
reported in patients treated with a TNF-antagonist. There is an increased background risk for
lymphoma and leukemia 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, leukemia, 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-blocking agents (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-blockers cannot be excluded.
Rare postmarketing 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 Humira have occurred in young
adult patients on concomitant treatment with azathioprine or 6-mercaptopurine used for Crohn’s
disease. A risk for the development of hepatosplenic T-cell lymphoma in patients treated with Humira
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 Humira is continued following development of malignancy. Thus additional caution
should be exercised in considering Humira 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 non-
melanoma skin cancer prior to and during treatment with Humira.
In an exploratory clinical trial evaluating the use of another anti-TNF agent, infliximab, in patients
with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in
the lung or head and neck, were reported in infliximab-treated patients compared with control patients.
All patients had a history of heavy smoking. Therefore, caution should be exercised when using any
TNF-antagonist in COPD patients, as well as in patients with increased risk for malignancy due to
heavy smoking.
7
Haematologic reactions
Rare reports of pancytopenia including aplastic anaemia have been reported with TNF antagonists.
Adverse events of the haematologic system, including medically significant cytopoenia (e.g.
thrombocytopaenia, leucopaenia) have been reported with Humira. 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 Humira. Discontinuation of Humira 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 Humira.
It is recommended that polyarticular juvenile idiopathic arthritis patients, if possible, be brought up to
date with all immunisations in agreement with current immunisation guidelines prior to initiating
Humira therapy.
Patients on Humira may receive concurrent vaccinations, except for live vaccines.
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 Humira. Humira should be used with caution in
patients with mild heart failure (NYHA class I/II). Humira is contraindicated in moderate to severe
heart failure (see section 4.3). Treatment with Humira must be discontinued in patients who develop
new or worsening symptoms of congestive heart failure.
Autoimmune processes
Treatment with Humira may result in the formation of autoimmune antibodies.
The impact of long-
term treatment with Humira on the development of autoimmune diseases is unknown. If a patient
develops symptoms suggestive of a lupus-like syndrome following treatment with Humira and is
positive for antibodies against double-stranded DNA, further treatment with Humira should not be
given (see section 4.8).
Concurrent administration of TNF-antagonists and anakinra
Serious infections were seen in clinical studies with concurrent use of anakinra and another
TNF-antagonist, 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).
Concurrent administration of TNF-antagonists and abatacept
Concurrent administration of TNF-antagonists and abatacept has been associated with an increased
risk of infections including serious infections compared to TNF-antagonists alone, without increased
clinical benefit. The combination of Humira and abatacept is not recommended. (See section 4.5).
Surgery
8
There is limited safety experience of surgical procedures in patients treated with Humira. The long
half-life of adalimumab should be taken into consideration if a surgical procedure is planned. A
patient who requires surgery while on Humira should be closely monitored for infections, and
appropriate actions should be taken. There is limited safety experience in patients undergoing
arthroplasty while receiving Humira.
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 Humira does not worsen or cause
strictures.
Elderly Population
The frequency of serious infections among HUMIRA treated subjects over 65 years of age (3.9%) was
higher than for those under 65 years of age (1.4%). Some of those had a fatal outcome. Particular
attention regarding the risk for infection should be paid when treating the elderly.
Humira has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic
arthritis patients taking Humira as monotherapy and those taking concomitant methotrexate. Antibody
formation was lower when Humira was given together with methotrexate in comparison with use as
monotherapy. Administration of Humira without methotrexate resulted in increased formation of
antibodies, increased clearance and reduced efficacy of adalimumab (see section 5.1).
The combination of Humira and anakinra is not recommended (see section 4.4 “Concurrent
administration of TNF-antagonists and anakinra”).
The combination of Humira and abatacept is not recommended (see section 4.4 “Concurrent
administration of TNF-antagonists and abatacept”).
For Humira, no clinical data on exposed pregnancies are available
In a developmental toxicity study conducted in monkeys, there was no indication of maternal toxicity,
embryotoxicity or teratogenicity. Preclinical data on postnatal toxicity and fertility effects 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. Administration of adalimumab is not recommended during
pregnancy. Women of childbearing potential are strongly recommended to use adequate contraception
to prevent pregnancy and continue its use for at least five months after the last Humira treatment.
It is not known whether adalimumab is excreted in human milk or absorbed systemically after
ingestion.
However, because human immunoglobulins are excreted in milk, women must not breast-feed for at
least five months after the last Humira treatment.
9
Humira may have a minor influence on the ability to drive and use machines. Vertigo and visual
impairment may occur following administration of Humira (see Section 4.8)
Clinical Trials
Humira was studied in 6,728 patients in controlled and open label trials for up to 60 months. These
trials included rheumatoid arthritis patients with short term and long standing disease, polyarticular
juvenile idiopathic arthritis as well as psoriatic arthritis, ankylosing spondylitis, Crohn’s disease and
psoriasis patients. The data in Table 1 is based on the pivotal controlled Studies involving 4,419
patients receiving Humira and 2,552 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 4.5% for patients taking Humira and 4.5% for control treated
patients.
In general, the adverse events in paediatric patients were similar in frequency and type to those seen in
adult patients.
Adverse events, at least possibly causally-related to adalimumab for clinical studies both clinical and
laboratory, are displayed by system organ class and frequency (very common ≥ 1/10; common
≥ 1/100 to < 1/10; uncommon ≥ 1/1,000 to< 1/100, rare ≥ 1/10,000 to < 1/1,000 and very rare
<1/10,000) in Table 1 below. 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.
Approximately 15% of patients can be expected to experience injection site reactions, based on one of
the most common adverse events with adalimumab in controlled clinical studies.
Table 1
Undesirable Effects in Clinical Studies
System Organ Class
Frequency
Adverse Reaction
Infections and
infestations*
Very common
respiratory tract infections (including lower and
upper respiratory tract infection, pneumonia,
sinusitis, pharyngitis, nasopharyngitis and
pneumonia herpes viral)
Common
systemic infections (including sepsis, candidiasis
and influenza),
intestinal infections (including gastroenteritis
viral),
skin and soft tissue infections (including
paronychia, cellulitis, impetigo, necrotising
fasciitis and herpes zoster),
ear infections,
oral infections (including herpes simplex, oral
10
System Organ Class
Frequency
Adverse Reaction
herpes and tooth infections),
reproductive tract infections (including
vulvovaginal mycotic infection),
urinary tract infections (including
pyelonephritis),
fungal infections
Uncommon
opportunistic infections and tuberculosis
(including coccidioidomycosis, histoplasmosis
and mycobacterium avum complex infection),
neurological infections (including viral
meningitis),
eye infections,
bacterial infections,
joint infections
Neoplasms benign,
malignant and unspecified
(including cysts and
polyps)*
Common
benign neoplasm,
skin cancer excluding melanoma (including basal
cell carcinoma and squamous cell carcinoma)
Uncommon
lymphoma**,
solid organ neoplasm (including breast cancer,
lung neoplasm and thyroid neoplasm),
melanoma**
Blood and the lymphatic
system disorders*
Very common
leucopaenia (including neutropaenia and
agranulocytosis),
anaemia
Common
thrombocytopaenia,
leucocytosis
Uncommon
idiopathic thrombocytopaenic purpura
Rare
pancytopaenia
Immune system disorders* Common
hypersensitivity,
allergies (including seasonal allergy)
Metabolism and nutrition
disorders
Very common
lipids increased
Common
hypokalaemia,
uric acid increased,
blood sodium abnormal,
hypocalcaemia
hyperglycemia,
hypophosphotemia,
blood potassium increased
Uncommon
dehydration
11
System Organ Class
Frequency
Adverse Reaction
Psychiatric disorders
Common
mood alterations (including depression),
anxiety, insomnia
Nervous system disorders*
Very common
headache
Common
paraesthesias (including hypoaesthesia),
migraine,
sciatica
Uncommon
tremor
Rare
multiple sclerosis
Eye disorders
Common
visual impairment,
conjunctivitis,
Uncommon
blepharitis,
eye swelling,
diplopia
Ear and labyrinth
disorders
Common
vertigo
Uncommon
deafness,
tinnitus
Cardiac disorders*
Common
tachycardia
Uncommon
arrhythmia,
congestive heart failure
Rare
cardiac arrest
Vascular disorders
Common
hypertension,
flushing,
haematoma
Rare
vascular arterial occlusion,
thrombophlebitis,
aortic aneurysm
Respiratory, thoracic and
mediastinal disorders*
Common
cough,
asthma,
dyspnoea
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System Organ Class
Frequency
Adverse Reaction
Uncommon
chronic obstructive pulmonary disease,
interstitial lung disease,
pneumonitis
Gastrointestinal disorders
Very common
abdominal pain,
nausea and vomiting
Common
GI haemorrhage,
dyspepsia,
gastroesophageal reflux disease,
sicca syndrome
Uncommon
pancreatitis,
dysphagia
face oedema
Hepato-biliary disorders*
Very Common
elevated liver enzymes
Uncommon
cholecystitis and cholelithiasis,
bilirubin increased,
hepatic steatosis
Skin and subcutaneous
tissue disorders
Very Common
rash (including exfoliative rash),
Common
pruritus,
urticaria,
bruising (including purpura),
dermatitis (including eczema),
onychoclasis,
hyperhydrosis
Uncommon
night sweats,
scar
Musculoskeletal,
connective tissue and bone
disorders
Very common
musculoskeletal pain
Common
muscle spasms (including blood creatine
phosphokinase increased)
Uncommon
rhabdomyolysis
Rare
systemic lupus erythematosus
Renal and urinary
disorders
Common
haematuria,
renal impairment
Uncommon
nocturia
Reproductive system and
breast disorders
Uncommon
erectile dysfunction
13
System Organ Class
Frequency
Adverse Reaction
General disorders and
administration site
conditions*
Very Common
injection site reaction (including injection site
erythema)
Common
chest pain,
oedema
Uncommon
inflammation
Investigations*
Common
coagulation and bleeding disorders (including
activated partial thromboplastin time prolonged),
autoantibody test positive (including double
stranded DNA antibody),
blood lactate dehydrogenase increased
Injury and poisoning
Common
impaired healing
* further information is found elsewhere in sections 4.3, 4.4 and 4.8
** including open label extension studies
Injection site reactions
In the pivotal controlled trials, 15% of patients treated with Humira developed injection site reactions
(erythema and/or itching, haemorrhage, pain or swelling), compared to 9% 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, the rate of infection was 1.50 per patient year in the Humira treated
patients and 1.42 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 Humira after the infection resolved.
The incidence of serious infections was 0.03 per patient year in Humira treated patients and 0.03 per
patient year in placebo and active control − treated patients.
In controlled and open label studies with Humira, 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 171 patients with an exposure of 192.5 patient years during a
Humira trial in juvenile idiopathic arthritis patients.
During the controlled portions of pivotal Humira trials at least 12 weeks in duration in patients with
moderately to severely active rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s
disease and psoriasis, malignancies, other than lymphoma and non-melanoma skin cancer, were
observed at a rate (95% confidence interval) of 6.6 (4.0, 10.8) per 1,000 patient-years among 3,917
Humira treated patients
versus
a rate of 4.2 (1.8, 10.1) per 1,000 patient-years among 2,247 control
patients (median duration of treatment was 5.6 months for Humira and 4.0 months for control-treated
14
patients). The rate (95% confidence interval) of non-melanoma skin cancers was 9.9 (6.6, 14.8) per
1,000 patient-years among Humira-treated patients and 2.5 (0.8, 7.9) per 1,000 patient-years among
control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence
interval) of 2.5 (1.1, 5.5) per 1,000 patient-years among Humira-treated patients and 0.8 (0.1, 6.0) per
1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.8
(0.2, 3.3) per 1,000 patient-years among Humira-treated patients and 0.8 (0.1, 6.0) 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 3.4 years including 4,954 patients and over 21,021
patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma
skin cancers is approximately 9.1 per 1,000 patient years. The observed rate of non-melanoma skin
cancers is approximately 10.1 per 1,000 patient years, and the observed rate of lymphomas is
approximately 1.1 per 1000 patient years.
In post-marketing experience from January 2003, predominately in patients with rheumatoid arthritis,
the reported rate of malignancies other than lymphomas and non-melanoma skin cancers is
approximately 1.7 per 1,000 patient years. The reported rates for non-melanoma skin cancers and
lymphomas are approximately 0.2 and 0.4 per 1,000 patient 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 Humira 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 Humira 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.
Liver Enzyme Elevations
Rheumatoid arthritis clinical trials:
in controlled rheumatoid arthritis clinical trials (RA studies
I − IV), elevations of ALT were similar in patients receiving adalimumab or placebo. In patients with
early rheumatoid arthritis (disease duration of less than 3 years) (RA study V), elevations of ALT were
more common in the combination arm (Humira /methotrexate) compared to the methotrexate
monotherapy arm or the Humira monotherapy arm. In the JIA trial the few transaminase elevations
were small and similar in the placebo and adalimumab exposed patients, and mostly occurred in
combination with methotrexate.
Psoriatic arthritis clinical trials:
elevations in ALT were more common in psoriatic arthritis patients
(PsA studies I - II) compared with patients in rheumatoid arthritis clinical studies.
In all rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic arthritis studies,
patients with raised ALT were asymptomatic and in most cases elevations were transient and resolved
on continued treatment.
Crohn’s disease clinical trials:
in controlled clinical trials, elevations of ALT were similar in patients
receiving adalimumab or placebo.
Psoriasis clinical trials:
in controlled psoriasis clinical trials, elevations of ALT were similar in
patients receiving adalimumab or placebo.
Additional Adverse Reactions from Postmarketing Surveillance or Phase IV Clinical Trials
15
The additional adverse reactions in Table 2 have been reported from postmarketing surveillance or
Phase IV clinical trials:
Table 2
Undesirable Effects in Postmarketing Surveillance and Phase IV Clinical Studies
System Organ Class
Adverse Reaction
Infections and Infestations
diverticulitis
Neoplasm benign, malignant and unspecified
(including cysts and polyps)*
hepatosplenic T-cell lymphoma; leukemia
Immune system disorders* Anaphylaxis, sarcoidosis
Nervous system disorders* demyelinating disorders (e.g. optic neuritis,
Guillain-Barré syndrome); cerebrovascular
accident
Respiratory, thoracic and mediastinal disorders pulmonary embolism
pleural effusion, pulmonary fibrosis
Gastrointestinal disorders* intestinal perforation
Hepatobiliary disorders* reactivation of hepatitis B
Skin and subcutaneous tissue disorders cutaneous vasculitis, Stevens-Johnson syndrome,
angioedema, new onset or worsening of
psoriasis (including palmoplantar pustular
psoriasis), erythema multiforme, alopecia
Musculoskeletal and connective tissue disorders lupus-like syndrome
Cardiac disorders
myocardial infarction
*further information is found elsewhere in sections 4.3, 4.4 and 4.8
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective immunosuppressive agents. ATC code: L04AB04
Mechanism of action
Adalimumab binds specifically to TNF and neutralizes 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 IC
50
of0.1-0.2 nM).
Pharmacodynamic effects
After treatment with Humira, 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
16
destruction were also decreased after Humira administration. Patients treated with Humira usually
experienced improvement in haematological signs of chronic inflammation.
In patients with Crohn’s disease, a rapid decrease in CRP levels was also observed, as well as a
reduction of the number of cells expressing inflammatory markers in the colon including a significant
reduction of expression of TNFα. Endoscopic studies in intestinal mucosa have shown evidence of
mucosal healing in adalimumab treated patient.
A rapid decrease in CRP levels was also observed in patients with polyarticular juvenile idiopathic
arthritis.
Clinical trials
Rheumatoid arthritis
Humira was evaluated in over 3,000 patients in all rheumatoid arthritis clinical trials. Some patients
were treated for up to 60 months duration. The efficacy and safety of Humira for the treatment of
rheumatoid arthritis were assessed in five randomised, double-blind and well-controlled 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 Humira 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 or 40 mg of Humira 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 Humira every
week for 52 weeks. The third group received 40 mg of Humira every other week with placebo
injections on alternate weeks. Thereafter, patients enrolled in an open-label extension phase in which
40 mg of Humira was administered every other week up to 60 months.
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,
anti-rheumatic 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 Humira 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
Humira 40 mg every other week/methotrexate combination therapy, Humira 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.
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.
17
ACR response
The percent of Humira-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 3.
Table 3 ACR Responses in Placebo-Controlled Trials
(Percent of Patients)
Response
RA Study I
a
**
RA Study II
a
**
RA Study III
a
**
Placebo/
MTX
c
n=60
Humira
b
/ MTX
c
n=63
Placebo
n=110
Humira
b
n=113
Placebo/
MTX
c
n=200
Humira
b
/ MTX
c
n=207
6 months
13.3%
65.1%
19.1%
46.0%
29.5%
63.3%
12 months
NA
NA
NA
NA
24.0%
58.9%
ACR 50
6 months
6.7%
52.4%
8.2%
22.1%
9.5%
39.1%
12 months
NA
NA
NA
NA
9.5%
41.5%
ACR 70
6 months
3.3%
23.8%
1.8%
12.4%
2.5%
20.8%
12 months
NA
NA
NA
NA
4.5%
23.2%
a
RA study I at 24 weeks, RA study II at 26 weeks , and RA study III at 24 and 52 weeks
b
40 mg Humira administered every other week
c
MTX = methotrexate
**p < 0.01, Humira
versus
placebo
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 addition, ACR response rates were
maintained in the majority of patients followed in the open-label extension phase to Week 104. There
were 114 out of 207 patients who continued on Humira 40 mg every other week for 60 months.
Among those, 86, 72, and 41 patients had ACR 20/50/70 response, respectively at Month 60.
In RA study IV, the ACR 20 response of patients treated with Humira 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, Humira-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 Humira and methotrexate led to faster and significantly greater ACR responses than
methotrexate monotherapy and Humira monotherapy at Week 52 and responses were sustained at
Week 104 (see Table 4).
Table 4 ACR Responses in RA Study V
(percent of patients)
Response
MTX
n=257
Humira
n=274
Humira/MTX
n=268
p-value
a
p-value
b
p-value
c
ACR 20
Week 52
62.6%
54.4%
72.8%
0.013
< 0.001
0.043
Week 104
56.0%
49.3%
69.4%
0.002
< 0.001
0.140
ACR 50
Week 52
45.9%
41.2%
61.6%
< 0.001
< 0.001
0.317
18
ACR 20
Week 104 42.8% 36.9% 59.0% < 0.001 < 0.001 0.162
ACR 70
Week 52 27.2% 25.9% 45.5% < 0.001 < 0.001 0.656
Week 104 28.4% 28.1% 46.6% < 0.001 < 0.001 0.864
a
p-value is from the pairwise comparison of methotrexate monotherapy and Humira/methotrexate
combination therapy using the Mann-Whitney U test.
b
p-value is from the pairwise comparison of Humira monotherapy and Humira/methotrexate
combination therapy using the Mann-Whitney U test
c
p-value is from the pairwise comparison of Humira monotherapy and methotrexate monotherapy using
the Mann-Whitney U test
At Week 52, 42.9% of patients who received Humira/methotrexate combination therapy achieved
clinical remission (DAS28 < 2.6) compared to 20.6% of patients receiving methotrexate monotherapy
and 23.4% of patients receiving Humira monotherapy. Humira/methotrexate combination therapy was
clinically and statistically superior to methotrexate (p < 0.001) and Humira 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).
Radiographic response
In RA study III, where Humira 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. Humira/methotrexate patients demonstrated significantly less radiographic
progression than patients receiving methotrexate alone at 6 and 12 months (see Table 5). Data from the
open-label extension phase indicate that the reduction in rate of progression of structural damage is
maintained for 60 months in a subset of patients. 113/207 of patients originally treated with 40 mg
Humira every other week were evaluated radiographically at 5 years. Among those, 66 patients
showed no progression of structural damage defined by a change in the TSS of zero or less.
Table 5 Radiographic Mean Changes Over 12 Months in RA Study III
Placebo/
MTX
a
HUMIRA/MTX
40 mg every
other week
Placebo/MTX-
HUMIRA/MTX
(95% Confidence
Interval
b
)
p-value
Total Sharp Score
2.7
0.1
2.6 (1.4, 3.8)
< 0.001
c
Erosion score
1.6
0.0
1.6 (0.9, 2.2)
< 0.001
JSN
d
score
1.0
0.1
0.9 (0.3, 1.4)
0.002
a
methotrexate
b
95% confidence intervals for the differences in change scores between methotrexate and Humira.
c
Based on rank analysis
d
Joint Space Narrowing
In RA study V, structural joint damage was assessed radiographically and expressed as change in
modified Total Sharp Score (see Table 6).
Table 6 Radiographic Mean Changes at Week 52 in RA Study V
MTX
n=257
(95%
confidence
interval)
Humira
n=274
(95%
confidence
interval)
Humira/MTX
n=268
(95%
confidence
interval)
p-value
a
p-value
b
p-value
c
Total Sharp
Score
5.7 (4.2-7.3)
3.0 (1.7-4.3) 1.3 (0.5-2.1) < 0.001 0.0020 < 0.001
19
Erosion score 3.7 (2.7-4.7) 1.7 (1.0-2.4) 0.8 (0.4-1.2) < 0.001 0.0082 < 0.001
JSN score 2.0 (1.2-2.8) 1.3 (0.5-2.1) 0.5 (0-1.0) < 0.001 0.0037 0.151
a
p-value is from the pairwise comparison of methotrexate monotherapy and Humira/methotrexate
combination therapy using the Mann-Whitney U test.
b
p-value is from the pairwise comparison of Humira monotherapy and Humira/methotrexate
combination therapy using the Mann-Whitney U test
c
p-value is from the pairwise comparison of Humira monotherapy and methotrexate monotherapy
using the Mann-Whitney U test
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
Humira/methotrexate combination therapy (63.8% and 61.2% respectively) compared to methotrexate
monotherapy (37.4% and 33.5% respectively, p < 0.001) and Humira monotherapy (50.7%, p < 0.002
and 44.5%, p < 0.001 respectively).
Quality of life and physical function
Health-related quality of life and physical function was 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
Humira 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 Humira 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, improvement in physical function was maintained through Week 260 (60 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 Humira/methotrexate combination therapy
versus
methotrexate monotherapy and Humira monotherapy at Week 52, which was maintained through
Week 104.
20
Polyarticular juvenile
idiopathic
arthritis (JIA)
The safety and efficacy of Humira 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- MTX-
treated. 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/m
2
up to a maximum of 40 mg Humira 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 7.
Table 7
Distribution of patients by age and adalimumab dose received during the OL LI phase
Age Group
Number of patients at Baseline
n (%)
Minimum, median and maximum
dose
4 to 7 years
31 (18.1)
10, 20 and 25 mg
8 to 12 years
71 (41.5)
20, 25 and 40 mg
13 to 17 years
69 (40.4)
25, 40 and 40 mg
Patients demonstrating a Pediatric ACR 30 response at Week 16 were eligible to be randomised into
the double blind (DB) phase and received either Humira 24 mg/m
2
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 Pediatric 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 enrol into the open label extension phase
Table 8
Ped ACR Responses in the JIA study
Stratum
MTX
Without MTX
Phase
OL-LI 16 weeks
Ped ACR 30
response (n/N)
94.1% (80/85)
74.4% (64/86)
Double Blind
Humira
(n = 38)
Placebo
(n = 37)
Humira
(n = 30)
Placebo
(n = 28)
Disease flares at
the end of 32
weeks
a
(n/N)
36.8% (14/38)
64.9% (24/37)
b
43.3% (13/30) 71.4%
(20/28)
c
Median time to
disease flare
>32 weeks
20 weeks
>32 weeks
14 weeks
a
Ped ACR 30/50/70 responses week 48 significantly greater than those of placebo treated patients
b
p = 0.015
c
p = 0.031
Amongst those who responded at Week 16
(n=144), the Pediatric ACR 30/50/70/90 responses were
maintained for up to two years in the OLE phase in patients who received Humira throughout the
study.
21
Overall responses were generally better and, fewer patients developed antibodies when treated with
the combination of Humira and MTX compared to Humira alone. Taking these results into
consideration, Humira 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).
Psoriatic arthritis
Humira, 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 Humira was
administered eow.
There is insufficient evidence of the efficacy of Humira in patients with ankylosing spondylitis-like
psoriatic arthropathy due to the small number of patients studied.
Table 9 ACR Response in Placebo-Controlled Psoriatic Arthritis Studies
(Percent of Patients)
PsA Study I
PsA Study II
Response
Placebo
N=162
Humira
N=151
Placebo
N=49
Humira
N=51
ACR 20
Week 12
14%
58%
***
16%
39%
*
Week 24
15%
57%
***
N/A
N/A
ACR 50
Week 12
4%
36%
***
2%
25%
***
Week 24
6%
39%
***
N/A
N/A
ACR 70
Week 12
1%
20%
***
0%
14%
*
Week 24
1%
23%
***
N/A
N/A
*** p < 0.001 for all comparisons between Humira and placebo
* p < 0.05 for all comparisons between Humira and placebo
N/A not applicable
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
Humira or placebo and at Week 48 when all patients were on open-label Humira. A modified Total
Sharp Score (mTSS), which included distal interphalangeal joints (i.e., not identical to the TSS used
for rheumatoid arthritis), was used.
Humira 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 Humira group (at Week 48).
In subjects treated with Humira with no radiographic progression from baseline to Week 48 (n=102),
84% continued to show no radiographic progression through 144 weeks of treatment.
Humira 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.
22
Ankylosing spondylitis
Humira 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 Humira 40 mg 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 adalimumab 40 mg 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 Humira compared to placebo.
Significant response was first observed at Week 2 and maintained through 24 weeks (Table 10).
Table 10–
Efficacy Responses in Placebo-Controlled AS Study – Study I
Reduction of Signs and Symptoms
Humira
N=208
ASAS
a
20
Week 2 16% 42%***
Week 12 21% 58%***
Week 24 19% 51%***
ASAS 50
Week 2 3% 16%***
Week 12 10% 38%***
Week 24 11% 35%***
ASAS 70
Week 2 0% 7%**
Week 12 5% 23%***
Week 24 8% 24%***
BASDAI
b
50
Week 2 4% 20%***
Week 12 16% 45%***
Week 24 15% 42%***
***,** Statistically significant at p < 0.001, < 0.01 for all comparisons between Humira
and placebo at Weeks 2, 12 and 24
a
ASsessments in Ankylosing Spondylitis
b
Bath Ankylosing Spondylitis Disease Activity Index
Placebo
N=107
Humira 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.
Crohn’s disease
The safety and efficacy of Humira were assessed in over 1500 patients with moderately to severely
active Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in randomised,
23
Response
double-blind, placebo-controlled studies. 524 of the enrolled patients (32%) were defined as having a
severe disease (CDAI score > 300 and concomitant corticosteroid and/or immunosuppressants)
corresponding to the population defined in the indication (see section 4.1). 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 Humira 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 Humira 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 11.
Table 11
Induction of Clinical Remission and Response
(Percent of Patients)
CD Study I: Infliximab Naive
Patients
CD Study II: Infliximab
Experienced Patients
Placebo
N=74
Humira
80/40 mg
N = 75
Humira
160/80 m
g N=76
Placebo
N=166
Humira
160/80 mg
N=159
Week 4
Clinical remission
12%
24%
36%
*
7%
21%
*
Clinical response (CR-
100)
24%
37%
49%
**
25%
38%
**
All p-values are pairwise comparisons of proportions for Humira
versus
placebo
*
p < 0.001
**
p < 0.01
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 anti-TNF therapy. Maintenance of remission and response rates are presented in Table 12.
Clinical remission results remained relatively constant irrespective of previous TNF antagonist
exposure.
Disease-related hospitalisation and surgeries were statistically significantly reduced with adalimumab
compared with placebo at Week 56.
24
Table 12
Maintenance of Clinical Remission and Response
(Percent of Patients)
Placebo
40 mg Humira
every other week
40 mg Humira
every week
Week 26
N=170
N=172
N=157
Clinical remission
17%
40%*
47%*
Clinical response (CR-100)
27%
52%*
52%*
Patients in steroid-free remission
for >=90 days
a
3% (2/66)
19% (11/58)**
15% (11/74)**
Week 56
N=170
N=172
N=157
Clinical remission
12%
36%*
41%*
Clinical response (CR-100)
17%
41%*
48%*
Patients in steroid-free remission
for >=90 days
a
5% (3/66)
29% (17/58)*
20% (15/74)**
* p < 0.001 for Humira
versus
placebo pairwise comparisons of proportions
** p < 0.02 for Humira
versus
placebo pairwise comparisons of proportions
a
Among patients who were not in response at Week 4, 43% of Humira 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 Humira 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.
Psoriasis
The safety and efficacy of Humira 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.
Psoriasis Study I (REVEAL) evaluated 1,212 patients within three treatment periods. In period A,
patients received placebo or Humira 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 Humira every other week. Patients who maintained ≥PASI 75 response at
Week 33 and were originally randomised to active therapy in Period A, were re-randomised in period
C to receive 40 mg Humira 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
25
Of those receiving corticosteroids at baseline
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 Humira
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 Humira followed
by 40 mg every other week (starting one week after the initial dose) for 16 weeks. There are no data
available comparing Humira 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 open-
label extension trial, where Humira 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 13 and 14).
Table 13
Ps Study I (REVEAL)
Efficacy - Results at 16 Weeks
Humira 40 mg eow
N=814
n (%)
≥
PASI 75
a
26 (6.5)
578 (70.9)
b
PASI 100
3 (0.8)
163 (20.0)
b
PGA: Clear/minimal
17 (4.3)
506 (62.2)
b
a
Percent of patients achieving PASI75 response was calculated as center-
adjusted rate
b
p<0.001, Humira vs. placebo
Placebo
N=398
n (%)
Table 14
Ps Study II (CHAMPION) Efficacy Results at 16 Weeks
Placebo
N=53
n (%)
MTX
N=110
n (%)
Humira 40 mg eow
N=108
n (%)
≥
PASI 75
10 (18.9)
39 (35.5)
86 (79.6)
a, b
PASI 100
1 (1.9)
8 (7.3)
18 (16.7)
c, d
PGA:
Clear/minimal
6 (11.3)
33 (30.0)
79 (73.1)
a, b
a
p<0.001 Humira vs. placebo
b
p<0.001 Humira vs. methotrexate
c
p<0.01 Humira vs. placebo
d
p<0.05 Humira vs. methotrexate
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 Humira, 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-randomization 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 Humira therapy for
52 weeks in Psoriasis Study I, and continued Humira 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
26
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 open-
label 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% and were evaluated at 12 weeks after dose escalation,
93/349 (26.6%) of patients achieved PASI 75 response.
Immunogenicity
Formation of anti-adalimumab 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.
Patients in RA Studies I, II and III were tested at multiple time points for anti-adalimumab antibodies
during the 6 to 12 month period. In the pivotal trials, anti-adalimumab antibodies were identified in
58/1053 (5.5%) patients treated with adalimumab, compared to 2/370 (0.5%) on placebo. In patients
not given concomitant methotrexate, the incidence was 12.4%, compared to 0.6% when adalimumab
was used as add-on to methotrexate.
In patients with polyarticular juvenile idiopathic arthritis, adalimumab antibodies were identified in
27/171 subjects (15.8%) treated with adalimumab. In patients not given concomitant methotrexate, the
incidence was 22/86 (25.6%), compared to 5/85 (5.9%) when adalimumab was used as add-on to
methotrexate.
In patients with psoriatic arthritis, anti-adalimumab antibodies were identified in 38/376 subjects
(10%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was
13.5% (24/178 subjects), compared to 7% (14 of 198 subjects) when adalimumab was used as add-on
to methotrexate.
In patients with ankylosing spondylitis anti-adalimumab antibodies were identified in 17/204 subjects
(8.3%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was
16/185 (8.6%), compared to 1/19 (5.3%) when adalimumab was used as add-on to methotrexate.
In patients with Crohn’s disease, anti-adalimumab antibodies were identified in 7/269 subjects (2.6%)
treated with adalimumab.
In patients with psoriasis, anti-adalimumab antibodies were identified in 77/920 subjects (8.4%)
treated with adalimumab monotherapy.
27
In plaque psoriasis patients on long term adalimumab monotherapy who participated in a withdrawal
and retreatment study, the rate of antibodies to adalimumab after retreatment (11 of 482 subjects,
2.3%) was similar to the rate observed prior to withdrawal (11 of 590 subjects, 1.9%)
Because immunogenicity analyses are product-specific, comparison of antibody rates with those from
other products is not appropriate.
5.2 Pharmacokinetic properties
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 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 (V
ss
) 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 Humira 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/m
2
(up to a maximum of 40 mg) subcutaneously every other
week to patients with polyarticular juvenile idiopathic arthritis (JIA) the mean trough steady-state
(values measured from Week 20 to 48) serum adalimumab concentration was 5.6 ± 5.6 µg/mL (102
%CV) Humira monotherapy and 10.9 ± 5.2 µg/mL (47.7% CV) with concomitant methotrexate.
In patients with Crohn’s disease, the loading dose of 80 mg Humira on Week 0 followed by 40 mg
Humira on Week 2 achieves serum adalimumab trough concentrations of approximately 5.5 μg/ml
during the induction period. A loading dose of 160 mg Humira on Week 0 followed by 80 mg Humira
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 Humira every other week.
In patients with psoriasis, the mean steady-state trough concentration was 5 μg/mL during adalimumab
40 mg every other week monotherapy treatment.
Population pharmacokinetic analyses with data from over 1300 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. Humira has not been studied in patients with hepatic or renal
impairment.
28
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
neutralizing antibodies in rodents.
6.
6.1 List of excipients
Mannitol
Citric acid monohydrate
Sodium citrate
Sodium dihydrogen phosphate dihydrate
Disodium phosphate dihydrate
Sodium chloride
Polysorbate 80
Sodium hydroxide
Water for injections.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
18 months
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial in the outer carton.
6.5 Nature and contents of container
Humira 40 mg solution for injection in single-use vial (type I glass), fitted with rubber stoppers,
aluminium crimps and flip-off seals.
Packs of:
1 vial (0.8 ml sterile solution), 1 empty sterile injection syringe in pouch and 2 alcohol pads, all in a
blister.
6.6 Special precautions for disposal
HUMIRA 40 mg solution for injection does not contain preservatives. Any unused product or waste
material should be disposed of in accordance with local requirements.
29
7.
Abbott Laboratories Ltd
Abbott House,
Vanwall Business Park
Vanwall Road
Maidenhead
Berkshire
SL6 4XE
United Kingdom
8.
EU/1/03/256/001
9.
Date of first authorisation: 8 September 2003
Date of latest renewal: 8 September 2008
{MM/YYYY}
30
1.
Humira 40 mg solution for injection in pre-filled syringe
2.
Each 0.8 ml single dose pre-filled syringe contains 40 mg of adalimumab.
Adalimumab is a recombinant human monoclonal antibody expressed in Chinese Hamster Ovary cells.
For a full list of excipients, see section 6.1.
3.
Clear solution for injection in pre-filled syringe.
4.
Rheumatoid arthritis
Humira 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 including methotrexate has been
inadequate.
the treatment of severe, active and progressive rheumatoid arthritis in adults not previously
treated with methotrexate.
Humira can be given as monotherapy in case of intolerance to methotrexate or when continued
treatment with methotrexate is inappropriate.
Humira 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.
Polyarticular juvenile idiopathic arthritis
Humira in combination with methotrexate is indicated for the treatment of active polyarticular juvenile
idiopathic arthritis, in adolescents aged 13 to 17 years who have had an inadequate response to one or
more disease-modifying anti-rheumatic drugs (DMARDs). Humira can be given as monotherapy in
case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.
(see section 5.1).
Psoriatic arthritis
Humira is indicated for the treatment of active and progressive psoriatic arthritis in adults when the
response to previous disease-modifying anti-rheumatic drug therapy has been inadequate. Humira 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.
31
Ankylosing spondylitis
Humira is indicated for the treatment of adults with severe active ankylosing spondylitis who have had
an inadequate response to conventional therapy.
Crohn’s disease
Humira is indicated for treatment of severe, active Crohn’s disease, in 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.
Psoriasis
Humira is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients
who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy
including cyclosporine, methotrexate or PUVA.
Humira treatment should be initiated and supervised by specialist physicians experienced in the
diagnosis and treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic
arthritis, ankylosing spondylitis, Crohn’s disease or psoriasis. Patients treated with Humira should be
given the special alert card.
After proper training in injection technique, patients may self-inject with Humira if their physician
determines that it is appropriate and with medical follow-up as necessary.
During treatment with Humira, other concomitant therapies (e.g., corticosteroids and/or
immunomodulatory agents) should be optimised.
Adults
Rheumatoid arthritis
The recommended dose of Humira 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 Humira.
Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, or analgesics can be continued
during treatment with Humira. 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 may benefit from an
increase in dose intensity to 40 mg adalimumab every week.
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 Humira after discontinuation for 70 days or longer
resulted in the same magnitudes of clinical response and similar safety profile as before dose
interruption.
32
Psoriatic arthritis and ankylosing spondylitis
The recommended dose of Humira for patients with psoriatic arthritis or ankylosing spondylitis is
40 mg adalimumab administered every other week as a single dose via subcutaneous injection.
For all of the above indications, available data suggest that the 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.
Crohn’s disease
The recommended Humira induction dose regimen for adult patients with severe 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 (dose can be administered as four injections in one day or as
two injections per day for two consecutive days), 80 mg at Week 2, 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 Humira and signs and symptoms of disease recur,
Humira 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 may benefit from an increase in dose
intensity to 40 mg Humira every 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.
Psoriasis
The recommended dose of Humira 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.
Elderly patients
No dose adjustment is required.
Children and adolescents (aged 13 to 17 years)
Polyarticular Juvenile Idiopathic Arthritis
The recommended dose of Humira for patients with polyarticular juvenile idiopathic arthritis, aged 13
years and above is 40 mg adalimumab administered every other week as a single dose 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.
33
Impaired renal and/or hepatic function
Humira has not been studied in these patient populations. No dose recommendations can be made.
Hypersensitivity to the active substance or to any of the excipients.
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).
Infections
Patients taking TNF-blockers 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 Humira. Because the elimination of
adalimumab may take up to five months, monitoring should be continued throughout this period.
Treatment with Humira should not be initiated in patients with active infections including chronic or
localized 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 Humira
should be considered prior to initiating therapy (see
Opportunistic infections
).
Patients who develop a new infection while undergoing treatment with Humira, should be monitored
closely and undergo a complete diagnostic evaluation. Administration of Humira 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 Humira 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, and pneumocystis have been reported in patients
receiving Humira.
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:
There have been reports of tuberculosis in patients receiving Humira. It should be noted that in the
majority of those reports, tuberculosis was extra-pulmonary, i.e. disseminated.
Before initiation of therapy with Humira, all patients must be evaluated for both, active or inactive
(latent) tuberculosis infection. This evaluation should include a detailed medical history of patients
with a personal history of tuberculosis or possible previous exposure to patients 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 of these tests should be recorded in the patient alert card.
34
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, Humira therapy must not be initiated (see section 4.3).
If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be
consulted. In all situations described below, the benefit/risk balance of therapy should be very
carefully considered.
If inactive (‘latent’) tuberculosis is diagnosed, appropriate treatment for latent tuberculosis must be
started with anti-tuberculosis prophylaxis therapy before the initiation of Humira, and in accordance
with local recommendations.
In patients who have several or significant risk factors for tuberculosis and have a negative
test for latent tuberculosis, anti-tuberculosis therapy should also be considered before the
initiation of Humira.
Use of anti-tuberculosis therapy should also be considered before the initiation of Humira in patients
with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be
confirmed. Some patients who have previously received treatment for latent or active tuberculosis
have developed active tuberculosis while being treated with Humira.
Patients should be instructed to seek medical advice if signs/symptoms (e.g., persistent cough,
wasting/weight loss, low grade fever) suggestive of a tuberculosis infection occur during or after
therapy with Humira.
Other opportunistic infections:
Opportunistic infections, including invasive fungal infections have been observed in patients receiving
Humira. These infections have not consistently been recognised in patients taking TNF-blockers and
this 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,
dyspnea, and/or pulmonary infiltrates or other serious systemic illness with or without concomitant
shock an invasive fungal infection should be suspected and administration of Humira 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 who are chronic carriers of this virus when
receiving a TNF-antagonist including Humira. Some cases have had a fatal outcome. Patients at risk
for HBV infection should be evaluated for prior evidence of HBV infection before initiating Humira
therapy. Carriers of HBV who require treatment with Humira 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 the treatment of 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, Humira should be stopped and effective anti-
viral therapy with appropriate supportive treatment should be initiated.
Neurological events
TNF-antagonists including Humira have been associated in rare instances with new onset or
exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease including
multiple sclerosis. Prescribers should exercise caution in considering the use of Humira in patients
with pre-existing or recent-onset central nervous system demyelinating disorders.
35
Allergic reactions
Serious allergic adverse reactions have not been reported with subcutaneous administration of Humira
during clinical trials. Non-serious allergic reactions associated with Humira were uncommon during
clinical trials. In postmarketing, serious allergic reactions including anaphylaxis have been reported
very rarely following Humira administration. If an anaphylactic reaction or other serious allergic
reaction occurs, administration of Humira should be discontinued immediately and appropriate therapy
initiated.
The needle cover of the syringe contains natural rubber (latex). This may cause severe allergic
reactions in patients sensitive to latex.
Immunosuppression
In a study of 64 patients with rheumatoid arthritis that were treated with Humira, 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 leukemia have been
reported in patients treated with a TNF-antagonist. There is an increased background risk for
lymphoma and leukemia 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, leukemia, 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-blocking agents (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-blockers cannot be excluded.
Rare postmarketing 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 Humira have occurred in young
adult patients on concomitant treatment with azathioprine or 6-mercaptopurine used for Crohn’s
disease. A risk for the development of hepatosplenic T-cell lymphoma in patients treated with Humira
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 Humira is continued following development of malignancy. Thus additional caution
should be exercised in considering Humira 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 non-
melanoma skin cancer prior to and during treatment with Humira. In an exploratory clinical trial
evaluating the use of another anti-TNF agent, infliximab, in patients with moderate to severe chronic
obstructive pulmonary disease (COPD), more malignancies, mostly in the lung or head and neck, were
reported in infliximab-treated patients compared with control patients. All patients had a history of
heavy smoking. Therefore, caution should be exercised when using any TNF-antagonist in COPD
patients, as well as in patients with increased risk for malignancy due to heavy smoking.
Haematologic reactions
36
Rare reports of pancytopenia including aplastic anaemia have been reported with TNF antagonists.
Adverse events of the haematologic system, including medically significant cytopoenia (e.g.
thrombocytopaenia, leucopaenia) have been reported with Humira. 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 Humira. Discontinuation of Humira 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 Humira.
It is recommended that polyarticular juvenile idiopathic arthritis patients, if possible, be brought up to
date with all immunisations in agreement with current immunisation guidelines prior to initiating
Humira therapy.
Patients on Humira may receive concurrent vaccinations, except for live vaccines.
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 Humira. Humira should be used with caution in
patients with mild heart failure (NYHA class I/II). Humira is contraindicated in moderate to severe
heart failure (see section 4.3). Treatment with Humira must be discontinued in patients who develop
new or worsening symptoms of congestive heart failure.
Autoimmune processes
Treatment with Humira may result in the formation of autoimmune antibodies.
The impact of long-
term treatment with Humira on the development of autoimmune diseases is unknown. If a patient
develops symptoms suggestive of a lupus-like syndrome following treatment with Humira and is
positive for antibodies against double-stranded DNA, further treatment with Humira should not be
given (see section 4.8).
Concurrent administration of TNF-antagonists and anakinra
Serious infections were seen in clinical studies with concurrent use of anakinra and another
TNF-antagonist, 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).
37
Concurrent administration of TNF-antagonists and abatacept
Concurrent administration of TNF-antagonists and abatacept has been associated with an increased
risk of infections including serious infections compared to TNF-antagonists alone, without increased
clinical benefit. The combination of Humira and abatacept is not recommended. (See section 4.5).
Surgery
There is limited safety experience of surgical procedures in patients treated with Humira. The long
half-life of adalimumab should be taken into consideration if a surgical procedure is planned. A
patient who requires surgery while on Humira should be closely monitored for infections, and
appropriate actions should be taken. There is limited safety experience in patients undergoing
arthroplasty while receiving Humira.
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 Humira does not worsen or cause
strictures.
Elderly Population
The frequency of serious infections among HUMIRA treated subjects over 65 years of age (3.9%) was
higher than for those under 65 years of age (1.4%). Some of those had a fatal outcome. Particular
attention regarding the risk for infection should be paid when treating the elderly.
Humira has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic
arthritis patients taking Humira as monotherapy and those taking concomitant methotrexate. Antibody
formation was lower when Humira was given together with methotrexate in comparison with use as
monotherapy. Administration of Humira without methotrexate resulted in increased formation of
antibodies, increased clearance and reduced efficacy of adalimumab (see section 5.1).
The combination of Humira and anakinra is not recommended (see section 4.4 “Concurrent
administration of TNF-antagonists and anakinra”).
The combination of Humira and abatacept is not recommended (see section 4.4 “Concurrent
administration of TNF-antagonists and abatacept”).
For Humira, no clinical data on exposed pregnancies are available
In a developmental toxicity study conducted in monkeys, there was no indication of maternal toxicity,
embryotoxicity or teratogenicity. Preclinical data on postnatal toxicity and fertility effects 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. Administration of adalimumab is not recommended during
pregnancy. Women of childbearing potential are strongly recommended to use adequate contraception
to prevent pregnancy and continue its use for at least five months after the last Humira treatment.
It is not known whether adalimumab is excreted in human milk or absorbed systemically after
ingestion.
38
However, because human immunoglobulins are excreted in milk, women must not breast-feed for at
least five months after the last Humira treatment.
Humira may have a minor influence on the ability to drive and use machines. Vertigo and visual
impairment may occur following administration of Humira (see Section 4.8).
Clinical Trials
Humira was studied in 6,728 patients in controlled and open label trials for up to 60 months. These
trials included rheumatoid arthritis patients with short term and long standing disease, polyarticular
juvenile idiopathic arthritis as well as psoriatic arthritis, ankylosing spondylitis, Crohn’s disease and
psoriasis patients. The data in Table 1 is based on the pivotal controlled Studies involving 4,419
patients receiving Humira and 2,552 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 4.5% for patients taking Humira and 4.5% for control treated
patients.
In general, the adverse events in paediatric patients were similar in frequency and type to those seen in
adult patients.
Adverse events at least possibly causally-related to adalimumab, for clinical studies both clinical and
laboratory, are displayed by system organ class and frequency (very common ≥ 1/10; common
≥ 1/100 to < 1/10; uncommon ≥ 1/1,000 to < 1/100, rare ≥ 1/10,000 to < 1/1,000 and very rare
<1/10,000) in Table 1 below. 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.
Approximately 15% of patients can be expected to experience injection site reactions, based on one of
the most common adverse events with adalimumab in controlled clinical studies.
39
Table 1
Undesirable Effects in Clinical Studies
System Organ Class
Frequency
Adverse Reaction
Infections and
infestations*
Very common
respiratory tract infections (including lower and
upper respiratory tract infection, pneumonia,
sinusitis, pharyngitis, nasopharyngitis and
pneumonia herpes viral)
Common
systemic infections (including sepsis, candidiasis
and influenza),
intestinal infections (including gastroenteritis
viral),
skin and soft tissue infections (including
paronychia, cellulitis, impetigo, necrotising
fasciitis and herpes zoster),
ear infections,
oral infections (including herpes simplex, oral
herpes and tooth infections),
reproductive tract infections (including
vulvovaginal mycotic infection),
urinary tract infections (including
pyelonephritis),
fungal infections
Uncommon
opportunistic infections and tuberculosis
(including coccidioidomycosis, histoplasmosis
and mycobacterium avum complex infection),
neurological infections (including viral
meningitis),
eye infections,
bacterial infections,
joint infections
Neoplasms benign,
malignant and unspecified
(including cysts and
polyps)*
Common
benign neoplasm,
skin cancer excluding melanoma (including basal
cell carcinoma and squamous cell carcinoma)
Uncommon
lymphoma**,
solid organ neoplasm (including breast cancer,
lung neoplasm and thyroid neoplasm),
melanoma**
Blood and the lymphatic
system disorders*
Very common
leucopaenia (including neutropaenia and
agranulocytosis),
anaemia
Common
thrombocytopaenia,
leucocytosis
Uncommon
idiopathic thrombocytopaenic purpura
Rare
pancytopaenia
40
System Organ Class
Frequency
Adverse Reaction
Immune system disorders* Common
hypersensitivity,
allergies (including seasonal allergy)
Metabolism and nutrition
disorders
Very common
lipids increased
Common
hypokalaemia,
uric acid increased,
blood sodium abnormal,
hypocalcaemia
hyperglycemia,
hypophosphotemia,
blood potassium increased
Uncommon
dehydration
Psychiatric disorders
Common
mood alterations (including depression),
anxiety, insomnia
Nervous system disorders*
Very common
headache
Common
paraesthesias (including hypoaesthesia),
migraine,
sciatica
Uncommon
tremor
Rare
multiple sclerosis
Eye disorders
Common
visual impairment,
conjunctivitis
Uncommon
blepharitis,
eye swelling,
diplopia
Ear and labyrinth
disorders
Common
vertigo
Uncommon
deafness,
tinnitus
Cardiac disorders*
Common
tachycardia
Uncommon
arrhythmia,
congestive heart failure
Rare
cardiac arrest
Vascular disorders
Common
hypertension,
41
System Organ Class
Frequency
Adverse Reaction
flushing,
haematoma
Rare
vascular arterial occlusion,
thrombophlebitis,
aortic aneurysm
Respiratory, thoracic and
mediastinal disorders*
Common
cough,
asthma,
dyspnoea
Uncommon
chronic obstructive pulmonary disease,
interstitial lung disease,
pneumonitis
Gastrointestinal disorders
Very common
abdominal pain,
nausea and vomiting
Common
GI haemorrhage,
dyspepsia,
gastroesophageal reflux disease,
sicca syndrome
Uncommon
pancreatitis,
dysphagia,
face oedema
Hepato-biliary disorders*
Very Common
elevated liver enzymes
Uncommon
cholecystitis and cholelithiasis,
bilirubin increased,
hepatic steatosis
Skin and subcutaneous
tissue disorders
Very Common
rash (including exfoliative rash),
Common
pruritus,
urticaria,
bruising (including purpura),
dermatitis (including eczema),
onychoclasis,
hyperhydrosis
Uncommon
night sweats,
scar
Musculoskeletal,
connective tissue and bone
disorders
Very common
musculoskeletal pain
Common
muscle spasms (including blood creatine
42
System Organ Class
Frequency
Adverse Reaction
phosphokinase increased)
Uncommon
rhabdomyolysis
Rare
systemic lupus erythematosus
Renal and urinary
disorders
Common
haematuria,
renal impairment
Uncommon
nocturia
Reproductive system and
breast disorders
Uncommon
erectile dysfunction
General disorders and
administration site
conditions*
Very Common
injection site reaction (including injection site
erythema)
Common
chest pain,
oedema
Uncommon
inflammation
Investigations*
Common
coagulation and bleeding disorders (including
activated partial thromboplastin time prolonged),
autoantibody test positive (including double
stranded DNA antibody),
blood lactate dehydrogenase increased
Injury and poisoning
Common
impaired healing
* further information is found elsewhere in sections 4.3, 4.4 and 4.8
** including open label extension studies
Injection site reactions
In the pivotal controlled trials, 15% of patients treated with Humira developed injection site reactions
(erythema and/or itching, haemorrhage, pain or swelling), compared to 9% 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, the rate of infection was 1.50 per patient year in the Humira treated
patients and 1.42 per patient year in the placebo and active control-treated patients. The infections
consisted primarily nasopharyngitis, upper respiratory tract infection, and sinusitis. Most patients
continued on Humira after the infection resolved.
The incidence of serious infections was 0.03 per patient year in Humira treated patients and 0.03 per
patient year in placebo and active control − treated patients.
In controlled and open label studies with Humira, 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
43
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 171 patients with an exposure of 192.5 patient years during a
Humira trial in juvenile idiopathic arthritis patients.
During the controlled portions of pivotal Humira trials at least 12 weeks in duration in patients with
moderately to severely active rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s
disease or psoriasis, malignancies, other than lymphoma and non-melanoma skin cancer, were
observed at a rate (95% confidence interval) of 6.6 (4.0, 10.8) per 1,000 patient-years among 3,917
Humira treated patients
versus
a rate of 4.2 (1.8, 10.1) per 1,000 patient-years among 2,247 control
patients (median duration of treatment was 5.6 months for Humira and 4.0 months for control-treated
patients). The rate (95% confidence interval) of non-melanoma skin cancers was 9.9 (6.6, 14.8) per
1,000 patient-years among Humira-treated patients and 2.5 (0.8, 7.9) per 1,000 patient-years among
control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% confidence
interval) of 2.5 (1.1, 5.5) per 1,000 patient-years among Humira-treated patients and 0.8 (0.1, 6.0) per
1,000 patient-years among control patients. The rate (95% confidence interval) of lymphomas was 0.8
(0.2, 3.3) per 1,000 patient-years among Humira-treated patients and 0.8 (0.1, 6.0) 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 3.4 years including 4,954 patients and over 21,021
patient-years of therapy, the observed rate of malignancies, other than lymphoma and non-melanoma
skin cancers is approximately 9.1 per 1,000 patient years. The observed rate of non-melanoma skin
cancers is approximately 10.1 per 1,000 patient years, and the observed rate of lymphomas is
approximately 1.1 per 1,000 patient years.
In post-marketing experience from January 2003, predominately in patients with rheumatoid arthritis,
the reported rate of malignancies other than lymphomas and non-melanoma skin cancers is
approximately 1.7 per 1,000 patient years. The reported rates for non-melanoma skin cancers and
lymphomas are approximately 0.2 and 0.4 per 1,000 patient 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 Humira 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 Humira 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.
Liver Enzyme Elevations
Rheumatoid arthritis clinical trials:
in controlled rheumatoid arthritis clinical trials (RA studies
I − IV), elevations of ALT were similar in patients receiving adalimumab or placebo. In patients with
early rheumatoid arthritis (disease duration of less than 3 years) (RA study V), elevations of ALT were
more common in the combination arm (Humira /methotrexate) compared to the methotrexate
monotherapy arm or the Humira monotherapy arm. In the JIA trial the few transaminase elevations
were small and similar in the placebo and adalimumab exposed patients, and mostly occurred in
combination with methotrexate.
44
Psoriatic arthritis clinical trials:
elevations in ALT were more common in psoriatic arthritis patients
(PsA studies I - II) compared with patients in rheumatoid arthritis clinical studies.
In all rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic arthritis studies,
patients with raised ALT were asymptomatic and in most cases elevations were transient and resolved
on continued treatment.
Crohn’s disease clinical trials:
in controlled clinical trials, elevations of ALT were similar in patients
receiving adalimumab or placebo.
Psoriasis clinical trials:
in controlled psoriasis clinical trials, elevations of ALT were similar in
patients receiving adalimumab or placebo.
Additional Adverse Reactions from Postmarketing Surveillance or Phase IV Clinical Trials
The additional adverse reactions in Table 2 have been reported from postmarketing surveillance or
Phase IV clinical trials:
Table 2
Undesirable Effects in Postmarketing Surveillance and Phase IV Clinical Studies
System Organ Class
Adverse Reaction
Infections and Infestations
diverticulitis
Neoplasm benign, malignant and unspecified
(including cysts and polyps)*
hepatosplenic T-cell lymphoma, leukemia
Immune system disorders* anaphylaxis, sarcoidosis
Nervous system disorders* demyelinating disorders (e.g. optic neuritis,
Guillain-Barré syndrome); cerebrovascular
accident
Respiratory, thoracic and mediastinal disorders pulmonary embolism
pleural effusion, pulmonary fibrosis
Gastrointestinal disorders* intestinal perforation
Hepatobiliary disorders* reactivation of hepatitis B
Skin and subcutaneous tissue disorders cutaneous vasculitis, Stevens-Johnson syndrome,
angioedema, new onset or worsening of psoriasis
(including palmoplantar pustular psoriasis),
erythema multiforme, alopecia
Musculoskeletal and connective tissue disorders lupus-like syndrome
Cardiac disorders
myocardial infarction
* further information is found elsewhere in sections 4.3, 4.4 and 4.8
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.
45
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective immunosuppressive agents. ATC code: L04AB04
Mechanism of action
Adalimumab binds specifically to TNF and neutralizes 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 IC
50
of0.1-0.2 nM).
Pharmacodynamic effects
After treatment with Humira, 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 Humira administration. Patients treated with Humira usually
experienced improvement in haematological signs of chronic inflammation.
In patients with Crohn’s disease, a rapid decrease in CRP levels was also observed, as well as a
reduction of the number of cells expressing inflammatory markers in the colon including a significant
reduction of expression of TNFα. Endoscopic studies in intestinal mucosa have shown evidence of
mucosal healing in adalimumab treated patient.
A rapid decrease in CRP levels was also observed in patients with polyarticular juvenile idiopathic
arthritis.
Clinical trials
Rheumatoid arthritis
Humira was evaluated in over 3000 patients in all rheumatoid arthritis clinical trials. Some patients
were treated for up to 60 months duration. The efficacy and safety of Humira for the treatment of
rheumatoid arthritis were assessed in five randomised, double-blind and well-controlled 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 Humira 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 or 40 mg of Humira 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
46
received placebo injections every week for 52 weeks. The second received 20 mg of Humira every
week for 52 weeks. The third group received 40 mg of Humira every other week with placebo
injections on alternate weeks. Thereafter, patients enrolled in an open-label extension phase in which
40 mg of Humira was administered every other week up to 60 months.
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,
anti-rheumatic 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 Humira 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
Humira 40 mg every other week/methotrexate combination therapy, Humira 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.
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.
ACR response
The percent of Humira-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 3.
Table 3
ACR Responses in Placebo-Controlled Trials
(Percent of Patients)
Response
RA Study I
a
**
RA Study II
a
**
RA Study III
a
**
Placebo/
MTX
c
n=60
Humira
b
/ MTX
c
n=63
Placebo
n=110
Humira
b
n=113
Placebo/
MTX
c
n=200
Humira
b
/ MTX
c
n=207
ACR 20
6 months
13.3%
65.1%
19.1%
46.0%
29.5%
63.3%
12 months
NA
NA
NA
NA
24.0%
58.9%
ACR 50
6 months
6.7%
52.4%
8.2%
22.1%
9.5%
39.1%
12 months
NA
NA
NA
NA
9.5%
41.5%
ACR 70
6 months
3.3%
23.8%
1.8%
12.4%
2.5%
20.8%
12 months
NA
NA
NA
NA
4.5%
23.2%
a
RA study I at 24 weeks, RA study II at 26 weeks , and RA study III at 24 and 52 weeks
b
40 mg Humira administered every other week
c
MTX = methotrexate
**p < 0.01, Humira
versus
placebo
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 addition, ACR response rates were
maintained in the majority of patients followed in the open-label extension phase to Week 104. There
47
were 114 out of 207 patients who continued on Humira 40 mg every other week for 60 months.
Among those, 86, 72, and 41 patients had ACR 20/50/70 response, respectively at Month 60.
In RA study IV, the ACR 20 response of patients treated with Humira 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, Humira-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 Humira and methotrexate led to faster and significantly greater ACR responses than
methotrexate monotherapy and Humira monotherapy at Week 52 and responses were sustained at
Week 104 (see Table 4).
Table 4
ACR Responses in RA Study V
(percent of patients)
n=268
p-value
a
p-value
b
p-value
c
ACR 20
Week 52 62.6% 54.4% 72.8% 0.013 < 0.001 0.043
Week 104 56.0% 49.3% 69.4% 0.002 < 0.001 0.140
ACR 50
Week 52 45.9% 41.2% 61.6% < 0.001 < 0.001 0.317
Week 104 42.8% 36.9% 59.0% < 0.001 < 0.001 0.162
ACR 70
Week 52 27.2% 25.9% 45.5% < 0.001 < 0.001 0.656
Week 104 28.4% 28.1% 46.6% < 0.001 < 0.001 0.864
a. p-value is from the pairwise comparison of methotrexate monotherapy and Humira/methotrexate
combination therapy using the Mann-Whitney U test.
b. p-value is from the pairwise comparison of Humira monotherapy and Humira/methotrexate
combination therapy using the Mann-Whitney U test
c. p-value is from the pairwise comparison of Humira monotherapy and methotrexate monotherapy
using the Mann-Whitney U test
MTX
n=257
Humira
n=274
Humira/MTX
At Week 52, 42.9% of patients who received Humira/methotrexate combination therapy achieved
clinical remission (DAS28 < 2.6) compared to 20.6% of patients receiving methotrexate monotherapy
and 23.4% of patients receiving Humira monotherapy. Humira/methotrexate combination therapy was
clinically and statistically superior to methotrexate (p < 0.001) and Humira 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).
Radiographic response
In RA study III, where Humira 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. Humira/methotrexate patients demonstrated significantly less radiographic
progression than patients receiving methotrexate alone at 6 and 12 months (see Table 5). Data from
the open-label extension phase indicate that the reduction in rate of progression of structural damage is
maintained for 60 months in a subset of patients. 113/207 of patients originally treated with 40 mg
Humira every other week were evaluated radiographically at 5 years. Among those, 66 patients
showed no progression of structural damage defined by a change in the TSS of zero or less.
48
Response
Table 5
Radiographic Mean Changes Over 12 Months in RA Study III
Placebo/
MTX
a
HUMIRA/MTX
40 mg every
other week
Placebo/MTX-
HUMIRA/MTX
(95% Confidence
Interval
b
)
p-value
Total Sharp Score
2.7
0.1
2.6 (1.4, 3.8)
< 0.001
c
Erosion score
1.6
0.0
1.6 (0.9, 2.2)
< 0.001
JSN
d
score
1.0
0.1
0.9 (0.3, 1.4)
0.002
a
methotrexate
b
95% confidence intervals for the differences in change scores between methotrexate and Humira.
c
Based on rank analysis
d
Joint Space Narrowing
In RA study V, structural joint damage was assessed radiographically and expressed as change in
modified Total Sharp Score (see Table 6).
Table 6
Radiographic Mean Changes at Week 52 in RA Study V
MTX
n=257
(95%
confidence
interval)
Humira
n=274
(95%
confidence
interval)
Humira/MTX
n=268
(95%
confidence
interval)
p-value
a
p-value
b
p-value
c
Total Sharp
Score
5.7 (4.2-7.3)
3.0 (1.7-4.3) 1.3 (0.5-2.1) < 0.001 0.0020 < 0.001
Erosion score 3.7 (2.7-4.7) 1.7 (1.0-2.4) 0.8 (0.4-1.2) < 0.001 0.0082 < 0.001
JSN score 2.0 (1.2-2.8) 1.3 (0.5-2.1) 0.5 (0-1.0) < 0.001 0.0037 0.151
a
p-value is from the pairwise comparison of methotrexate monotherapy and Humira/methotrexate
combination therapy using the Mann-Whitney U test.
b
p-value is from the pairwise comparison of Humira monotherapy and Humira/methotrexate
combination therapy using the Mann-Whitney U test
c
p-value is from the pairwise comparison of Humira monotherapy and methotrexate monotherapy
using the Mann-Whitney U test
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
Humira/methotrexate combination therapy (63.8% and 61.2% respectively) compared to methotrexate
monotherapy (37.4% and 33.5% respectively, p < 0.001) and Humira monotherapy (50.7%, p < 0.002
and 44.5%, p < 0.001 respectively).
49
Quality of life and physical function
Health-related quality of life and physical function was 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
Humira 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 Humira 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, improvement in physical function was maintained through Week 260 (60 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 Humira/methotrexate combination therapy
versus
methotrexate monotherapy and Humira monotherapy at Week 52, which was maintained through
Week 104.
Polyarticular juvenile
idiopathic
arthritis (JIA)
The safety and efficacy of Humira 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-MTX-
treated. 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/m
2
up to a maximum of 40 mg Humira 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 7.
Table 7
Distribution of patients by age and adalimumab dose received during the OL LI phase
Age Group
Number of patients at Baseline
n (%)
Minimum, median and maximum
dose
4 to 7 years
31 (18.1)
10, 20 and 25 mg
8 to 12 years
71 (41.5)
20, 25 and 40 mg
13 to 17 years
69 (40.4)
25, 40 and 40 mg
Patients demonstrating a Pediatric ACR 30 response at Week 16 were eligible to be randomised into
the double blind (DB) phase and received either Humira 24 mg/m
2
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 Pediatric 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
50
Table 8
Ped ACR Responses in the JIA study
Stratum
MTX
Without MTX
Phase
OL-LI 16 weeks
Ped ACR 30
response (n/N)
94.1% (80/85)
74.4% (64/86)
Double Blind
Humira
(n = 38)
Placebo
(n = 37)
Humira
(n = 30)
Placebo
(n = 28)
Disease flares at
the end of 32
weeks
a
(n/N)
36.8% (14/38)
64.9% (24/37)
b
43.3% (13/30) 71.4%
(20/28)
c
Median time to
disease flare
>32 weeks
20 weeks
>32 weeks
14 weeks
a
Ped ACR 30/50/70 responses week 48 significantly greater than those of placebo treated patients
b
p = 0.015
c
p = 0.031
Amongst those who responded at Week 16 (n=144), the Pediatric ACR 30/50/70/90 responses were
maintained for up to two years in the OLE phase in patients who received Humira throughout the
study.
Overall responses were generally better and, fewer patients developed antibodies when treated with
the combination of Humira and MTX compared to Humira alone. Taking these results into
consideration, Humira 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).
Psoriatic arthritis
Humira, 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 Humira was
administered eow.
There is insufficient evidence of the efficacy of Humira in patients with ankylosing spondylitis-like
psoriatic arthropathy due to the small number of patients studied.
51
Table 9
ACR Response in Placebo-Controlled Psoriatic Arthritis Studies
(Percent of Patients)
PsA Study I
PsA Study II
Response
Placebo
N=162
Humira
N=151
Placebo
N=49
Humira
N=51
ACR 20
Week 12
14%
58%
***
16%
39%
*
Week 24
15%
57%
***
N/A
N/A
ACR 50
Week 12
4%
36%
***
2%
25%
***
Week 24
6%
39%
***
N/A
N/A
ACR 70
Week 12
1%
20%
***
0%
14%
*
Week 24
1%
23%
***
N/A
N/A
*** p < 0.001 for all comparisons between Humira and placebo
* p < 0.05 for all comparisons between Humira and placebo
N/A not applicable
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
Humira or placebo and at Week 48 when all patients were on open-label Humira. A modified Total
Sharp Score (mTSS), which included distal interphalangeal joints (i.e., not identical to the TSS used
for rheumatoid arthritis), was used.
Humira 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 Humira group (at Week 48).
In subjects treated with Humira with no radiographic progression from baseline to Week 48 (n=102),
84% continued to show no radiographic progression through 144 weeks of treatment.
Humira 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.
Ankylosing spondylitis
Humira 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 Humira 40 mg 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 adalimumab 40 mg 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 Humira compared to placebo.
Significant response was first observed at Week 2 and maintained through 24 weeks (Table 10).
52
Table 10 –
Efficacy Responses in Placebo-Controlled AS Study – Study I
Reduction of Signs and Symptoms
Humira
N=208
ASAS
a
20
Week 2 16% 42%***
Week 12 21% 58%***
Week 24 19% 51%***
ASAS 50
Week 2 3% 16%***
Week 12 10% 38%***
Week 24 11% 35%***
ASAS 70
Week 2 0% 7%**
Week 12 5% 23%***
Week 24 8% 24%***
BASDAI
b
50
Week 2 4% 20%***
Week 12 16% 45%***
Week 24 15% 42%***
***,** Statistically significant at p < 0.001, < 0.01 for all comparisons between Humira
and placebo at Weeks 2, 12 and 24
a
ASsessments in Ankylosing Spondylitis
b
Bath Ankylosing Spondylitis Disease Activity Index
Placebo
N=107
Humira 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.
Crohn’s disease
The safety and efficacy of Humira were assessed in over 1500 patients with moderately to severely
active Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in randomised,
double-blind, placebo-controlled studies. 524 of the enrolled patients (32%) were defined as having a
severe disease (CDAI score > 300 and concomitant corticosteroid and/or immunosuppressants)
corresponding to the population defined in the indication (see section 4.1). 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 Humira 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 Humira 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.
53
Response
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 11.
Table 11
Induction of Clinical Remission and Response
(Percent of Patients)
CDStudy I: Infliximab Naive
Patients
CD Study II: Infliximab
Experienced Patients
Placebo
N=74
Humira
80/40 mg
N = 75
Humira
160/80 m
g N=76
Placebo
N=166
Humira
160/80 mg
N=159
Week 4
Clinical remission
12%
24%
36%
*
7%
21%
*
Clinical response (CR-
100)
24%
37%
49%
**
25%
38%
**
All p-values are pairwise comparisons of proportions for Humira
versus
placebo
*
p < 0.001
**
p < 0.01
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 anti-TNF therapy. Maintenance of remission and response rates are presented in Table 12.
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.
54
Table 12
Maintenance of Clinical Remission and Response
(Percent of Patients)
Placebo
40 mg Humira
every other week
40 mg Humira
every week
Week 26
N=170
N=172
N=157
Clinical remission
17%
40%*
47%*
Clinical response (CR-100)
27%
52%*
52%*
Patients in steroid-free remission
for >=90 days
a
3% (2/66)
19% (11/58)**
15% (11/74)**
Week 56
N=170
N=172
N=157
Clinical remission
12%
36%*
41%*
Clinical response (CR-100)
17%
41%*
48%*
Patients in steroid-free remission
for >=90 days
a
5% (3/66)
29% (17/58)*
20% (15/74)**
* p < 0.001 for Humira
versus
placebo pairwise comparisons of proportions
** p < 0.02 for Humira
versus
placebo pairwise comparisons of proportions
a
Among patients who were not in response at Week 4, 43% of Humira 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 Humira 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.
Psoriasis
The safety and efficacy of Humira 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.
Psoriasis Study I (REVEAL) evaluated 1,212 patients within three treatment periods. In period A,
patients received placebo or Humira 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 Humira every other week. Patients who maintained ≥PASI 75 response at
Week 33 and were originally randomised to active therapy in Period A, were re-randomised in period
C to receive 40 mg Humira 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
55
Of those receiving corticosteroids at baseline
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 Humira
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 Humira followed
by 40 mg every other week (starting one week after the initial dose) for 16 weeks. There are no data
available comparing Humira 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 open-
label extension trial, where Humira 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 13 and 14).
Table 13
Ps Study I (REVEAL) - Efficacy Resul
ts at 16 Weeks
Humira 40 mg eow
N=814
n (%)
≥
PASI 75
a
26 (6.5)
578 (70.9)
b
PASI 100
3 (0.8)
163 (20.0)
b
PGA: Clear/minimal
17 (4.3)
506 (62.2)
b
a
Percent of patients achieving PASI75 response was calculated as center-
adjusted rate
b
p<0.001, Humira vs. placebo
Placebo
N=398
n (%)
Table 14
Ps Study II (CHAMPION) Efficacy Results at 16 Weeks
Placebo
N=53
n (%)
MTX
N=110
n (%)
Humira 40 mg eow
N=108
n (%)
≥
PASI 75
10 (18.9)
39 (35.5)
86 (79.6)
a, b
PASI 100
1 (1.9)
8 (7.3)
18 (16.7)
c, d
PGA:
Clear/minimal
6 (11.3)
33 (30.0)
79 (73.1)
a, b
a
p<0.001 Humira vs. placebo
b
p<0.001 Humira vs. methotrexate
c
p<0.01 Humira vs. placebo
d
p<0.05 Humira vs. methotrexate
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 Humira, 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-randomization 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 Humira therapy for
52 weeks in Psoriasis Study I, and continued Humira 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
56
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 open-
label 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% and were evaluated at 12 weeks after dose escalation,
93/349 (26.6%) of patients achieved PASI 75 response.
Immunogenicity
Formation of anti-adalimumab 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.
Patients in RA Studies I, II and III were tested at multiple time points for anti-adalimumab antibodies
during the 6 to 12 month period. In the pivotal trials, anti-adalimumab antibodies were identified in
58/1053 (5.5%) patients treated with adalimumab, compared to 2/370 (0.5%) on placebo. In patients
not given concomitant methotrexate, the incidence was 12.4%, compared to 0.6% when adalimumab
was used as add-on to methotrexate.
In patients with polyarticular juvenile idiopathic arthritis, adalimumab antibodies were identified in
27/171 subjects (15.8%) treated with adalimumab. In patients not given concomitant methotrexate, the
incidence was 22/86 (25.6%), compared to 5/85 (5.9%) when adalimumab was used as add-on to
methotrexate.
In patients with psoriatic arthritis, anti-adalimumab antibodies were identified in 38/376 subjects
(10%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was
13.5% (24/178 subjects), compared to 7% (14 of 198 subjects) when adalimumab was used as add-on
to methotrexate.
In patients with ankylosing spondylitis anti-adalimumab antibodies were identified in 17/204 subjects
(8.3%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was
16/185 (8.6%), compared to 1/19 (5.3%) when adalimumab was used as add-on to methotrexate.
In patients with Crohn’s disease, anti-adalimumab antibodies were identified in 7/269 subjects (2.6%)
treated with adalimumab.
In patients with psoriasis, anti-adalimumab antibodies were identified in 77/920 subjects (8.4%)
treated with adalimumab monotherapy.
57
In plaque psoriasis patients on long term adalimumab monotherapy who participated in a withdrawal
and retreatment study, the rate of antibodies to adalimumab after retreatment (11 of 482 subjects,
2.3%) was similar to the rate observed prior to withdrawal (11 of 590 subjects, 1.9%).
Because immunogenicity analyses are product-specific, comparison of antibody rates with those from
other products is not appropriate.
5.2 Pharmacokinetic properties
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 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 (V
ss
) 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 Humira 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/m
2
(up to a maximum of 40 mg) subcutaneously every other
week to patients with polyarticular juvenile idiopathic arthritis (JIA) the mean trough steady-state
(values measured from Week 20 to 48) serum adalimumab concentration was 5.6 ± 5.6 µg/mL (102
%CV) Humira monotherapy and 10.9 ± 5.2 µg/mL (47.7% CV) with concomitant methotrexate.
In patients with Crohn’s disease, the loading dose of 80 mg Humira on Week 0 followed by 40 mg
Humira on Week 2 achieves serum adalimumab trough concentrations of approximately 5.5 μg/ml
during the induction period. A loading dose of 160 mg Humira on Week 0 followed by 80 mg Humira
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 Humira every other week.
In patients with psoriasis, the mean steady-state trough concentration was 5 μg/mL during adalimumab
40 mg every other week monotherapy treatment.
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. Humira has not been studied in patients with hepatic or renal
impairment.
58
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
neutralizing antibodies in rodents.
6.
6.1 List of excipients
Mannitol
Citric acid monohydrate
Sodium citrate
Sodium dihydrogen phosphate dihydrate
Disodium phosphate dihydrate
Sodium chloride
Polysorbate 80
Sodium hydroxide
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
24 months
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the syringe in the outer carton.
6.5 Nature and contents of container
Humira 40 mg solution for injection in single-use pre-filled syringe (type I glass) for patient use:
Packs of:
•
1 pre-filled syringe (0.8 ml sterile solution) with 1 alcohol pad in a blister.
•
2 pre-filled syringes (0.8 ml sterile solution), each with 1 alcohol pad, in a blister.
•
4 pre-filled syringes (0.8 ml sterile solution), each with 1 alcohol pad, in a blister.
•
6 pre-filled syringes (0.8 ml sterile solution), each with 1 alcohol pad, in a blister.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
HUMIRA 40 mg solution for injection does not contain preservatives. Any unused product or waste
material should be disposed of in accordance with local requirements.
59
7.
Abbott Laboratories Ltd
Abbott House,
Vanwall Business Park
Vanwall Road
Maidenhead
Berkshire
SL6 4XE
United Kingdom
8.
EU/1/03/256/002
EU/1/03/256/003
EU/1/03/256/004
EU/1/03/256/005
9.
DATE OF FIRST AU`THORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 8 September 2003
Date of latest renewal: 8 September 2008
{MM/YYYY}
60
1.
Marketing Authorisation Holder
Abbott Laboratories Ltd
Abbott House,
Vanwall Business Park
Vanwall Road
Maidenhead
Berkshire
SL6 4XE
United Kingdom
Manufacturer
Abbott Biotechnology Deutschland GmbH
Max-Planck-Ring 2
D – 65205 Wiesbaden
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
Abbott SA
Tél/Tel: + 32 10 475311
Luxembourg/Luxemburg
Abbott SA
Tél/Tel: + 32 10 475311
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Т.П. Абот Лабораторис С.А.
Teл.: + 359 2 489 19 50
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Abbott Laboratories (Magyarország) Kft.
Tel.: + 36 1 465 2100
Česká republika
Abbott Laboratories s. r. o.
Tel: + 420 267 292 111
Malta
V.J.Salomone Pharma Limited
Tel: + 356 22983201
Danmark
Abbott Laboratories A/S
Tlf: + 45 39 77-00-00
Nederland
Abbott B.V.
Tel: + 31 (0) 888 222 688
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Abbott GmbH & Co. KG
Tel: + 49 (0) 6122 58-0
Norge
Abbott Norge AS
Tlf: + 47 81 55 99 20
Eesti
Abbott Laboratories Baltics
Tel: + 371 67605580
Österreich
Abbott Ges.m.b.H.
Tel: + 43 1 891 22
Ελλάδα
Abbott Laboratories (ΕΛΛΑΣ)Α.Β.Ε.Ε.
Τηλ: + 30 21 0 9985-222
Polska
Abbott Laboratories Poland Sp. z o.o.
Tel.: + 48 22 319 12 00
España
Abbott Laboratories, S.A.
Tel: + 34 91 3375200
Portugal
Abbott Laboratórios, Lda.
Tel: + 351 (0) 21 472 7100
209
France
Abbott France
Tél: + 33 (0) 1 45 60 25 00
România
Abbott Laboratories S.A.
Tel: +40 21 529 30 00
Ireland
Abbott Laboratories, Ireland, Ltd
Tel: + 353 (0) 1 469-1500
Slovenija
Abbott Laboratories d.o.o.
Tel: + 386 (1) 23 63 160
Ísland
Vistor hf.
Tel: + 354 535 7000
Slovenská republika
Abbott Laboratories Slovakia s.r.o.
Tel: + 421 (0) 2 4445 4176
Italia
Abbott Srl
Tel: + 39 06 928921
Suomi/Finland
Abbott OY
Puh/Tel: + 358 (0) 9 7518 4120
Κύπρος
Lifepharma (Z.A.M.) Ltd
Τηλ.: + 357 22 34 74 40
Sverige
Abbott Scandinavia AB
Tel: + 46 (0) 8 5465 67 00
Latvija
Abbott Laboratories Baltics
Tel: + 371 67605580
United Kingdom
Abbott Laboratories Ltd
Tel: + 44 (0) 1628 773355
Lietuva
Abbott Laboratories Baltics
Tel: + 371 67605580
This leaflet was last approved in {MM/YYYY}
210
Source: European Medicines Agency
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