ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Remicade 100 mg powder for concentrate for solution for infusion.
2.
Each vial contains 100 mg of infliximab. Infliximab is a chimeric human-murine IgG1 monoclonal
antibody produced by recombinant DNA technology. After reconstitution each ml contains 10 mg of
infliximab.
For a full list of excipients, see section 6.1.
3.
Powder for concentrate for solution for infusion.
The powder is a freeze-dried white pellet.
4.
Rheumatoid arthritis:
Remicade, in combination with methotrexate, is indicated for the reduction of signs and symptoms as
well as the improvement in physical function in:
•
adult patients with active disease when the response to disease-modifying anti-rheumatic drugs
(DMARDs), including methotrexate, has been inadequate.
•
adult patients with severe, active and progressive disease not previously treated with
methotrexate or other DMARDs.
In these patient populations, a reduction in the rate of the progression of joint damage, as measured by
X-ray, has been demonstrated (see section 5.1).
Adult Crohn’s disease:
Remicade is indicated for:
•
treatment of severe, active Crohn’s disease, in adult patients who have not responded despite a
full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who
are intolerant to or have medical contraindications for such therapies.
•
treatment of fistulising, active Crohn’s disease, in adult patients who have not responded despite
a full and adequate course of therapy with conventional treatment (including antibiotics,
drainage and immunosuppressive therapy).
Paediatric Crohn’s disease:
Remicade is indicated for treatment of severe, active Crohn’s disease, in paediatric patients aged 6 to
17 years, who have not responded to conventional therapy including a corticosteroid, an
immunomodulator and primary nutrition therapy; or who are intolerant to or have contraindications for
such therapies. Remicade has been studied only in combination with conventional immunosuppressive
therapy.
Ulcerative colitis:
Remicade is indicated for treatment of moderately to severely active ulcerative colitis in adult patients
who have had an inadequate response to conventional therapy including corticosteroids and 6-
mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical
contraindications for such therapies.
2
Ankylosing spondylitis:
Remicade is indicated for treatment of severe, active ankylosing spondylitis, in adult patients who have
responded inadequately to conventional therapy.
Psoriatic arthritis:
Remicade is indicated for treatment of active and progressive psoriatic arthritis in adult patients when
the response to previous DMARD therapy has been inadequate.
Remicade should be administered
- in combination with methotrexate
- or alone in patients who show intolerance to methotrexate or for whom methotrexate is
contraindicated
Remicade has been shown to improve physical function in patients with psoriatic arthritis, and 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).
Psoriasis:
Remicade is indicated for treatment of moderate to severe 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 (see section 5.1).
Remicade treatment is to be initiated and supervised by qualified physicians experienced in the
diagnosis and treatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosing spondylitis,
psoriatic arthritis or psoriasis. Remicade infusions should be administered by qualified healthcare
professionals trained to detect any infusion related issues. Patients treated with Remicade should be
given the package leaflet and the special Alert card.
Remicade should be administered intravenously. The recommended infusion duration for patients with
each indication is described below under the respective indication. All patients administered Remicade
are to be observed for at least 1-2 hours post-infusion for acute infusion-related reactions. Emergency
equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway must be
available. Patients may be pre-treated with e.g., an antihistamine, hydrocortisone and/or paracetamol
and infusion rate may be slowed in order to decrease the risk of infusion-related reactions especially if
infusion-related reactions have occurred previously (see section 4.4).
During Remicade treatment, other concomitant therapies, e.g., corticosteroids and immunosuppressants
should be optimised.
For preparation and administration instructions, see section 6.6.
Adults (
≥
18 years)
Rheumatoid arthritis
Patients not previously treated with Remicade: 3 mg/kg given as an intravenous infusion over a 2-hour
period followed by additional 3 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then
every 8 weeks thereafter.
In carefully selected patients with rheumatoid arthritis who have tolerated 3 initial 2-hour infusions of
Remicade, consideration may be given to administering subsequent infusions over a period of not less
than 1 hour. Shortened infusions at doses > 6 mg/kg have not been studied.
Remicade must be given concomitantly with methotrexate.
Available data suggest that the clinical response is usually achieved within 12 weeks of treatment. If a
patient has an inadequate response or loses response after this period, consideration may be given to
increase the dose step-wise by approximately 1.5 mg/kg, up to a maximum of 7.5 mg/kg every 8
3
weeks. Alternatively, administration of 3 mg/kg as often as every 4 weeks may be considered. If
adequate response is achieved, patients should be continued on the selected dose or dose frequency.
Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic
benefit within the first 12 weeks of treatment or after dose adjustment.
Severe, active Crohn’s disease
5 mg/kg given as an intravenous infusion over a 2-hour period followed by an additional 5 mg/kg
infusion 2 weeks after the first infusion. If a patient does not respond after 2 doses, no additional
treatment with infliximab should be given. Available data do not support further infliximab treatment,
in patients not responding within 6 weeks of the initial infusion.
In responding patients, the alternative strategies for continued treatment are:
•
Maintenance: Additional infusion of 5 mg/kg at 6 weeks after the initial dose, followed by
infusions every 8 weeks or
•
Re-administration: Infusion of 5 mg/kg if signs and symptoms of the disease recur (see ‘Re-
administration’ below and section 4.4).
Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg but
who lost response indicate that some patients may regain response with dose escalation (see section
5.1). Continued therapy should be carefully reconsidered in patients who show no evidence of
therapeutic benefit after dose adjustment.
Fistulising, active Crohn’s disease
5 mg/kg given as an intravenous infusion over a 2-hour period followed by additional 5 mg/kg
infusions at 2 and 6 weeks after the first infusion. If a patient does not respond after 3 doses, no
additional treatment with infliximab should be given.
In responding patients, the alternative strategies for continued treatment are:
•
Maintenance: Additional infusions of 5 mg/kg every 8 weeks or
•
Re-administration: Infusion of 5 mg/kg if signs and symptoms of the disease recur followed by
infusions of 5 mg/kg every 8 weeks (see ‘Re-administration’ below and section 4.4).
Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg but
who lost response indicate that some patients may regain response with dose escalation (see section
5.1). Continued therapy should be carefully reconsidered in patients who show no evidence of
therapeutic benefit after dose adjustment.
In Crohn’s disease, experience with re-administration if signs and symptoms of disease recur is limited
and comparative data on the benefit/risk of the alternative strategies for continued treatment are
lacking.
Ulcerative colitis
5 mg/kg given as an intravenous infusion over a 2 hour period followed by additional 5 mg/kg infusion
doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.
Available data suggest that the clinical response is usually achieved within 14 weeks of treatment, i.e.
three doses. Continued therapy should be carefully reconsidered in patients who show no evidence of
therapeutic benefit within this time period.
Ankylosing spondylitis
5 mg/kg given as an intravenous infusion over a 2-hour period followed by additional 5 mg/kg infusion
doses at 2 and 6 weeks after the first infusion, then every 6 to 8 weeks. If a patient does not respond by
6 weeks (i.e. after 2 doses), no additional treatment with infliximab should be given.
Psoriatic arthritis
5 mg/kg given as an intravenous infusion over a 2-hour period followed by additional 5 mg/kg infusion
doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.
4
Psoriasis
5 mg/kg given as an intravenous infusion over a 2-hour period followed by additional 5 mg/kg infusion
doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. If a patient shows no
response after 14 weeks (i.e. after 4 doses), no additional treatment with infliximab should be given.
Re-administration for Crohn’s disease and rheumatoid arthritis
If the signs and symptoms of disease recur, Remicade can be re-administered within 16 weeks
following the last infusion. In clinical studies, delayed hypersensitivity reactions have been uncommon
and have occurred after Remicade-free intervals of less than 1 year (see sections 4.4 and 4.8). The
safety and efficacy of re-administration after a Remicade-free interval of more than 16 weeks has not
been established. This applies to both Crohn’s disease patients and rheumatoid arthritis patients.
Re-administration for ulcerative colitis
The safety and efficacy of re-administration, other than every 8 weeks, has not been established (see
sections 4.4 and 4.8).
Re-administration for ankylosing spondylitis
The safety and efficacy of re-administration, other than every 6 to 8 weeks, has not been established
(see sections 4.4 and 4.8).
Re-administration for psoriatic arthritis
The safety and efficacy of re-administration, other than every 8 weeks, has not been established (see
sections 4.4 and 4.8).
Re-administration for psoriasis
Limited experience from re-treatment with one single Remicade dose in psoriasis after an interval of
20 weeks suggests reduced efficacy and a higher incidence of mild to moderate infusion reactions
when compared to the initial induction regimen (see section 5.1).
Limited experience from re-treatment following disease flare by a re-induction regimen suggests a
higher incidence of infusion reactions, including serious ones, when compared to 8-weekly
maintenance treatment (see section 4.8).
Re-administration across indications
In case maintenance therapy is interrupted, and there is a need to restart treatment, use of a re-
induction regimen is not recommended (see section 4.8). In this situation, Remicade should be re-
initiated as a single dose followed by the maintenance dose recommendations described above.
Elderly patients (≥ 65 years)
Specific studies of Remicade in elderly patients have not been conducted. No major age-related
differences in clearance or volume of distribution were observed in clinical studies. No dose
adjustment is required (see section 5.2). For more information about the safety of Remicade in elderly
patients see sections 4.4 and 4.8.
Paediatric population
Crohn’s disease (6 to 17 years)
5 mg/kg given as an intravenous infusion over a 2-hour period followed by additional 5 mg/kg infusion
doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Some patients may
require a shorter dosing interval to maintain clinical benefit, while for others a longer dosing interval
may be sufficient. Available data do not support further infliximab treatment in paediatric patients not
responding within the first 10 weeks of treatment (see section 5.1).
Remicade has not been studied in patients with Crohn’s disease below the age of 6 years.
5
Due to insufficient data on safety and efficacy, Remicade is not recommended for use in any other
paediatric indication (see section 4.8: “juvenile rheumatoid arthritis”).
Impaired renal and/or hepatic function
Remicade has not been studied in these patient populations. No dose recommendations can be made
(see section 5.2).
Patients with a history of hypersensitivity to infliximab (see section 4.8), to other murine proteins, or
to any of the excipients.
Patients with tuberculosis or other severe infections such as sepsis, abscesses, and opportunistic
infections (see section 4.4).
Patients with moderate or severe heart failure (NYHA class III/IV) (see sections 4.4 and 4.8).
Infusion reactions and hypersensitivity
Infliximab has been associated with acute infusion-related reactions, including anaphylactic shock, and
delayed hypersensitivity reactions (see section 4.8).
Acute infusion reactions including anaphylactic reactions may develop during (within seconds) or
within a few hours following infusion. If acute infusion reactions occur, the infusion must be
interrupted immediately. Emergency equipment, such as adrenaline, antihistamines, corticosteroids and
an artificial airway must be available. Patients may be pre-treated with e.g., an antihistamine,
hydrocortisone and/or paracetamol to prevent mild and transient effects.
Antibodies to infliximab may develop and have been associated with an increased frequency of
infusion reactions. A low proportion of the infusion reactions was serious allergic reactions. An
association between development of antibodies to infliximab and reduced duration of response has also
been observed. Concomitant administration of immunomodulators has been associated with lower
incidence of antibodies to infliximab and a reduction in the frequency of infusion reactions. The effect
of concomitant immunomodulator therapy was more profound in episodically treated patients than in
patients given maintenance therapy. Patients who discontinue immunosuppressants prior to or during
Remicade treatment are at greater risk of developing these antibodies. Antibodies to infliximab cannot
always be detected in serum samples. If serious reactions occur, symptomatic treatment must be given
and further Remicade infusions must not be administered (see section 4.8).
In clinical studies, delayed hypersensitivity reactions have been reported. Available data suggest an
increased risk for delayed hypersensitivity with increasing Remicade-free interval. Patients should be
advised to seek immediate medical advice if they experience any delayed adverse event (see section
4.8). If patients are re-treated after a prolonged period, they must be closely monitored for signs and
symptoms of delayed hypersensitivity.
Infections
Patients must be monitored closely for infections including tuberculosis before, during and after
treatment with Remicade. Because the elimination of infliximab may take up to six months, monitoring
should be continued throughout this period. Further treatment with Remicade must not be given if a
patient develops a serious infection or sepsis.
Caution should be exercised when considering the use of Remicade in patients with chronic infection
or a history of recurrent infections, including concomitant immunosuppressive therapy. Patients should
be advised of and avoid exposure to potential risk factors for infection as appropriate.
6
Tumour necrosis factor alpha (TNF
α
) mediates inflammation and modulates cellular immune
responses. Experimental data show that TNF
α
is essential for the clearing of intracellular infections.
Clinical experience shows that host defence against infection is compromised in some patients treated
with infliximab.
It should be noted that suppression of TNF
α
may mask symptoms of infection such as fever. Early
recognition of atypical clinical presentations of serious infections and of typical clinical presentation of
rare and unusual infections
is critical in order to minimize delays in diagnosis and treatment.
Patients taking TNF-blockers are more susceptible to serious infections.
Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral, and other
opportunistic infections have been observed in patients treated with infliximab. Some of these
infections have been fatal; the most frequently reported opportunistic infections with a mortality rate of
> 5% include pneumocystosis, candidiasis, listeriosis and aspergillosis.
Patients who develop a new infection while undergoing treatment with Remicade, should be monitored
closely and undergo a complete diagnostic evaluation. Administration of Remicade 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.
For patients who have resided in or travelled to regions where invasive fungal infections such as
histoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefits and risks of Remicade
treatment should be carefully considered before initiation of Remicade therapy.
There have been reports of active tuberculosis in patients receiving Remicade. It should be noted that
in the majority of these reports tuberculosis was extrapulmonary, presenting as either local or
disseminated disease.
In clinical studies, infections have been reported more frequently in paediatric patient populations than
in adult patient populations (see section 4.8).
Before starting treatment with Remicade, all patients must be evaluated for both active and inactive
(‘latent’) tuberculosis. This evaluation should include a detailed medical history with personal history
of tuberculosis or possible previous contact with 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’s 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, Remicade 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 Remicade therapy should be
very carefully considered.
If inactive (‘latent’) tuberculosis is diagnosed, treatment for latent tuberculosis must be started with
anti-tuberculosis therapy before the initiation of Remicade, 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 be considered before the initiation of Remicade.
Use of anti-tuberculosis therapy should also be considered before the initiation of Remicade in patients
with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be
confirmed.
All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis
(e.g. persistent cough, wasting/weight loss, low-grade fever) appear during or after Remicade
treatment.
7
Patients with fistulising Crohn’s disease with acute suppurative fistulas must not initiate Remicade
therapy until a source for possible infection, specifically abscess, has been excluded (see section 4.3).
Hepatitis B (HBV) reactivation
Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including infliximab,
who are chronic carriers of this virus. Some cases have had fatal outcome.
Patients should be tested for HBV infection before initiating treatment with Remicade. For patients
who test positive for HBV infection, consultation with a physician with expertise in the treatment of
hepatitis B is recommended. Carriers of HBV who require treatment with Remicade should be closely
monitored for signs and symptoms of active HBV infection throughout therapy and for several months
following termination of therapy. Adequate data of treating patients who are carriers of HBV with anti-
viral therapy in conjunction with TNF-antagonist therapy to prevent HBV reactivation are not
available. In patients who develop HBV reactivation, Remicade should be stopped and effective anti-
viral therapy with appropriate supportive treatment should be initiated.
Hepatobiliary events
Very rare cases of jaundice and non-infectious hepatitis, some with features of autoimmune hepatitis,
have been observed in the post-marketing experience of Remicade. Isolated cases of liver failure
resulting in liver transplantation or death have occurred. Patients with symptoms or signs of liver
dysfunction should be evaluated for evidence of liver injury. If jaundice and/or ALT elevations ≥ 5
times the upper limit of normal develop(s), Remicade should be discontinued, and a thorough
investigation of the abnormality should be undertaken.
Concurrent administration of TNF-alpha inhibitor and anakinra
Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and
another TNF
α
-blocking agent, etanercept, with no added clinical benefit compared to etanercept alone.
Because of the nature of the adverse events seen with combination of etanercept and anakinra therapy,
similar toxicities may also result from the combination of anakinra and other TNF
α
-blocking agents.
Therefore, the combination of Remicade and anakinra is not recommended.
Concurrent administration of TNF-alpha inhibitor and abatacept
In clinical studies 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 Remicade and abatacept is not recommended.
Switching between biological DMARDS
When switching from one biologic to another, patients should continue to be monitored for signs of
infection.
Vaccinations
No data are available on the response to vaccination with live vaccines or on the secondary
transmission of infection by live vaccines in patients receiving anti-TNF therapy. It is recommended
that live vaccines not be given concurrently.
It is recommended that paediatric Crohn’s disease patients, if possible, be brought up to date with all
vaccinations in agreement with current vaccination guidelines prior to initiating Remicade therapy.
Autoimmune processes
The relative deficiency of TNF
α
caused by anti-TNF therapy may result in the initiation of an
autoimmune process. If a patient develops symptoms suggestive of a lupus-like syndrome following
treatment with Remicade and is positive for antibodies against double-stranded DNA, further treatment
with Remicade must not be given (see section 4.8).
Neurological events
Use of TNF-blocking agents, including infliximab, has been associated with cases of new onset or
exacerbation of clinical symptoms and/or radiographic evidence of central nervous system
8
demyelinating disorders, including multiple sclerosis, and peripheral demyelinating disorders,
including Guillain-Barré syndrome. In patients with pre-existing or recent onset of demyelinating
disorders, the benefits and risks of anti-TNF treatment should be carefully considered before initiation
of Remicade therapy. Discontinuation of Remicade should be considered if these disorders develop.
Malignancies and lymphoproliferative disorders
In the controlled portions of clinical studies of TNF-blocking agents, more cases of malignancies
including lymphoma have been observed among patients receiving a TNF blocker compared with
control patients. During clinical studies of Remicade across all approved indications the incidence of
lymphoma in Remicade-treated patients was higher than expected in the general population, but the
occurrence of lymphoma was rare. In the post-marketing setting, cases of leukaemia have been
reported in patients treated with a TNF-antagonist. There is an increased background risk for
lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active,
inflammatory disease, which complicates risk estimation.
In an exploratory clinical study evaluating the use of Remicade in patients with moderate to severe
chronic obstructive pulmonary disease (COPD), more malignancies were reported in Remicade-treated
patients compared with control patients. All patients had a history of heavy smoking. Caution should
be exercised in considering treatment of patients with increased risk for malignancy due to heavy
smoking.
With the current knowledge, a risk for the development of lymphomas or other malignancies in
patients treated with a TNF-blocking agent cannot be excluded (see section 4.8). Caution should be
exercised when considering TNF-blocking therapy for patients with a history of malignancy or when
considering continuing treatment in patients who develop a malignancy.
Caution should also be exercised in patients with psoriasis and a medical history of extensive
immunosuppressant therapy or prolonged PUVA treatment.
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
Remicade 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 post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated
with
TNF-blocking agents including infliximab. This rare type of T-cell lymphoma has a very
aggressive disease course and is usually fatal. All Remicade cases have occurred in patients with
Crohn’s disease or ulcerative colitis and the majority were reported in adolescent or young adult
males. All of these patients had received treatment with AZA or 6-MP concomitantly with or
immediately prior to Remicade. The potential risk with the combination of AZA or 6-MP and
Remicade should be carefully considered. A risk for the development for hepatosplenic T-cell
lymphoma in patients treated with Remicade cannot be excluded (see sections 4.2 and 4.8).
All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (for
example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a
prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals
before therapy and throughout their disease course. This evaluation should include colonoscopy and
biopsies per local recommendations. With current data it is not known if infliximab treatment
influences the risk for developing dysplasia or colon cancer (see section 4.8).
Since the possibility of increased risk of cancer development in patients with newly diagnosed
dysplasia treated with Remicade is not established, the risk and benefits to the individual patients must
be carefully reviewed and consideration should be given to discontinuation of therapy.
Heart failure
9
Remicade should be used with caution in patients with mild heart failure (NYHA class I/II). Patients
should be closely monitored and Remicade must not be continued in patients who develop new or
worsening symptoms of heart failure (see sections 4.3 and 4.8).
Haematologic reactions
There have been reports of pancytopenia, leucopenia, neutropenia, and thrombocytopenia in patients
receiving TNF-blockers, including Remicade. 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). Discontinuation of Remicade therapy should be considered in
patients with confirmed significant haematologic abnormalities.
Others
There is limited safety experience of Remicade treatment in patients who have undergone surgical
procedures, including arthroplasty. The long half-life of infliximab should be taken into consideration
if a surgical procedure is planned. A patient who requires surgery while on Remicade should be closely
monitored for infections, and appropriate actions should be taken.
Failure to respond to treatment for Crohn’s disease may indicate the presence of a fixed fibrotic
stricture that may require surgical treatment. Available data suggest that infliximab does not worsen or
cause strictures.
Special populations
Elderly patients (≥ 65 years)
The incidence of serious infections in Remicade-treated patients 65 years and older was greater than in
those under 65 years of age. Some of those had a fatal outcome. Particular attention regarding the risk
for infection should be paid when treating the elderly (see section 4.8).
In rheumatoid arthritis, psoriatic arthritis and Crohn's disease patients, there are indications that
concomitant use of methotrexate and other immunomodulators reduces the formation of antibodies
against infliximab and increases the plasma concentrations of infliximab. However, the results are
uncertain due to limitations in the methods used for serum analyses of infliximab and antibodies
against infliximab.
Corticosteroids do not appear to affect the pharmacokinetics of infliximab to a clinically relevant
extent.
The combination of Remicade and anakinra or abatacept is not recommended (see section 4.4).
It is recommended that live vaccines not be given concurrently with Remicade (see section 4.4).
Pregnancy
The moderate number (approximately 450) of prospectively collected pregnancies exposed to
infliximab with known outcomes, including a limited number (approximately 230) exposed during the
first trimester, does not indicate unexpected effects on pregnancy outcome. Due to its inhibition of
TNFα, infliximab administered during pregnancy could affect normal immune responses in the
newborn. In a developmental toxicity study conducted in mice using an analogous antibody that
selectively inhibits the functional activity of mouse TNFα, there was no indication of maternal
toxicity, embryotoxicity or teratogenicity (see section 5.3).
The available clinical experience is too limited to exclude a risk, and administration of infliximab is
therefore not recommended during pregnancy.
10
Infliximab crosses the placenta and has been detected up to 6 months in the serum of infants born to
women treated with infliximab during pregnancy. Consequently, these infants may be at increased risk
for infection. Administration of live vaccines to infants exposed to infliximab in utero is not
recommended for 6 months following the mother’s last infliximab infusion during pregnancy (see
sections 4.4 and 4.5).
Women of childbearing potential
Women of childbearing potential must use adequate contraception to prevent pregnancy and continue
its use for at least 6 months after the last Remicade treatment.
Lactation
It is not known whether infliximab is excreted in human milk or absorbed systemically after ingestion.
Because human immunoglobulins are excreted in milk, women must not breast feed for at least
6 months after Remicade treatment.
Fertility
There are insufficient preclinical data to draw conclusions on the effects of infliximab on fertility and
general reproductive function (see section 5.3).
No studies on the effects on the ability to drive and use machines have been performed. Remicade may
have a minor influence on the ability to drive and use machines. Dizziness may occur following
administration of Remicade (see section 4.8).
In clinical studies with infliximab, adverse reactions were observed in approximately 60% of
infliximab-treated patients and 40% of placebo-treated patients. Infusion-related reactions were the
most common adverse reactions reported. Infusion-related reactions (dyspnoea, urticaria and headache)
were the most common cause for discontinuation.
Table 1 lists the adverse reactions based on experience from clinical studies as well as adverse
reactions, some with fatal outcome, reported from post-marketing experience. Within the organ system
classes, adverse reactions are listed under headings of frequency using the following categories: 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); very rare (<1/10,000), not known (cannot be estimated from the available data). Because
post-marketing events are reported voluntarily from a population of uncertain size, it is not possible to
estimate their frequency. Therefore, the frequency of these adverse reactions is categorised as not
known. Within each frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
Infections and infestations
Common: Viral infection (e.g. influenza, herpes virus infection).
Uncommon: Tuberculosis, bacterial infections (e.g. sepsis, cellulitis, abscess),
fungal infections (e.g. candidiasis).
Not known: Opportunistic infections (such as invasive fungal infections
[pneumocystosis, histoplasmosis, aspergillosis,
coccidioidomycosis, cryptococcosis, blastomycosis], bacterial
infections [atypical mycobacterial, listeriosis, salmonellosis], and
viral infections [cytomegalovirus]), parasitic infections, hepatitis B
reactivation.
11
Neoplasms benign, malignant and
unspecified (including cysts and
polyps)
Rare: Lymphoma.
Not known: Hepatosplenic T-cell lymphoma (primarily in adolescents and
young adults with Crohn’s disease and ulcerative colitis), non-
Hodgkin’s lymphoma, Hodgkin’s disease,
leukaemia.
Blood and lymphatic system
disorders
Anaphylactic reaction, lupus-like syndrome, allergic respiratory
symptom.
Sarcoid-like reaction.
Not known: Anaphylactic shock, serum sickness, vasculitis.
Psychiatric disorders
Uncommon: Depression, amnesia, agitation, confusion, insomnia, somnolence,
nervousness, apathy.
Nervous system disorders
Common: Headache, vertigo, dizziness.
Uncommon: Central nervous system demyelinating disorders (multiple
sclerosis-like disease).
Rare: Meningitis.
Not known: Peripheral demyelinating disorders (such as Guillain-Barré
syndrome, chronic inflammatory demyelinating polyneuropathy
and multifocal motor neuropathy), central nervous system
demyelinating disorders (such as optic neuritis), transverse
myelitis, seizure, neuropathy, hypoaesthesia, paraesthesia.
Rare:
Eye disorders
Uncommon: Endophthalmitis, keratitis, conjunctivitis, periorbital oedema,
hordeolum.
Not known Transient visual loss occurring during or within two hours of
infusion.
Cardiac disorders
Uncommon: Cardiac failure aggravated, arrhythmia, syncope, bradycardia,
cyanosis, palpitation.
Rare: Tachycardia.
Not known: Myocardial ischaemia/myocardial infarction occurring during or
within two hours of infusion,
cardiac failure, pericardial effusion.
Vascular disorders
Common: Flushing.
Uncommon: Hypotension, peripheral ischaemia, hypertension,
thrombophlebitis, haematoma, ecchymosis, petechia, vasospasm,
hot flush.
Rare: Circulatory failure.
Respiratory, thoracic and
mediastinal disorders
Common: Lower respiratory tract infection (e.g. bronchitis, pneumonia),
upper respiratory tract infection, sinusitis, dyspnoea.
Uncommon: Pulmonary oedema, bronchospasm, pleurisy, epistaxis.
Rare: Pleural effusion.
12
Uncommon: Neutropenia, leucopenia, thrombocytopenia, anaemia,
lymphopenia, lymphadenopathy, lymphocytosis.
Not known: Agranulocytosis, thrombotic thrombocytopenic purpura,
pancytopenia, haemolytic anaemia, idiopathic thrombocytopenic
purpura.
Immune system disorders
Common: Serum sickness-like reaction.
Uncommon:
Not known: Interstitial lung disease (including rapidly progressive disease,
lung fibrosis and pneumonitis).
Gastrointestinal disorders
Common: Abdominal pain, diarrhoea, nausea, dyspepsia.
Uncommon: Diverticulitis, gastroesophageal reflux, constipation, cheilitis.
Rare: Intestinal perforation, gastrointestinal haemorrhage, intestinal
stenosis.
Not known: Pancreatitis.
Hepatobiliary disorders
Common: Transaminases increased.
Uncommon: Cholecystitis, hepatic function abnormal.
Rare: Hepatitis.
Not known: Liver failure, autoimmune hepatitis, hepatocellular damage,
jaundice.
Skin and subcutaneous tissue
disorders
Common: Urticaria, rash, pruritus, hyperhidrosis, dry skin.
Uncommon: Bullous eruption, furunculosis, fungal dermatitis, onychomycosis,
eczema, seborrhoea, rosacea, skin papilloma, hyperkeratosis,
alopecia, abnormal skin pigmentation.
Not known: Toxic epidermal necrolysis, Stevens-Johnson-Syndrome, new
onset or worsening psoriasis, including pustular psoriasis
(primarily palm & soles), erythema multiforme.
Musculoskeletal and connective
tissue disorders
Uncommon: Arthralgia, myalgia, back pain.
Renal and urinary disorders
Uncommon: Pyelonephritis, urinary tract infection.
Reproductive system and breast
disorders
Uncommon: Vaginitis.
General disorders and
administration site conditions
Common: Infusion-related reaction, chest pain, fatigue, fever.
Uncommon: Impaired healing, injection site reaction, chills, oedema, pain.
Rare: Granulomatous lesion.
Investigations
Uncommon: Autoantibody positive, complement factor abnormal.
Infusion-related reactions:
An infusion-related reaction was defined in clinical studies as any adverse
event occurring during an infusion or within 1 to 2 hours after an infusion. In clinical studies,
approximately 20% of infliximab-treated patients compared with approximately 10% of placebo-
treated patients experienced an infusion-related effect. Approximately 3% of patients discontinued
treatment due to infusions reactions and all patients recovered with or without medical therapy. In a
clinical study of patients with rheumatoid arthritis (ASPIRE), sixty six percent of the patients (686 out
of 1,040) received at least one shortened infusion of 90 minutes or less and 44% of the patients (454
out of 1,040) received at least one shortened infusion of 60 minutes or less. Of the infliximab-treated
patients who received at least one shortened infusion, infusion-related reactions occurred in 15% of
patients and serious infusion reactions occurred in 0.4% of patients.
In post-marketing experience, cases of anaphylactic-like reactions, including laryngeal/pharyngeal
oedema and severe bronchospasm, and seizure have been associated with Remicade administration.
Exceedingly rare cases of transient visual loss and myocardial ischaemia/infarction occurring during or
within 2 hours of Remicade infusion have also been reported.
13
Infusion reactions following re-administration of Remicade
:
A clinical study in patients with moderate
to severe psoriasis was designed to assess the efficacy and safety of long-term maintenance therapy
versus re-treatment with an induction regimen of Remicade (maximum of four infusions at 0, 2, 6 and
14 weeks) following disease flare. Patients did not receive any concomitant immunosuppressant
therapy. In the re-treatment arm, 4% (8/219) of patients experienced a serious infusion reaction versus
< 1% (1/222) on maintenance therapy. The majority of serious infusion reactions occurred during the
second infusion at Week 2. The interval between the last maintenance dose and the first re-induction
dose ranged from 35-231 days. Symptoms included, but were not limited to, dyspnea, urticaria, facial
oedema, and hypotension. In all cases, Remicade treatment was discontinued and/or other treatment
instituted with complete resolution of signs and symptoms.
Delayed hypersensitivity
: In clinical studies delayed hypersensitivity reactions have been uncommon
and have occurred after Remicade-free intervals of less than 1 year. In the psoriasis studies, delayed
hypersensitivity reactions occurred early in the treatment course. Signs and symptoms included
myalgia and/or arthralgia with fever and/or rash, with some patients experiencing pruritus, facial, hand
or lip oedema, dysphagia, urticaria, sore throat and headache.
There are insufficient data on the incidence of delayed hypersensitivity reactions after Remicade-free
intervals of more than 1 year but limited data from clinical studies suggest an increased risk for
delayed hypersensitivity with increasing Remicade-free interval.
In a 1-year clinical study with repeated infusions in patients with Crohn's disease (ACCENT I study),
the incidence of serum sickness-like reactions was 2.4%.
Immunogenicity:
Patients who developed antibodies to infliximab were more likely (approximately 2-
3 fold) to develop infusion-related reactions. Use of concomitant immunosuppressant agents appeared
to reduce the frequency of infusion-related reactions.
In clinical studies using single and multiple infliximab doses ranging from 1 to 20 mg/kg, antibodies to
infliximab were detected in 14% of patients with any immunosuppressant therapy, and in 24%
of patients without immunosuppressant therapy. In rheumatoid arthritis patients who received the
recommended repeated treatment dose regimens with methotrexate, 8% of patients developed
antibodies to infliximab. In psoriatic arthritis patients who received 5 mg/kg with and without
methotrexate, antibodies occurred overall in 15% of patients (antibodies occurred in 4% of patients
receiving methotrexate and in 26% of patients not receiving methotrexate at baseline). Of Crohn's
disease patients who received maintenance treatment, approximately 6-13% developed antibodies to
infliximab. The antibody incidence was 2-3 fold higher for patients treated episodically. Due to
methodological limitations, a negative assay did not exclude the presence of antibodies to infliximab.
Some patients who developed high titres of antibodies to infliximab had evidence of reduced efficacy.
In psoriasis patients treated with infliximab as a maintenance regimen in the absence of concomitant
immunomodulators, approximately 28% developed antibodies to infliximab (see section 4.4: "Infusion
reactions and hypersensitivity").
Infections:
Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral,
and other opportunistic infections have been observed in patients receiving Remicade. Some of these
infections have been fatal; the most frequently reported opportunistic infections with a mortality rate of
> 5% include pneumocystosis, candidiasis, listeriosis and aspergillosis (see section 4.4).
In clinical studies 36% of infliximab-treated patients were treated for infections compared with 25% of
placebo-treated patients.
In rheumatoid arthritis clinical studies, the incidence of serious infections including pneumonia was
higher in infliximab plus methotrexate treated patients compared with methotrexate alone especially at
doses of 6 mg/kg or greater (see section 4.4).
In post-marketing spontaneous reporting, infections are the most common serious adverse event. Some
of the cases have resulted in a fatal outcome. Nearly 50% of reported deaths have been associated with
14
infection. Cases of tuberculosis, sometimes fatal, including miliary tuberculosis and tuberculosis with
extra-pulmonary location have been reported (see section 4.4).
Malignancies and lymphoproliferative disorders:
In clinical studies with infliximab in which 5,780
patients were treated, representing 5,494 patient years, 5 cases of lymphomas and 26 non-lymphoma
malignancies were detected as compared with no lymphomas and 1 non-lymphoma malignancy in
1,600 placebo-treated patients representing 941 patient years.
In long-term safety follow-up of clinical studies with infliximab of up to 5 years, representing 6,234
patients-years (3,210 patients), 5 cases of lymphoma and 38 cases of non-lymphoma malignancies
were reported.
From August 1998 to August 2005, 1,909 cases of suspected malignancies have been reported from
post-marketing, clinical studies and registries (321 in Crohn’s disease patients, 1,302 in rheumatoid
arthritis patients and 286 in patients with other or unknown indications). Among those there were 347
lymphoma cases. During this period, the estimated exposure is 1,909,941 patient years since first
exposure (see section 4.4).
In an exploratory clinical study involving patients with moderate to severe COPD who were either
current smokers or ex-smokers, 157 patients were treated with Remicade at doses similar to those used
in rheumatoid arthritis and Crohn’s disease. Nine of these patients developed malignancies, including 1
lymphoma. The median duration of follow-up was 0.8 years (incidence 5.7% [95% CI 2.65% - 10.6%].
There was one reported malignancy amongst 77 control patients (median duration of follow-up 0.8
years; incidence 1.3% [95% CI 0.03% - 7.0%]). The majority of the malignancies developed in the
lung or head and neck.
Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients with
Crohn’s disease and ulcerative colitis treated with Remicade, the majority of whom were adolescent or
young adult males (see section 4.4).
Heart failure:
In a phase II study aimed at evaluating Remicade in congestive heart failure (CHF),
higher incidence of mortality due to worsening of heart failure were seen in patients treated with
Remicade, especially those treated with the higher dose of 10 mg/kg (i.e. twice the maximum approved
dose). In this study 150 patients with NYHA Class III-IV CHF (left ventricular ejection fraction
≤35%) were treated with 3 infusions of Remicade 5 mg/kg, 10 mg/kg, or placebo over 6 weeks. At
38 weeks, 9 of 101 patients treated with Remicade (2 at 5 mg/kg and 7 at 10 mg/kg) died compared to
one death among the 49 patients on placebo.
There have been post-marketing reports of worsening heart failure, with and without identifiable
precipitating factors, in patients taking Remicade. There have also been rare post-marketing reports of
new onset heart failure, including heart failure in patients without known pre-existing cardiovascular
disease. Some of these patients have been under 50 years of age.
Hepatobiliary events:
In clinical studies, mild or moderate elevations of ALT and AST have been
observed in patients receiving Remicade without progression to severe hepatic injury. Elevations of
ALT ≥5 x Upper Limit of Normal (ULN) have been observed (see Table 2). Elevations of
aminotransferases were observed (ALT more common than AST) in a greater proportion of patients
receiving Remicade than in controls, both when Remicade was given as monotherapy and when it was
used in combination with other immunosuppressive agents. Most aminotransferase abnormalities were
transient; however, a small number of patients experienced more prolonged elevations. In general,
patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased
or resolved with either continuation or discontinuation of Remicade, or modification of concomitant
therapy.
In post-marketing surveillance, very rare cases of jaundice and hepatitis, some with features of
autoimmune hepatitis, have been reported in patients receiving Remicade (see section 4.4).
Table 2: Proportion of patients with increased ALT activity in clinical studies
15
Indication
Number of patients
3
Median follow-up
(wks)
4
≥3 x ULN ≥5 x ULN
placebo infliximab placebo
infliximab placebo infliximab placebo infliximab
Rheumatoid
arthritis
1
375
1,087
58.1
58.3
3.2%
3.9%
0.8%
0.9%
Crohn’s
disease
2
173
703
54.1
54.1
3.5%
5.1%
0.0%
1.7%
Paediatric
Crohn’s
disease
N/A
139
N/A
53.0
N/A
4.4%
N/A
1.5%
Ulcerative
colitis
242
482
30.1
30.8
1.2%
2.5%
0.4%
0.6%
Ankylosing
spondylitis
76
275
24.1
101.9
0.0%
9.5%
0.0%
3.6%
Psoriatic
arthritis
98
191
18.1
39.1
0.0%
6.8%
0.0%
2.1%
Plaque
psoriasis
281
1,175
16.1
50.1
0.4%
7.7%
0.0%
3.4%
1
Placebo patients received methotrexate while infliximab patients received both infliximab and methotrexate.
2
Placebo patients in the 2 Phase III studies in Crohn’s disease, ACCENT I and ACCENT II, received an initial dose of 5
mg/kg infliximab at study start and were on placebo in the maintenance phase. Patients who were randomized to the
placebo maintenance group and then later crossed over to infliximab are included in the infliximab group in the ALT
analysis.
3
Number of patients evaluated for ALT.
4
Median follow-up is based on patients treated.
Antinuclear antibodies (ANA)/Anti-double-stranded DNA (dsDNA) antibodies:
Approximately half of
infliximab-treated patients in clinical studies who were ANA negative at baseline developed a positive
ANA during the study compared with approximately one-fifth of placebo-treated patients. Anti-
dsDNA antibodies were newly detected in approximately 17% of infliximab-treated patients compared
with 0% of placebo-treated patients. At the last evaluation, 57% of infliximab-treated patients
remained anti-dsDNA positive. Reports of lupus and lupus-like syndromes, however, remain
uncommon.
Additional information on special populations
Elderly patients (≥ 65 years)
In rheumatoid arthritis clinical studies, the incidence of serious infections was greater in infliximab
plus methotrexate treated patients 65 years and older (11.3%) than in those under 65 years of age
(4.6%). In patients treated with methotrexate alone, the incidence of serious infections was 5.2% in
patients 65 years and older compared to 2.7% in patients under 65.
Paediatric population
Juvenile rheumatoid arthritis patients:
Remicade was studied in a clinical study in 120 patients (age range: 4-17 years old) with active
juvenile rheumatoid arthritis despite methotrexate. Patients received 3 or 6 mg/kg infliximab as a 3-
dose induction regimen (weeks 0, 2, 6 or weeks 14, 16, 20 respectively) followed by maintenance
therapy every 8 weeks, in combination with methotrexate.
Infusion reactions
Infusion reactions occurred in 35 % of patients with juvenile rheumatoid arthritis receiving 3 mg/kg
compared with 17.5% of patients receiving 6 mg/kg. In the 3 mg/kg Remicade group, 4 out of 60
patients had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of
which were among the serious infusion reactions). In the 6 mg/kg group, 2 out of 57 patients had a
serious infusion reaction, one of whom had a possible anaphylactic reaction.
16
Immunogenicity
Antibodies to infliximab developed in 38 % of patients receiving 3 mg/kg compared with 12% of
patients receiving 6 mg/kg. The antibody titres were notably higher for the 3 mg/kg compared to the 6
mg/kg group.
Infections
Infections occurred in 68% (41/60) of children receiving 3 mg/kg over 52 weeks, 65% (37/57) of
children receiving infliximab 6 mg/kg over 38 weeks and 47% (28/60) of children receiving placebo
over 14 weeks.
Paediatric Crohn’s disease patients:
The following adverse events were reported more commonly in paediatric Crohn’s disease patients in
the REACH study (see section 5.1) than in adult Crohn’s disease patients: anaemia (10.7%), blood in
stool (9.7%), leucopenia (8.7%), flushing (8.7%), viral infection (7.8%), neutropenia (6.8%), bone
fracture (6.8%), bacterial infection (5.8%), and respiratory tract allergic reaction (5.8%). Other special
considerations are discussed below.
Infusion-related reactions
Overall, in REACH, 17.5% of randomized patients experienced 1 or more infusion reactions. There
were no serious infusion reactions, and 2 subjects in REACH had non-serious anaphylactic reactions.
Immunogenicity
Antibodies to infliximab were detected in 3 (2.9%) paediatric patients.
Infections
In the REACH study, infections were reported in 56.3% of randomized subjects treated with
infliximab. Infections were reported more frequently for subjects who received q8 week as opposed to
q12 week infusions (73.6% and 38.0%, respectively), while serious infections were reported for 3
subjects in the q8 week and 4 subjects in the q12 week maintenance treatment group. The most
commonly reported infections were upper respiratory tract infection and pharyngitis, and the most
commonly reported serious infection was abscess. Three cases of pneumonia (1 serious) and 2 cases of
herpes zoster (both non-serious) were reported.
Post-marketing spontaneous serious adverse events with infliximab in the paediatric population have
included malignancies including hepatosplenic T-cell lymphomas, transient hepatic enzyme
abnormalities, lupus-like syndromes, and positive auto-antibodies (see sections 4.4 and 4.8).
No case of overdose has been reported. Single doses up to 20 mg/kg have been administered without
toxic effects.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: tumour necrosis factor alpha (TNF
α
) inhibitors, ATC code: L04AB02.
Pharmacodynamic properties
Infliximab is a chimeric human-murine monoclonal antibody that binds with high affinity to both
soluble and transmembrane forms of TNF
α
but not to lymphotoxin α (TNF
ß
). Infliximab inhibits the
functional activity of TNF
α
in a wide variety of
in vitro
bioassays. Infliximab prevented disease in
transgenic mice that develop polyarthritis as a result of constitutive expression of human TNF
α
and
17
when administered after disease onset, it allowed eroded joints to heal.
In vivo
, infliximab rapidly
forms stable complexes with human TNF
α
, a process that parallels the loss of TNF
α
bioactivity.
Elevated concentrations of TNF
α
have been found in the joints of rheumatoid arthritis patients and
correlate with elevated disease activity. In rheumatoid arthritis, treatment with infliximab reduced
infiltration of inflammatory cells into inflamed areas of the joint as well as expression of molecules
mediating cellular adhesion, chemoattraction and tissue degradation. After infliximab treatment,
patients exhibited decreased levels of serum interleukin 6 (IL-6) and C-reactive protein (CRP)
,
and
increased haemoglobin levels in rheumatoid arthritis patients with reduced haemoglobin levels,
compared with baseline. Peripheral blood lymphocytes further showed no significant decrease in
number or in proliferative responses to
in vitro
mitogenic stimulation when compared with untreated
patients’ cells. In psoriasis patients, treatment with infliximab resulted in decreases in epidermal
inflammation and normalization of keratinocyte differentiation in psoriatic plaques. In psoriatic
arthritis, short term treatment with Remicade reduced the number of T-cells and blood vessels in the
synovium and psoriatic skin.
Histological evaluation of colonic biopsies, obtained before and 4 weeks after administration of
infliximab, revealed a substantial reduction in detectable TNF
α
. Infliximab treatment of Crohn’s
disease patients was also associated with a substantial reduction of the commonly elevated serum
inflammatory marker, CRP. Total peripheral white blood cell counts were minimally affected in
infliximab-treated patients, although changes in lymphocytes, monocytes and neutrophils reflected
shifts towards normal ranges. Peripheral blood mononuclear cells (PBMC) from infliximab-treated
patients showed undiminished proliferative responsiveness to stimuli compared with untreated patients,
and no substantial changes in cytokine production by stimulated PBMC were observed following
treatment with infliximab. Analysis of lamina propria mononuclear cells obtained by biopsy of the
intestinal mucosa showed that infliximab treatment caused a reduction in the number of cells capable
of expressing TNF
α
and interferonγ. Additional histological studies provided evidence that treatment
with infliximab reduces the infiltration of inflammatory cells into affected areas of the intestine and the
presence of inflammation markers at these sites. Endoscopic studies of intestinal mucosa have shown
evidence of mucosal healing in infliximab treated patients.
Clinical Efficacy
Rheumatoid arthritis
The efficacy of infliximab was assessed in two multicentre, randomised, double-blind,
pivotal clinical
studies: ATTRACT and ASPIRE. In both studies concurrent use of stable doses of folic acid, oral
corticosteroids (≤ 10 mg/day) and/or non-steroidal anti-inflammatory drugs (NSAIDs) was permitted.
The primary endpoints were the reduction of signs and symptoms as assessed by the American College
of Rheumatology criteria (ACR20 for ATTRACT, landmark ACR-N for ASPIRE), the prevention of
structural joint damage, and the improvement in physical function. A reduction in signs and symptoms
was defined to be at least a 20% improvement (ACR20) in both tender and swollen joint counts, and in
3 of the following 5 criteria: (1) evaluator’s global assessment, (2) patient’s global assessment, (3)
functional/disability measure, (4) visual analogue pain scale and (5) erythrocyte sedimentation rate or
C-reactive protein. ACR-N uses the same criteria as the ACR20, calculated by taking the lowest
percent improvement in swollen joint count, tender joint count, and the median of the remaining 5
components of the ACR response. Structural joint damage (erosions and joint space narrowing) in both
hands and feet was measured by the change from baseline in the total van der Heijde-modified Sharp
score (0-440). The Health Assessment Questionnaire (HAQ; scale 0-3) was used to measure patients’
average change from baseline scores over time, in physical function.
The ATTRACT study evaluated responses at 30, 54 and 102 weeks in a placebo-controlled study of
428 patients with active rheumatoid arthritis despite treatment with methotrexate. Approximately 50%
of patients were in functional Class III. Patients received placebo, 3 mg/kg or 10 mg/kg infliximab at
weeks 0, 2 and 6, and then every 4 or 8 weeks thereafter. All patients were on stable methotrexate
18
doses (median 15 mg/wk) for 6 months prior to enrolment and were to remain on stable doses
throughout the study.
Results from week 54 (ACR20, total van der Heijde-modified Sharp score and HAQ) are shown in
Table 3. Higher degrees of clinical response (ACR50 and ACR70) were observed in all infliximab
groups at 30 and 54 weeks compared with methotrexate alone.
A reduction in the rate of the progression of structural joint damage (erosions and joint space
narrowing) was observed in all infliximab groups at 54 weeks (Table 3).
The effects observed at 54 weeks were maintained through 102 weeks. Due to a number of treatment
withdrawals, the magnitude of the effect difference between infliximab and the methotrexate alone
group cannot be defined.
Table 3
Effects on ACR20, Structural Joint Damage and Physical Function at week 54, ATTRACT
infliximab
b
Control
a
3 mg/kg
q 8 wks
3 mg/kg
q 4 wks
10 mg/kg
q 8 wks
10 mg/kg
q 4 wks
All
infliximab
b
Patients with ACR20 response/
Patients evaluated (%)
c
15/88
(17%)
36/86
(42%)
41/86
(48%)
51/87
(59%)
48/81
(59%)
176/340
(52%)
Total score
d
(van der Heijde-modified
Sharp score)
Change from baseline (Mean ± SD
c
)
7.0 ± 10.3 1.3 ± 6.0 1.6 ± 8.5 0.2 ± 3.6 -0.7 ± 3.8 0.6 ± 5.9
Median
c
(Interquartile range)
4.0
(0.5,9.7)
0.5
(-1.5,3.0)
0.1
(-2.5,3.0)
0.5
(-1.5,2.0)
-0.5
(-3.0,1.5)
0.0
(-1.8,2.0)
Patients with no deterioration/patients
evaluated (%)
c
13/64
(20%)
34/71
(48%)
35/71
(49%)
37/77
(48%)
44/66
(67%)
150/285
(53%)
HAQ change from baseline over time
e
(patients evaluated)
87
86
85
87
81
339
Mean ± SD
c
0.2 ± 0.3 0.4 ± 0.3 0
.5 ± 0.4
0.5 ± 0.5 0.4 ± 0.4 0.4 ± 0.4
a: control = All patients had active RA despite treatment with stable methotrexate doses for 6 months prior to enrolment and were to remain on stable
doses throughout the study. Concurrent use of stable doses of oral corticosteroids (≤ 10 mg/day) and/or NSAIDs was permitted, and folate
supplementation was given.
b: all infliximab doses given in combination with methotrexate and folate with some on corticosteroids and/or NSAIDs
c: p < 0.001, for each infliximab treatment group vs. control
d: greater values indicate more joint damage.
e: HAQ = Health Assessment Questionnaire; greater values indicate less disability.
The ASPIRE study evaluated responses at 54 weeks in 1,004 methotrexate naive patients with early
(≤3 years disease duration, median 0.6 years) active rheumatoid arthritis (median swollen and tender
joint count of 19 and 31, respectively). All patients received methotrexate (optimised to 20 mg/wk by
week 8) and either placebo, 3 mg/kg or 6 mg/kg infliximab at weeks 0, 2, and 6 and every 8 weeks
thereafter. Results from week 54 are shown in Table 4.
After 54 weeks of treatment, both doses of infliximab + methotrexate resulted in statistically
significantly greater improvement in signs and symptoms compared to methotrexate alone as measured
by the proportion of patients achieving ACR20, 50 and 70 responses.
In ASPIRE, more than 90% of patients had at least two evaluable X-rays. Reduction in the rate of
progression of structural damage was observed at weeks 30 and 54 in the infliximab + methotrexate
groups compared to methotrexate alone.
Table 4
Effects on ACRn, Structural Joint Damage and Physical Function at week 54, ASPIRE
19
Infliximab + MTX
Placebo + MTX
3 mg/kg
6 mg/kg
Combined
Subjects randomised
282
359
363
722
Percentage ACR improvement
Mean ± SD
a
24.8 ± 59.7
37.3 ± 52.8 42.0 ± 47.3 39.6 ± 50.1
Change from baseline in total van der
Heijde modified Sharp score
b
Mean ± SD
a
3.70 ± 9.61
0.42 ± 5.82 0.51 ± 5.55 0.46 ± 5.68
Median
0.43
0.00
0.00
0.00
Improvement from baseline in HAQ
averaged over time from week 30 to
week 54
c
Mean ± SD
d
0.68 ± 0.63
0.80 ± 0.65
0.88 ± 0.65 0.84 ± 0.65
a: p < 0.001, for each infliximab treatment group vs. control
b: greater values indicate more joint damage.
c: HAQ = Health Assessment Questionnaire; greater values indicate less disability.
d: p = 0.030 and < 0.001 for the 3mg/kg and 6mg/kg treatment groups respectively vs. placebo + MTX.
Data to support dose titration in rheumatoid arthritis come from ATTRACT, ASPIRE and the START
study. START was a randomised, multicenter, double-blind, 3-arm, parallel-group safety study. In one
of the study arms (group 2, n=329), patients with an inadequate response were allowed to dose titrate
with 1.5 mg/kg increments from 3 up to 9 mg/kg. The majority (67%) of these patients did not require
any dose titration. Of the patients who required a dose titration, 80% achieved clinical response and the
majority (64%) of these required only one adjustment of 1.5 mg/kg.
Adult Crohn’s disease
Induction treatment in severe active Crohn’s disease
The efficacy of a single dose treatment with infliximab was assessed in 108 patients with active
Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥ 220 ≤ 400) in a randomised, double-
blinded, placebo-controlled, dose-response study. Of these 108 patients, 27 were treated with the
recommended dosage of infliximab 5 mg/kg. All patients had experienced an inadequate response to
prior conventional therapies. Concurrent use of stable doses of conventional therapies was permitted,
and 92% of patients continued to receive these therapies.
The primary endpoint was the proportion of patients who experienced a clinical response, defined as a
decrease in CDAI by ≥ 70 points from baseline at the 4-week evaluation and without an increase in the
use of medicinal products or surgery for Crohn’s disease. Patients who responded at week 4 were
followed to week 12. Secondary endpoints included the proportion of patients in clinical remission at
week 4 (CDAI < 150) and clinical response over time.
At week 4, following administration of a single dose, 22/27 (81%) of infliximab-treated patients
receiving a 5 mg/kg dose achieved a clinical response vs. 4/25 (16%) of the placebo-treated patients
(p < 0.001). Also at week 4, 13/27 (48%) of infliximab-treated patients achieved a clinical remission
(CDAI < 150) vs. 1/25 (4%) of placebo-treated patients. A response was observed within 2 weeks,
with a maximum response at 4 weeks. At the last observation at 12 weeks, 13/27 (48%) of infliximab-
treated patients were still responding.
Maintenance treatment in severe active Crohn’s disease
The efficacy of repeated infusions with infliximab was studied in a 1-year clinical study (ACCENT I).
A total of 573 patients with moderately to severely active Crohn’s disease (CDAI ≥ 220 ≤ 400)
received a single infusion of 5 mg/kg at week 0. 178 of the 580 enrolled patients (30.7%) were defined
as having severe disease (CDAI score > 300 and concomitant corticosteroid and/or
immunosuppressants) corresponding to the population defined in the indication (see section 4.1).
At
week 2, all patients were assessed for clinical response and randomised to one of 3 treatment groups; a
20
placebo maintenance group, 5 mg/kg maintenance group and 10 mg/kg maintenance group. All 3
groups received repeated infusions at week 2, 6 and every 8 weeks thereafter.
Of the 573 patients randomised, 335 (58%) achieved clinical response by week 2. These patients were
classified as Week-2 responders and were included in the primary analysis (see Table 5). Among
patients classified as non-responders at week 2, 32% (26/81) in the placebo maintenance group and
42% (68/163) in the infliximab group achieved clinical response by week 6. There was no difference
between groups in the number of late responders thereafter.
The co-primary endpoints were the proportion of patients in clinical remission (CDAI<150) at week 30
and time to loss of response through week 54. Corticosteroid tapering was permitted after week 6.
Table 5: Effects on response and remission rate, data from ACCENT I (Week-2 responders)
ACCENT I (Week-2 responders)
% of Patients
Placebo
Maintenance
(n=110)
Infliximab
Maintenance
5 mg/kg
(n=113)
(p value)
Infliximab
Maintenance
10 mg/kg
(n=112)
(p value)
Median time to loss of response
through week 54
19 weeks
38 weeks
(0.002)
>54 weeks
(<0.001)
Week 30
Clinical Response
a
27.3
51.3
(<0.001)
59.1
(<0.001)
Clinical Remission
20.9
38.9
(0.003)
45.5
(<0.001)
Steroid-Free Remission
10.7 (6/56)
31.0 (18/58)
(0.008)
36.8 (21/57)
(0.001)
Week 54
Clinical Response
a
15.5
38.1
(<0.001)
47.7
(<0.001)
Clinical Remission
13.6
28.3
(0.007)
38.4
(<0.001)
Sustained Steroid-Free Remission
b
5.7 (3/53)
17.9 (10/56)
(0.075)
28.6 (16/56)
(0.002)
a: Reduction in CDAI ≥25% and ≥70 points.
b: CDAI<150 at both Week 30 and 54 and not receiving corticosteroids in the 3 months prior to Week 54 among patients
who were receiving corticosteroids at baseline.
Beginning at week 14, patients who had responded to treatment, but subsequently lost their clinical
benefit, were allowed to cross over to a dose of infliximab 5 mg/kg higher than the dose to which they
were originally randomised. Eighty-nine percent (50/56) of patients who lost clinical response on
infliximab 5 mg/kg maintenance therapy after week 14 responded to treatment with infliximab
10 mg/kg.
Improvements in quality of life measures, a reduction in disease-related hospitalizations and
corticosteroid use were seen in the infliximab maintenance groups compared with the placebo
maintenance group at weeks 30 and 54.
Induction treatment in fistulising active Crohn’s disease
The efficacy was assessed in a randomised, double-blinded, placebo-controlled study in 94 patients
with fistulising Crohn’s disease who had fistulae that were of at least 3 months’ duration. Thirty-one of
21
these patients were treated with infliximab 5 mg/kg. Approximately 93% of the patients had previously
received antibiotic or immunosuppressive therapy.
Concurrent use of stable doses of conventional therapies was permitted, and 83% of patients continued
to receive at least one of these therapies. Patients received three doses of either placebo or infliximab at
weeks 0, 2 and 6. Patients were followed up to 26 weeks. The primary endpoint was the proportion of
patients who experienced a clinical response, defined as ≥ 50% reduction from baseline in the number
of fistulae draining upon gentle compression on at least two consecutive visits (4 weeks apart), without
an increase in the use of medicinal products or surgery for Crohn’s disease.
Sixty-eight percent (21/31) of infliximab-treated patients receiving a 5 mg/kg dose regimen achieved a
clinical response vs. 26% (8/31) placebo-treated patients (p = 0.002). The median time to onset of
response in the infliximab-treated group was 2 weeks. The median duration of response was 12 weeks.
Additionally, closure of all fistulae was achieved in 55% of infliximab-treated patients compared with
13% of placebo-treated patients (p = 0.001).
Maintenance treatment in fistulising active Crohn’s disease
The efficacy of repeated infusions with infliximab in patients with fistulising Crohn’s disease was
studied in a 1-year clinical study (ACCENT II). A total of 306 patients received 3 doses of infliximab
5 mg/kg at week 0,2 and 6. At baseline, 87% of the patients had perianal fistulae, 14% had abdominal
fistulae, 9% had rectovaginal fistulae. The median CDAI score was 180. At week 14, 282 patients were
assessed for clinical response and randomised to receive either placebo or 5 mg/kg infliximab every
8 weeks through week 46.
Week-14 responders (195/282) were analyzed for the primary endpoint, which was time from
randomisation to loss of response (see Table 6). Corticosteroid tapering was permitted after week 6.
Table 6: Effects on response rate, data from ACCENT II (Week-14 responders)
ACCENT II (Week-14 responders)
Placebo
Maintenance
(n=99)
Infliximab
Maintenance
(5 mg/kg)
(n=96)
p-value
Median time to loss of response
through week 54
14 weeks
>40 weeks
< 0.001
Week 54
Fistula Response (%)
a
23.5
46.2
0.001
Complete fistula response (%)
b
19.4
36.3
0.009
a: A ≥50% reduction from baseline in the number of draining fistulas over a period of ≥4 weeks
b: Absence of any draining fistulas
Beginning at week 22, patients who initially responded to treatment and subsequently lost their
response were eligible to cross over to active re-treatment every 8 weeks at a dose of infliximab 5
mg/kg higher than the dose to which they were originally randomised. Among patients in the
infliximab 5 mg/kg group who crossed over because of loss of fistula response after week 22, 57%
(12/21) responded to re-treatment with infliximab 10 mg/kg every 8 weeks.
There was no significant difference between placebo and infliximab for the proportion of patients with
sustained closure of all fistulas through week 54, for symptoms such as proctalgia, abscesses and
urinary tract infection or for number of newly developed fistulas during treatment.
Maintenance therapy with infliximab every 8 weeks significantly reduced disease-related
hospitalisations and surgeries compared with placebo. Furthermore, a reduction in corticosteroid use
and improvements in quality of life were observed.
22
Paediatric Crohn’s disease (6 to17 years)
In the REACH study, 112 patients (6 to 17 years, median age 13.0 years) with moderate to severe,
active Crohn’s disease (median paediatric CDAI of 40) and an inadequate response to conventional
therapies were to receive 5 mg/kg infliximab at weeks 0, 2, and 6. All patients were required to be on a
stable dose of 6-MP, AZA or MTX (35% were also receiving corticosteroids at baseline). Patients
assessed by the investigator to be in clinical response at week 10 were randomized and received 5
mg/kg infliximab at either q8 weeks or q12 weeks as a maintenance treatment regimen. If response was
lost during maintenance treatment, crossing over to a higher dose (10 mg/kg) and/or shorter dosing
interval (q8 weeks) was allowed. Thirty-two (32) evaluable paediatric patients crossed over (9 subjects
in the q8 weeks and 23 subjects in the q12 weeks maintenance groups). Twenty-four of these patients
(75.0%) regained clinical response after crossing over.
The proportion of subjects in clinical response at week 10 was 88.4% (99/112). The proportion of
subjects achieving clinical remission at week 10 was 58.9% (66/112).
At week 30, the proportion of subjects in clinical remission was higher in the q8 week (59.6%, 31/52)
than the q12 week maintenance treatment group (35.3%, 18/51; p=0.013). At week 54, the figures were
55.8% (29/52) and 23.5% (12/51) in the q8 weeks and q12 weeks maintenance groups, respectively
(p<0.001).
Data about fistulas were derived from PCDAI scores. Of the 22 subjects that had fistulas at baseline,
63.6% (14/22), 59.1% (13/22) and 68.2% (15/22) were in complete fistula response at week 10, 30 and
54, respectively, in the combined q8 weeks and q12 weeks maintenance groups.
In addition, statistically and clinically significant improvements in quality of life and height, as well as
a significant reduction in corticosteroid use, were observed versus baseline.
Ulcerative colitis
The safety and efficacy of Remicade were assessed in two (ACT 1 and ACT 2) randomized, double-
blind, placebo-controlled clinical studies in adult patients with moderately to severely active ulcerative
colitis (Mayo score 6 to 12; Endoscopy subscore ≥ 2) with an inadequate response to conventional
therapies [oral corticosteroids, aminosalicylates and/or immunomodulators (6-MP, AZA)].
Concomitant stable doses of oral aminosalicylates, corticosteroids, and/or immunomodulatory agents
were permitted. In both studies, patients were randomized to receive either placebo, 5 mg/kg
Remicade, or 10 mg/kg Remicade at weeks 0, 2, 6, 14 and 22, and in ACT 1 at weeks 30, 38 and 46.
Corticosteroid taper was permitted after week 8.
Table 7
Effects on clinical response, clinical remission and mucosal healing at Weeks 8 and 30.
Combined data from ACT 1 & 2.
Infliximab
Placebo
5 mg/kg
10 mg/kg
Combined
Subjects randomized
244
242
242
484
Percentage of subjects in clinical response and in sustained clinical response
Clinical response at Week 8
a
33.2%
66.9%
65.3%
66.1%
Clinical response at Week 30
a
27.9%
49.6%
55.4%
52.5%
Sustained response
(clinical response at both
Week 8 and Week 30)
a
19.3%
45.0%
49.6%
47.3%
Percentage of subjects in clinical remission and sustained remission
Clinical remission at Week 8
a
10.2%
36.4%
29.8%
33.1%
Clinical remission at Week 30
a
13.1%
29.8%
36.4%
33.1%
Sustained remission
(in remission at both
Week 8 and Week 30)
a
5.3%
19.0%
24.4%
21.7%
Percentage of subjects with mucosal healing
23
Infliximab
Placebo
5 mg/kg
10 mg/kg
Combined
Mucosal healing at Week 8
a
32.4%
61.2%
60.3%
60.7%
Mucosal healing at Week 30
a
27.5%
48.3%
52.9%
50.6%
a: p < 0.001, for each infliximab treatment group vs. placebo
The efficacy of Remicade through week 54 was assessed in the ACT 1 study.
At 54 weeks, 44.9% of patients in the combined infliximab treatment group were in clinical response
compared to 19.8% in the placebo treatment group (p<0.001). Clinical remission and mucosal healing
occurred in a greater proportion of patients in the combined infliximab treatment group compared to
the placebo treatment group at week 54 (34.6% vs. 16.5%, p<0.001 and 46.1% vs. 18.2%, p<0.001,
respectively). The proportions of patients in sustained response and sustained remission at week 54
were greater in the combined infliximab treatment group than in the placebo treatment group (37.9%
vs. 14.0%, p<0.001; and 20.2% vs. 6.6%, p<0.001, respectively).
A greater proportion of patients in the combined infliximab treatment group were able to discontinue
corticosteroids while remaining in clinical remission compared to the placebo treatment group at both
week 30 (22.3% vs. 7.2%, p < 0.001, pooled ACT 1 & ACT 2 data) and week 54 (21.0% vs. 8.9%,
p=0.022, ACT1 data).
The pooled data analysis from the ACT 1 and ACT 2 studies and their extensions, analysed from
baseline through 54 weeks, demonstrated a reduction of ulcerative colitis related hospitalisations and
surgical procedures with infliximab treatment. The number of ulcerative colitis-related hospitalisations
was significantly lower in the 5 and 10 mg/kg infliximab treatment groups than in the placebo group
(mean number of hospitalisations per 100 subject-years: 21 and 19 vs 40 in the placebo group; p=0.019
and p=0.007, respectively). The number of ulcerative colitis-related surgical procedures was also lower
in the 5 and 10 mg/kg infliximab treatment groups than in the placebo group (mean number of surgical
procedures per 100 subject-years: 22 and 19 vs 34
;
p=0.145 and p=0.022, respectively).
The proportion of subjects who underwent colectomy at any time within 54 weeks following the first
infusion of study agent were collected and pooled from the ACT 1 and ACT 2 studies and their
extensions. Fewer subjects underwent colectomy in the 5 mg/kg infliximab group (28/242 or 11.6%
[N.S.]) and the 10 mg/kg infliximab group (18/242 or 7.4% [p=0.011]) than in the placebo group
(36/244; 14.8%).
The reduction in incidence of colectomy was also examined in another randomised, double-blind study
(C0168Y06) in hospitalised patients (n= 45) with moderately to severely active ulcerative colitis who
failed to respond to IV corticosteroids and who were therefore at higher risk for colectomy.
Significantly fewer colectomies occurred within 3 months of study infusion in patients who received a
single dose of 5 mg/kg infliximab compared to patients who received placebo (29.2% vs 66.7%
respectively, p=0.017).
In ACT 1 and ACT 2, infliximab improved quality of life, confirmed by statistically significant
improvement in both a disease specific measure, IBDQ, and by improvement in the generic 36-item
short form survey SF-36.
Ankylosing spondylitis
Efficacy and safety of infliximab were assessed in two multicenter, double-blind, placebo-controlled
studies in patients with active ankylosing spondylitis (Bath Ankylosing Spondylitis Disease Activity
Index [BASDAI] score ≥4 and spinal pain ≥4 on a scale of 1-10).
In the first study (P01522), which had a 3 month double-blind phase, 70 patients received either 5
mg/kg infliximab or placebo at weeks 0, 2, 6 (35 patients in each group). At week 12, placebo patients
24
were switched to infliximab 5 mg/kg every 6 weeks up to week 54. After the first year of the study, 53
patients continued into an open-label extension to week 102.
In the second clinical study (ASSERT), 279 patients were randomized to receive either placebo (Group
1, n=78) or 5 mg/kg infliximab (Group 2, n=201) at 0, 2 and 6 weeks and every 6 weeks to week 24.
Thereafter, all subjects continued on infliximab every 6 weeks to week 96. Group 1 received 5 mg/kg
infliximab. In group 2, starting with the week-36 infusion, patients who had a BASDAI ≥ 3 at 2
consecutive visits, received 7.5 mg/kg infliximab every 6 weeks thereafter through week 96.
In ASSERT, improvement in signs and symptoms was observed as early as week 2. At week 24, the
number of ASAS 20 responders was 15/78 (19%) in the placebo group, and 123/201 (61%) in the 5
mg/kg infliximab group (p<0.001). There were 95 subjects from group 2 who continued on 5 mg/kg
every 6 weeks. At 102 weeks there were 80 subjects still on infliximab treatment and among those, 71
(89%) were ASAS 20 responders.
In P01522, improvement in signs and symptoms was also observed as early as week 2. At week 12, the
number of BASDAI 50 responders were 3/35 (9%) in the placebo group, and 20/35 (57%) in the 5
mg/kg group (p<0.01). There were 53 subjects who continued on 5 mg/kg every 6 weeks. At 102
weeks there were 49 subjects still on infliximab treatment and among those, 30 (61%) were
BASDAI 50 responders.
In both studies, physical function and quality of life as measured by the BASFI and the physical
component score of the SF-36 were also improved significantly.
Psoriatic arthritis
Efficacy and safety were assessed in two multicenter, double-blind, placebo-controlled studies in
patients with active psoriatic arthritis.
In the first clinical study (IMPACT), efficacy and safety of infliximab were studied in 104 patients
with active polyarticular psoriatic arthritis. During the 16-week double-blind phase, patients received
either 5 mg/kg infliximab or placebo at weeks 0, 2, 6, and 14 (52 patients in each group). Starting at
week 16, placebo patients were switched to infliximab and all patients subsequently received 5 mg/kg
infliximab every 8 weeks up to week 46. After the first year of the study, 78 patients continued into an
open-label extension to week 98.
In the second clinical study (IMPACT 2), efficacy and safety of infliximab were studied in 200
patients with active psoriatic arthritis (≥ 5 swollen joints and ≥ 5 tender joints). Forty-six percent of
patients continued on stable doses of methotrexate (≤25 mg/week). During the 24-week double-blind
phase, patients received either 5 mg/kg infliximab or placebo at weeks 0, 2, 6, 14, and 22 (100 patients
in each group). At week 16, 47 placebo patients with < 10% improvement from baseline in both
swollen and tender joint counts were switched to infliximab induction (early escape). At week 24, all
placebo-treated patients crossed over to infliximab induction. Dosing continued for all patients through
week 46.
Key efficacy results for IMPACT and IMPACT 2 are shown in Table 8 below:
Table 8: Effects on ACR and PASI in IMPACT and IMPACT 2
IMPACT
IMPACT 2*
Placebo
(Week 16)
Infliximab
(Week 16)
Infliximab
(Week 98)
Placebo
(Week 24)
Infliximab
(Week 24)
Infliximab
(Week 54)
Patients randomized
52
52
N/A
a
100
100
100
ACR response
(% of patients)
N
52
52
78
100
100
100
25
ACR 20
response*
5(10%)
34 (65%)
48 (62%)
16 (16%)
54 (54%)
53 (53%)
ACR 50
response*
0(0%)
24 (46%)
35 (45%)
4 (4%)
41(41%)
33 (33%)
ACR 70
response*
0(0%)
15 (29%)
27 (35%)
2 (2%)
27 (27%)
20 (20%)
PASI response
(% of patients)
b
N
87
83
82
PASI 75 response**
1 (1%)
50 (60%)
40 (48.8%)
* ITT-analysis where subjects with missing data were included as non-responders
a Week 98 data for IMPACT includes combined placebo crossover and infliximab patients who entered the open-label extension
b Based on patients with PASI
>
2.5 at baseline for IMPACT, and patients with
>
3% BSA psoriasis skin involvement at baseline in IMPACT
2
** PASI 75 response for IMPACT not included due to low N; p<0.001 for infliximab vs. placebo at week 24 for IMPACT 2
In IMPACT and IMPACT 2, clinical responses were observed as early as week 2 and were maintained
through week 98 and week 54 respectively. Efficacy has been demonstrated with or without
concomitant use of methotrexate. Decreases in parameters of peripheral activity characteristic of
psoriatic arthritis (such as number of swollen joints, number of painful/tender joints, dactylitis and
presence of enthesopathy) were seen in the infliximab-treated patients.
Radiographic changes were assessed in IMPACT 2. Radiographs of hands and feet were collected at
baseline, weeks 24 and 54. Infliximab treatment reduced the rate of progression of peripheral joint
damage compared with placebo treatment at the week 24 primary endpoint as measured by change
from baseline in total modified vdH-S score (mean ± SD score was 0.82 ± 2.62 in the placebo group
compared with -0.70 ± 2.53 in the infliximab group; p< 0.001). In the infliximab group, the mean
change in total modified vdH-S score remained below 0 at the week 54 timepoint.
Infliximab-treated patients demonstrated significant improvement in physical function as assessed by
HAQ. Significant improvements in health-related quality of life were also demonstrated as measured
by the physical and mental component summary scores of the SF-36 in IMPACT 2.
Psoriasis
The efficacy of infliximab was assessed in two multicenter, randomised, double blind
studies: SPIRIT
and EXPRESS. Patients in both studies had plaque psoriasis (Body Surface Area [BSA] ≥10% and
Psoriasis Area and Severity Index [PASI] score ≥12). The primary endpoint in both studies was the
percent of patients who achieved ≥ 75% improvement in PASI from baseline at week 10.
SPIRIT evaluated the efficacy of infliximab induction therapy in 249 patients with plaque psoriasis
that had previously received PUVA or systemic therapy. Patients received either 3 or 5 mg/kg
infliximab or placebo infusions at weeks 0, 2 and 6. Patients with a PGA score ≥3 were eligible to
receive an additional infusion of the same treatment at week 26.
In SPIRIT, the proportion of patients achieving PASI 75 at week 10 was 71.7% in the 3 mg/kg
infliximab group, 87.9% in the 5 mg/kg infliximab group, and 5.9% in the placebo group (p < 0.001).
By week 26, twenty weeks after the last induction dose, 30% of patients in the 5mg/kg group and
13.8% of patients in the 3mg/kg group were PASI 75 responders. Between weeks 6 and 26, symptoms
of psoriasis gradually returned with a median time to disease relapse of > 20 weeks. No rebound was
observed.
EXPRESS evaluated the efficacy of infliximab induction and maintenance therapy in 378 patients with
plaque psoriasis. Patients received 5 mg/kg infliximab or placebo infusions at weeks 0, 2 and 6
followed by maintenance therapy every 8 weeks through week 22 in the placebo group and through
week 46 in the infliximab group. At week 24, the placebo group crossed over to infliximab induction
therapy (5 mg/kg) followed by infliximab maintenance therapy (5 mg/kg). Nail psoriasis was assessed
using the Nail Psoriasis Severity Index (NAPSI). Prior therapy with PUVA, methotrexate, cyclosporin,
or acitretin had been received by 71.4% of patients, although they were not necessarily therapy
resistant. Key results are presented in Table 9. In infliximab treated subjects, significant PASI 50
26
responses were apparent at the first visit (week 2) and PASI 75 responses by the second visit (week 6).
Efficacy was similar in the subgroup of patients that were exposed to previous systemic therapies
compared to the overall study population.
27
Table 9
Summary of PASI response, PGA response and percent of patients with all nails cleared at Weeks 10,
24 and 50. EXPRESS.
Placebo →
Infliximab
5 mg/kg
(at week 24)
Infliximab
5 mg/kg
Week 10
N
77
301
≥ 90% improvement
1 (1.3%)
172 (57.1%)
a
≥ 75% improvement
2 (2.6%)
242 (80.4%)
a
≥ 50% improvement
6 (7.8%)
274 (91.0%)
PGA of cleared (0) or minimal (1)
3 (3.9%)
242 (82.9%)
ab
PGA of cleared (0), minimal (1), or mild (2)
14 (18.2%)
275 (94.2%)
ab
Week 24
N
77
276
≥ 90% improvement
1 (1.3%)
161 (58.3%)
a
≥ 75% improvement
3 (3.9%)
227 (82.2%)
a
≥ 50% improvement
5 (6.5%)
248 (89.9%)
PGA of cleared (0) or minimal (1)
2 (2.6%)
203 (73.6%)
a
PGA of cleared (0), minimal (1), or mild (2)
15 (19.5%)
246 (89.1%)
a
Week 50
N
68
281
≥ 90% improvement
34 (50.0%)
127 (45.2%)
≥ 75% improvement
52 (76.5%)
170 (60.5%)
≥ 50% improvement
61 (89.7%)
193 (68.7%)
PGA of cleared (0) or minimal (1)
46 (67.6%)
149 (53.0%)
PGA of cleared (0), minimal (1), or mild (2)
59 (86.8%)
189 (67.3%)
All nails cleared
c
Week 10
1/65(1.5%)
16/235 (6.8% )
Week 24
3/65 (4.6%)
58/223 (26,0%)
a
Week 50
27/64 (42.2%)
92/226 (40.7%)
a: p < 0.001, for each infliximab treatment group vs. control
b: n = 292
c: Analysis was based on subjects with nail psoriasis at baseline (81.8% of subjects). Mean baseline NAPSI scores were 4.6
and 4.3 in infliximab and placebo group.
Significant improvements from baseline were demonstrated in DLQI (p<0.001) and the physical and
mental component scores of the SF 36 (p<0.001 for each component comparison).
5.2 Pharmacokinetic properties
Single intravenous infusions of 1, 3, 5, 10 or 20 mg/kg of infliximab yielded dose proportional
increases in the maximum serum concentration (C
max
) and area under the concentration-time curve
(AUC). The volume of distribution at steady state (median V
d
of 3.0 to 4.1 litres) was not dependent on
the administered dose and indicated that infliximab is predominantly distributed within the vascular
compartment. No time-dependency of the Pharmacokinetics was observed. The elimination pathways
for infliximab have not been characterised. Unchanged infliximab was not detected in urine. No major
age- or weight-related differences in clearance or volume of distribution were observed in rheumatoid
arthritis patients. The pharmacokinetics of infliximab in elderly patients has not been studied. Studies
have not been performed in patients with liver or renal disease.
28
At single doses of 3, 5, or 10 mg/kg, the median C
max
values were 77, 118 and 277 micrograms/ml,
respectively. The median terminal half-life at these doses ranged from 8 to 9.5 days. In most patients,
infliximab could be detected in the serum for at least 8 weeks after the recommended single dose of
5 mg/kg for Crohn’s disease and the rheumatoid arthritis maintenance dose of 3 mg/kg every 8 weeks.
Repeated administration of infliximab (5 mg/kg at 0, 2 and 6 weeks in fistulising Crohn´s disease, 3 or
10 mg/kg every 4 or 8 weeks in rheumatoid arthritis) resulted in a slight accumulation of infliximab in
serum after the second dose. No further clinically relevant accumulation was observed. In most
fistulising Crohn’s disease patients, infliximab was detected in serum for 12 weeks (range 4-28 weeks)
after administration of the regimen.
Overall, serum levels in paediatric patients with Crohn's disease (53 patients aged 6 to 17 years old; 8
patients aged 6 to 10 years old) were similar to those in adult Crohn's disease patients. The median
terminal half-life for the 5 mg/kg dose in paediatric patients with Crohn's disease is 10.9 days.
5.3 Preclinical safety data
Infliximab does not cross react with TNF
α
from species other than human and chimpanzees. Therefore,
conventional preclinical safety data with infliximab are limited. In a developmental toxicity study
conducted in mice using an analogous antibody that selectively inhibits the functional activity of
mouse TNF
α
, there was no indication of maternal toxicity, embryotoxicity or teratogenicity. In a
fertility and general reproductive function study, the number of pregnant mice was reduced following
administration of the same analogous antibody. It is not known whether this finding was due to effects
on the males and/or the females. In a 6-month repeated dose toxicity study in mice, using the same
analogous antibody against mouse TNF
α
, crystalline deposits were observed on the lens capsule of
some of the treated male mice. No specific ophthalmologic examinations have been performed in
patients to investigate the relevance of this finding for humans.
Long-term studies have not been performed to evaluate the carcinogenic potential of infliximab.
Studies in mice deficient in TNF
α
demonstrated no increase in tumours when challenged with known
tumour initiators and/or promoters.
6.
6.1 List of excipients
Sucrose
Polysorbate 80
Monobasic sodium phosphate
Dibasic sodium phosphate
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
3 years.
Chemical and physical in use stability of the reconstituted solution has been demonstrated for 24 hours
at 25°C. From a microbiological point of view, the product should be used as soon as possible but
within 3 hours of reconstitution and dilution. If not used immediately, in use storage times and
conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2 to
8°C.
29
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C).
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
Type 1 glass vial with rubber stopper and aluminium crimp protected by a plastic cap, containing
100 mg of infliximab.
Remicade is available in packs of 1, 2, 3, 4 or 5 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
1.
Calculate the dose and the number of Remicade vials needed. Each Remicade vial contains
100 mg infliximab. Calculate the total volume of reconstituted Remicade solution required.
2.
Under aseptic conditions, reconstitute each Remicade vial with 10 ml of water for injections,
using a syringe equipped with a 21-gauge (0.8 mm) or smaller needle. Remove flip-top from the
vial and wipe the top with a 70% alcohol swab. Insert the syringe needle into the vial through
the centre of the rubber stopper and direct the stream of water for injections to the glass wall of
the vial. Do not use the vial if the vacuum is not present. Gently swirl the solution by rotating
the vial to dissolve the lyophilised powder. Avoid prolonged or vigorous agitation. DO NOT
SHAKE. Foaming of the solution on reconstitution is not unusual. Allow the reconstituted
solution to stand for 5 minutes. Check that the solution is colourless to light yellow and
opalescent. The solution may develop a few fine translucent particles, as infliximab is a protein.
Do not use if opaque particles, discolouration, or other foreign particles are present.
3.
Dilute the total volume of the reconstituted Remicade solution dose to 250 ml with sodium
chloride 9 mg/ml (0.9%) solution for infusion. This can be accomplished by withdrawing a
volume of the sodium chloride 9 mg/ml (0.9%) solution for infusion from the 250-ml glass
bottle or infusion bag equal to the volume of reconstituted Remicade. Slowly add the total
volume of reconstituted Remicade solution to the 250-ml infusion bottle or bag. Gently mix.
4.
Administer the infusion solution over a period of not less than the infusion time recommended
for the specific indication. Use only an infusion set with an in-line, sterile, non-pyrogenic, low
protein-binding filter (pore size 1.2 micrometer or less). Since no preservative is present, it is
recommended that the administration of the solution for infusion is to be started as soon as
possible and within 3 hours of reconstitution and dilution. When reconstitution and dilution are
performed under aseptic conditions, Remicade infusion solution can be used within 24 hours if
stored at 2°C to 8°C. Do not store any unused portion of the infusion solution for reuse.
5.
No physical biochemical compatibility studies have been conducted to evaluate the co-
administration of Remicade with other agents. Do not infuse Remicade concomitantly in the
same intravenous line with other agents.
6.
Visually inspect Remicade for particulate matter or discolouration prior to administration. Do
not use if visibly opaque particles, discolouration or foreign particles are observed.
7.
Any unused product or waste material should be disposed of in accordance with local
requirements.
30
7.
Janssen Biologics B.V.
Einsteinweg 101
2333 CB Leiden
The Netherlands
8.
EU/1/99/116/001
EU/1/99/116/002
EU/1/99/116/003
EU/1/99/116/004
EU/1/99/116/005
9.
Date of first authorisation: 13 August 1999.
Date of latest renewal: 2 July 2009.
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
31
ANNEX II
A.
MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE
SUBSTANCE(S) AND MANUFACTURING
AUTHORISATION HOLDER(S) RESPONSIBLE FOR
BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
32
A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Names and addresses of the manufacturer(s) of the biological active substance(s)
Janssen Biologics B.V., Einsteinweg 101, 2333 CB Leiden, The Netherlands
Centocor Inc., 200 Great Valley Parkway Malvern, Pennsylvania 19355-1307, United States of
America
Name and address of the manufacturer(s) responsible for batch release
Janssen Biologics B.V., Einsteinweg 101, 2333 CB Leiden, The Netherlands
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The Marketing Authorisation Holder (MAH) shall develop an educational programme for
Remicade to include paediatric Crohn’s disease patients to ensure that physicians who intend to
prescribe Remicade to these patients are aware of:
•
The risk of opportunistic infections and tuberculosis (TB) in patients treated with
Remicade.
•
The need to assess the risk of TB in patients prior to treating with Remicade.
•
The risk of acute infusion related reactions and delayed hypersensitivity reactions.
•
The risk of lymphoma and other malignancies.
•
The patient alert card, which is to be given to patients using Remicade.
•
That children may be at increased risk of developing infections and the need for
immunisations to be up to date.
•
OTHER CONDITIONS
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the pharmacovigilance plan, as agreed in version 2.0 of the Risk Management Plan (RMP) presented in
Module 1.8.2 of the marketing authorisation and any subsequent updates of the RMP agreed by the
CHMP.
As per the CHMP guideline on the risk management systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).
In addition, an updated RMP should be submitted:
33
•
When new information is received that may impact on the current safety specification,
pharmacovigilance plan or risk minimisation activities.
•
Within 60 days of an important (pharmacovigilance or minimisation) milestone being reached.
•
At the request of the European Medicines Agency.
The MAH will continue to submit annual PSURs.
34
ANNEX III
LABELLING AND PACKAGE LEAFLET
35
A. LABELLING
36
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Remicade 100 mg powder for concentrate for solution for infusion
Infliximab
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 100 mg of infliximab.
3.
LIST OF EXCIPIENTS
Excipients: sucrose, polysorbate 80, monobasic sodium phosphate and dibasic sodium phosphate.
4.
1 vial 100 mg
2 vials 100 mg
3 vials 100 mg
4 vials 100 mg
5 vials 100 mg
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous infusion after reconstitution and dilution.
Read the package leaflet before reconstitution and use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C – 8°C).
37
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Discard any unused solution in accordance with local requirements.
Marketing Authorisation Holder:
Janssen Biologics B.V.
Einsteinweg 101
2333 CB Leiden
The Netherlands
12.
EU/1/99/116/001 1 vial 100 mg
EU/1/99/116/002 2 vials 100 mg
EU/1/99/116/003 3 vials 100 mg
EU/1/99/116/004 4 vials 100 mg
EU/1/99/116/005 5 vials 100 mg
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
38
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
Remicade 100 mg powder for concentrate for solution for infusion
Infliximab
Intravenous use
2.
METHOD
OF ADMINISTRATION
For intravenous infusion after reconstitution and dilution.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
100 mg
6.
OTHER
Store in a refrigerator (2°C – 8°C).
Janssen Biologics B.V., Einsteinweg 101, 2333 CB Leiden, The Netherlands
39
Remicade
infliximab
Patient Alert Card
Infections
Before treatment with Remicade
•
Tell your doctor if you have an infection even
if it is a very minor one
•
It is very important that you tell your doctor if
you have ever had TB, or if you have been in
close contact with someone who has had TB.
Your doctor will test you to see if you have
TB. Ask your doctor to record the type and
date of your last screening(s) for TB on the
card
•
Tell your doctor if you have hepatitis B or if
you know or suspect you are a carrier of the
hepatitis B virus.
Patient:
Doctor:
Telephone:
This Alert Card contains important safety
information that you need to be aware of before
and during treatment with Remicade.
Show this card to any doctor involved in your
treatment.
Please read the Remicade ‘Package Leaflet’
carefully before you start using this medicine.
During treatment with Remicade
•
Tell your doctor straight away if you have
signs of an infection. Signs include a fever,
feeling tired, (persistent) cough, shortness of
breath, weight loss, night sweats, diarrhea,
wounds, dental problems, burning when
urinating or ‘flu-like’ signs.
Date of Remicade therapy initiation:
Current administrations:
When starting a new card, please keep this card as
a reference for four months after this date.
Heart Failure
Before treatment with Remicade
•
Tell your doctor if you have any heart
problems such as mild heart failure.
Ask your doctor to record the type and date of last
screening(s) for TB below:
Test Test
Date Date
Result: Result:
During treatment with Remicade
•
Tell your doctor straight away if you notice
signs of a heart problem. Signs include
shortness of breath, swelling of the feet or
changes in your heartbeat.
List of allergies
Please make sure you also have a list of all other
medicines that you are using with you at any visit
to a healthcare professional.
List of other medicines
Keep this card with you for 4 months after your
last dose of Remicade. Side effects may occur a
long time after your last dose.
40
B. PACKAGE LEAFLET
41
PACKAGE LEAFLET: INFORMATION FOR THE USER
Remicade 100 mg powder for concentrate for solution for infusion
Infliximab
Read all of this leaflet carefully before you start using this medicine.
•
Keep this leaflet. You may need to read it again.
•
Your doctor will also give you a Patient Alert Card, which contains important safety information
you need to be aware of before and during your treatment with Remicade.
•
If you have any further questions, ask your doctor.
•
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
•
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
1.
What Remicade is and what it is used for
2.
Before you are given Remicade
3.
How Remicade will be given
4.
Possible side effects
5.
How to store Remicade
6.
Further information
1.
WHAT REMICADE IS AND WHAT IT IS USED FOR
Remicade contains the active substance called infliximab. Infliximab is a type of protein of human and
mouse origin.
Remicade belongs to a group of medicines called ‘TNF blockers’. It is used in adults for the following
inflammatory diseases:
•
Rheumatoid arthritis
•
Psoriatic arthritis
•
Ankylosing spondylitis (Bechterew’s disease)
•
Psoriasis
•
Ulcerative colitis
Remicade is also used in adults and children 6 years of age or older for:
•
Crohn’s disease.
Remicade works by blocking the action of a protein called ‘tumour necrosis factor alpha’ (TNF
α
). This
protein is involved in inflammatory processes of the body and blocking it can reduce the inflammation
in your body.
Rheumatoid arthritis
Rheumatoid arthritis is an inflammatory disease of the joints
.
If you have active rheumatoid arthritis
you will first be given other medicines. If you do not respond well enough to these medicines, you will
be given Remicade which you will take in combination with another medicine called methotrexate to:
•
Reduce the signs and symptoms of your disease,
•
Slow down the damage in your joints,
•
Improve your physical function.
Psoriatic arthritis
42
Psoriatic arthritis is an inflammatory disease of the joints, usually accompanied by psoriasis. If you
have active psoriatic arthritis you will first be given other medicines. If you do not respond well
enough to these medicines, you will be given Remicade to:
•
Reduce the signs and symptoms of your disease,
•
Slow down the damage in your joints,
•
Improve your physical function.
Ankylosing spondylitis (Bechterew’s disease)
Ankylosing spondylitis is an inflammatory disease of the spine. If you have ankylosing spondylitis you
will first be given other medicines. If you do not respond well enough to these medicines, you will be
given Remicade to:
•
Reduce the signs and symptoms of your disease,
•
Improve your physical function.
Psoriasis
Psoriasis is an inflammatory disease of the skin. If you have moderate to severe plaque psoriasis, you
will first be given other medicines or treatments, such as phototherapy. If you do not respond well
enough to these medicines or treatments, you will be given Remicade to reduce the signs and
symptoms of your disease.
Ulcerative colitis
Ulcerative colitis is an inflammatory disease of the bowel. If you have ulcerative colitis you will first
be given other medicines. If you do not respond well enough to these medicines, you will be given
Remicade to treat your disease.
Crohn’s disease
Crohn’s disease is an inflammatory disease of the bowel. If you have Crohn’s disease you will first be
given other medicines. If you do not respond well enough to these, you will be given Remicade to:
•
Treat serious, active Crohn’s disease,
•
Reduce the number of abnormal openings (fistulae) between your bowel and your skin that have
not been controlled by other medicines or surgery.
2.
BEFORE YOU ARE GIVEN REMICADE
You should not be given Remicade if:
•
You are allergic (hypersensitive) to infliximab (the active ingredient in Remicade) or to any of
the other ingredients in Remicade (listed in section 6)
•
You are allergic (hypersensitive) to proteins that come from mice
•
You have tuberculosis (TB) or another serious infection such as pneumonia or sepsis
•
You have heart failure that is moderate or severe.
Do not have Remicade if any of the above applies to you. If you are not sure, talk to your doctor before
you are given Remicade.
Take special care with Remicade
Check with your doctor before you are given Remicade if you have:
Tell your doctor if you have had treatment with Remicade in the past and are now starting
Remicade treatment again.
If you have had a break in your Remicade treatment of more than 16 weeks, there is a
higher risk for allergic reactions when you start the treatment again.
Infections
43
Had treatment with Remicade before
•
•
Tell your doctor if you have an infection even if it is a very minor one before you are
given Remicade
•
Tell your doctor if you have lived in or travelled to an area where infections called
histoplasmosis, coccidioidomycosis, or blastomycosis are common before you are given
Remicade. These infections are caused by
specific types of fungi
that can affect the lungs
or other parts of your body
•
You may get infections more easily when you are being treated with Remicade. If you are
65 or older, you have a greater risk
•
These infections may be serious and include tuberculosis, infections caused by viruses,
fungi or bacteria, or other opportunistic infections and sepsis that may, in rare cases, be
life-threatening.
Tell your doctor straight away if you get signs of infection during treatment with Remicade.
Signs include fever, cough, flu-like signs, feeling unwell, red or hot skin, wounds or dental
problems. Your doctor may recommend temporary discontinuation of Remicade.
Tuberculosis (TB)
•
It is very important that you tell your doctor if you have ever had TB or if you have been
in close contact with someone who has had or has TB
•
Your doctor will test you to see if you have TB. Cases of TB have been reported in
patients treated with Remicade. Your doctor will record these tests on your Patient Alert
Card
•
If your doctor feels that you are at risk for TB, you may be treated with medicines for TB
before you are given Remicade.
Tell your doctor straight away if you get signs of TB during treatment with Remicade. Signs
include persistent cough, weight loss, feeling tired, fever, night sweats.
Hepatitis B virus (HBV)
•
Tell your doctor if you are a carrier or if you have or have had hepatitis B before you are
given Remicade
•
Tell your doctor if you think you might be at risk of contracting HBV
•
Your doctor should test you for HBV
•
Treatment with TNF blockers such as Remicade may result in reactivation of hepatitis B
virus in patients who carry this virus, which can be life-threatening in some cases.
Heart problems
•
Tell your doctor if you have any heart problems, such as mild heart failure
•
Your doctor will want to closely monitor your heart function.
Tell your doctor straight away if you get new or worsening signs of heart failure during
treatment with Remicade. Signs include shortness of breath or swelling of your feet.
Cancer and lymphoma
•
Tell your doctor if you have or have ever had lymphoma (a type of blood cancer) or any
other cancer before you are given Remicade
•
Patients with severe rheumatoid arthritis, who have had the disease for a long time, may
be at higher than average risk of developing lymphoma
•
Children and adults taking Remicade may have an increased risk of developing lymphoma
or another cancer
•
Some children and teenage patients who have received TNF-blockers such as Remicade
have developed cancers, including unusual types, which sometimes resulted in death
•
Some patients with Crohn's disease or ulcerative colitis who have received Remicade have
developed a rare type of cancer called Hepatosplenic T-cell Lymphoma. Most of these
patients were adolescent or young adult males. This type of cancer has usually resulted in
death. All of these patients had also received drugs known as azathioprine or 6-
mercaptopurine.
Lung disease or heavy smoking
44
•
Tell your doctor if you have a lung disease called Chronic Obstructive Pulmonary Disease
(COPD) or if you are a heavy smoker, before you are given Remicade
•
Patients with COPD and patients who are heavy smokers may have a higher risk of
developing cancer with Remicade treatment.
Nervous system disease
•
Tell your doctor if you have or have ever had a problem that affects your nervous system
before you are given Remicade. This includes multiple sclerosis, Guillain-Barre
syndrome, if you have fits or have been diagnosed with ‘optic neuritis’.
Tell your doctor straight away if you get symptoms of a nerve disease during treatment with
Remicade. Signs include changes in your vision, weakness in your arms or legs, numbness or
tingling in any part of your body.
Abnormal skin openings
•
Tell your doctor if you have any abnormal skin openings (fistulae) before you are given
Remicade.
Vaccinations
•
Talk to your doctor if you recently have had or are due to have a vaccine
•
You should not receive certain vaccines while using Remicade
•
Certain vaccinations may cause infections. If you received Remicade while you were
pregnant, your baby may be at higher risk for getting such an infection for up to
approximately six months after the last dose you received during pregnancy. It is
important that you tell your baby's doctors and other health care professionals about your
Remicade use so they can decide when your baby should receive any vaccine.
Operations or dental procedures
•
Tell your doctor if you are going to have any operations or dental procedures
•
Tell your surgeon or dentist performing the procedure that you are having treatment with
Remicade by showing them your Patient Alert Card.
If you are not sure if any of the above apply to you, talk to your doctor before you are given Remicade.
Using other medicines
Patients who have inflammatory diseases already take medicines to treat their problem. These
medicines may cause side effects. Your doctor will advise you what other medicines you must keep
using while you are having Remicade.
Tell your doctor if you are using or have recently used any other medicines, including medicines
obtained without a prescription, such as vitamins and herbal medicines.
In particular, tell your doctor if you are using any of the following medicines:
•
Medicines that affect your immune system
•
Kineret (anakinra). Remicade and Kineret should not be used together
•
Orencia (abatacept). Remicade and Orencia should not be used together.
If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before using
Remicade.
Pregnancy and breast-feeding
•
Talk to your doctor before you are given Remicade if you are pregnant or might become
pregnant
•
Remicade is not recommended for use during pregnancy
•
You must avoid getting pregnant when you are being treated with Remicade and for 6 months
after you stop being treated with it. Make sure you use contraception during this time
45
•
Do not breast-feed when you are being treated with Remicade or for 6 months after your last
treatment with Remicade
•
If you received Remicade during your pregnancy, your baby may have a higher risk for getting
an infection. It is important that you tell your baby’s doctors and other health care professionals
about your Remicade use before the baby receives any vaccine (for more information see section
on vaccination).
Driving and using machines
Remicade is not likely to affect your ability to drive or use tools or machines. If you feel tired or
unwell after having Remicade, do not drive or use any tools or machines.
3.
HOW REMICADE WILL BE GIVEN
How Remicade is given
•
Remicade will be given to you by your doctor or nurse, in a hospital or clinic
•
Your doctor or nurse will prepare the Remicade solution for injection
•
The Remicade solution will be slowly injected (over a 2 hour period) into one of your veins.
This will usually be in your arm. This is called an ‘intravenous infusion’ or drip
•
You will be monitored while you are given Remicade and also for 1 to 2 hours after.
How much Remicade is given
•
The doctor will decide your dose (in mg) and how often you will be given Remicade. This will
depend on your disease, weight and how well you respond to Remicade
•
The table below shows how often you will usually have this medicine.
1
st
treatment
0 weeks
2
nd
treatment
2 weeks after your 1
st
treatment
3
rd
treatment
6 weeks after your 1
st
treatment
Further treatments
Every 6 to 8 weeks depending on your disease
Rheumatoid arthritis
The usual dose is 3 mg for every kg of body weight. After the third treatment, your doctor may
decide to give you Remicade over a 1 hour period.
Psoriatic arthritis, ankylosing spondylitis (Bechterew’s disease), psoriasis, ulcerative colitis
and Crohn's disease
The usual dose is 5 mg for every kg of body weight.
Use in children
Remicade should only be used in children if they are being treated for Crohn’s disease. These children
must be 6 years of age or older.
If you are given too much Remicade
As this medicine is being given by your doctor or nurse, it is unlikely that you will be given too much.
There are no known side effects of having too much of Remicade.
If you forget or miss your Remicade infusion
If you forget or miss an appointment to receive Remicade, make another appointment as soon as
possible.
If you have any further questions on the use of this medicine, ask your doctor.
4.
POSSIBLE SIDE EFFECTS
46
Like all medicines, Remicade can cause side effects, although not everybody gets them. Most side
effects are mild to moderate. However some patients may experience serious side effects and may
require treatment. Side effects may also occur after your treatment with Remicade has stopped.
Tell your doctor straight away if you notice any of the following:
•
Signs of an allergic reaction
such as swelling of your face, lips, mouth or throat which may
cause difficulty in swallowing or breathing, skin rash, hives, swelling of the hands, feet or
ankles. An allergic reaction could happen within 2 hours of your injection or later. More signs of
an allergic reaction that may happen up to 12 days after your injection include pain in the
muscles, fever, joint or jaw pain, sore throat or headache
•
Signs of a heart problem
such as shortness of breath, swelling of your feet or changes in your heart
beat
•
Signs of infection (including TB)
such as fever, feeling tired, (persistent) cough, shortness of
breath, flu-like symptoms, weight loss, night sweats, diarrhoea, wounds, dental problems or
burning when urinating
•
Signs of a lung problem
such as coughing,
breathing difficulties or tightness in the chest
•
Signs of a nervous system problem (including eye problems)
such as fits, tingling or
numbness in any part of your body, weakness in arms or legs, changes in eyesight such as
double vision or other eye problems
•
Signs of a liver problem
such as yellowing of the skin or eyes, dark-brown coloured urine or
pain in the upper right side of the stomach area, fever
•
Signs of an immune system disorder called lupus
such as joint pain or a rash on cheeks or
arms that is sensitive to the sun
•
Signs of a low blood count
such as persistent fever, bleeding or bruising more easily or looking
pale.
Tell your doctor straight away if you notice any of the above.
Common side effects (affects 1 to 10 patients in 100)
•
Increase in liver enzymes (shown in blood tests taken by your doctor)
•
Allergic reactions to foreign proteins
•
Lung or chest infections such as bronchitis or pneumonia
•
Difficult or painful breathing, chest pain
•
Stomach pain, diarrhoea, feeling sick or indigestion
•
Nettle-type rash (hives), itchy rash or dry skin
•
Viral infections such as herpes or flu
•
Balance problems or feeling dizzy
•
Fever, increased sweating
•
Warm, red skin (flushing)
•
Feeling tired or weak
•
Sinus infections
•
Headache.
Uncommon side effects (affects 1 to 10 patients in 1,000)
•
Circulation problems such as low or high blood pressure, shortage of blood supply, swelling or
narrowing of a vein, bruising, hot flush or nosebleed
•
Skin problems such as blistering, boils, eczema, warts, abnormal skin colouration or
pigmentation, hair loss or swollen lips
•
Severe allergic reactions (e.g. anaphylaxis), an immune system disorder called lupus
•
Reactions where you have had the injection such as pain, swelling, redness or itching
•
Wounds taking longer to heal, chills, or a build up of fluid under the skin causing swelling
•
Swelling of the gall bladder or changes in how your liver works (shown in blood tests)
•
Depression, feeling forgetful, irritable, confused, nervous, lack of interest or emotion
•
Eye problems including blurred or reduced vision, red or puffy eyes or sties
47
•
Problems sleeping
•
Bacterial infections such as blood poisoning, abscess or infection under the skin (cellulitis)
•
Heart problems (such as worsening of existing heart failure)
•
Nervous system disorders (multiple sclerosis-like disease)
•
Stomach pain or cramps, heartburn, constipation
•
Fungal infections such as yeast infection
•
Lung problems (such as oedema)
•
Pain in the joints, muscles or back
•
Kidney or urinary tract infections
•
Blood problems such as anaemia
•
Infections of the vagina.
Rare side effects (affects 1 to 10 patients in 10,000)
•
A type of blood cancer (lymphoma)
•
Bleeding or a hole around the stomach area or blockage of the intestine
•
Your blood not supplying enough oxygen to your body
•
Inflammation of the lining of the brain (meningitis)
•
Too much fluid around the lungs (pleural effusion)
•
Abnormal tissue swelling or growth
•
Swelling of the liver (hepatitis)
•
Fast heart beat (tachycardia)
•
Immune disorders that could affect the lungs, skin and lymph nodes (such as sarcoidosis).
Other side effects (the frequency is unknown)
•
Cancer in children and adults
•
A rare blood cancer affecting young people (hepatosplenic T-cell lymphoma)
•
Psoriasis,serious skin problems such as toxic epidermal necrolysis, Stevens-Johnson Syndrome
or erythema multiforme
•
Serious nervous system disorders such as Guillain-Barré syndrome, optic neuritis or transverse
myelitis
•
A build up of fluid in the lining of the heart (pericardial effusion)
•
Hepatitis B infection when you have had hepatitis B in the past
•
Serious lung problems (such as interstitial lung disease)
•
Infections due to a weakened immune system
•
Swelling of small blood vessels (vasculitis)
•
Swelling of your pancreas (pancreatitis)
•
Infection with Salmonella bacteria
•
Liver failure or liver damage.
If any of the side effects gets serious or if you notice any side effects that are not listed in this leaflet,
please tell your doctor.
5.
HOW TO STORE REMICADE
Remicade will be stored by the health professionals at the hospital or clinic. The storage details should
you need them are as follows:
•
Keep out of the reach and sight of children
•
Do not use Remicade after the expiry date which is stated on the label and the carton. The expiry
date refers to the last day of that month
•
Store in a refrigerator (2°C to 8°C).
•
It is recommended that when Remicade is prepared for infusion, it is used as soon as possible
(within 3 hours). However, if the solution is prepared in germ-free conditions, it can be stored in
a refrigerator at 2°C to 8°C for 24 hours
48
The solution should not be used if discoloured or if there are particles present.
6.
FURTHER INFORMATION
What Remicade contains
•
The active substance is infliximab. Each vial contains 100 mg of infliximab. After preparation
each ml contains 10 mg of infliximab
•
The other ingredients are sucrose, polysorbate 80, monobasic sodium phosphate and dibasic
sodium phosphate.
What Remicade looks like and contents of the pack
Remicade is supplied as a glass vial containing a powder for concentrate for solution for infusion. The
powder is a freeze-dried white pellet.
Remicade is produced in packs of 1, 2, 3, 4 or 5 vials. Not all pack sizes may be marketed.
Marketing Authorisation Holder
Janssen Biologics B.V.
Einsteinweg 101
2333 CB Leiden
The Netherlands
Manufacturer
Janssen Biologics B.V.
Einsteinweg 101
2333 CB Leiden
The Netherlands
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Rue de Stalle/Stallestraat 73
B-1180 Bruxelles/Brussel/Brüssel
Tél/Tel: + 32-(0)2 370 92 11
Luxembourg/Luxemburg
Rue de Stalle 73
B-1180 Bruxelles/Brüssel
Belgique/Belgien
Tél/Tel: + 32-(0)2 370 92 11
България
Ийст Парк Трейд Център
Бул. „Н.Й.Вапцаров” 53А, ет. 2
BG-София 1407
Тел.: +359 2 806 3030
Magyarország
Alkotás u. 53
H-1123 Budapest
Tel.:+36 1 457-8500
Česká republika
Ke Štvanici 3
CZ-186 00 Praha 8
Tel: +420 221771250
Malta
Triq l-Esportaturi
Mrieħel
Birkirkara BKR 3000
Tel.: +35622778000
Danmark
Lautrupbjerg 2
DK-2750 Ballerup
Tlf: + 45-44 39 50 00
Nederland
Walmolen 1
NL-3994 DL Houten
Tel: + 31-(0)800 999 90 00
Deutschland
Norge
49
Thomas-Dehler-Straße 27
D-81737 München
Tel: + 49-(0)89 627 31-0
Pb. 398
N-1326 Lysaker
Tlf: + 47 67 16 64 50
Eesti
Järvevana tee 9
EE-11314 Tallinn
Tel: + 372 654 96 86
Österreich
Am Euro Platz 2
A-1120 Wien
Tel: +43 (0) 1 26 044
Ελλάδα
Αγίου Δημητρίου 63
GR-174 55 Άλιμος
Τηλ: + 30-210 98 97 300
Polska
ul. Taśmowa 7
PL-02-677 Warszawa
Tel.: + 48-(0)22 478 41 50
España
Josefa Valcárcel, 38
E-28027 Madrid
Tel: + 34 91 3210600
Portugal
Rua Agualva dos Açores 16
P-2735-557 Agualva-Cacém
Tel: + 351-21 433 93 00
France
34 avenue Léonard de Vinci
F-92400 Courbevoie
Tél: + 33-(0)1 80 46 40 40
România
Şos. Bucureşti-Ploieşti, nr. 17-21, Băneasa Center,
et. 8, sector 1
Bucureşti, 013682-RO
Tel. + 40 21 233 35 30
Ireland
Shire Park
Welwyn Garden City
Hertfordshire AL7 1TW
United Kingdom
Tel: + 44-(0)1 707 363 636
Slovenija
Dunajska 22
SI-1000 Ljubljana
Tel. + 386 01 3001070
Ísland
Hörgatún 2
IS-210 Garðabær
Sími: + 354 535 70 00
Slovenská republika
Strakova 5
SK-811 01 Bratislava
Tel.: + 421 (2) 5920 2712
Italia
Via fratelli Cervi snc
Centro Direzionale Milano Due
Palazzo Borromini
I-20090 Segrate (Milano)
Tel: + 39-02 21018.1
Suomi/Finland
PL 86/PB 86
FIN-02151 Espoo/Esbo
Puh/Tel: + 358-(0)20-7570 300
Κύπρος
Οδός Αγίου Νικολάου, 8
CY-1055 Λευκωσία
Τηλ: +357-22 757188
Sverige
Box 7125
S-192 07 Sollentuna
Tel: + 46-(0)8 626 14 00
Latvija
Bauskas 58a -401
Rīga LV-1004
Tel: + 371-7 21 38 25
United Kingdom
Shire Park
Welwyn Garden City
Hertfordshire AL7 1TW
Tel: + 44-(0)1707 363 636
Lietuva
Kęstučio g. 65/40
50
LT 08124 Vilnius
Tel. + 370 52 101 868
This leaflet was last approved in {MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
. There are also links to other websites about rare diseases and treatments.
51
THE FOLLOWING INFORMATION IS INTENDED FOR MEDICAL OR HEALTHCARE
PROFESSIONALS ONLY:
Instructions for use and handling – reconstitution, dilution and administration
1.
Calculate the dose and the number of Remicade vials needed. Each Remicade vial contains
100 mg infliximab. Calculate the total volume of reconstituted Remicade solution required.
2.
Under aseptic conditions, reconstitute each Remicade vial with 10 ml of water for injections,
using a syringe equipped with a 21-gauge (0.8 mm) or smaller needle. Remove flip-top from the
vial and wipe the top with a 70% alcohol swab. Insert the syringe needle into the vial through
the centre of the rubber stopper and direct the stream of water for injections to the glass wall of
the vial. Do not use the vial if the vacuum is not present. Gently swirl the solution by rotating
the vial to dissolve the lyophilised powder. Avoid prolonged or vigorous agitation. DO NOT
SHAKE. Foaming of the solution on reconstitution is not unusual. Allow the reconstituted
solution to stand for 5 minutes. Check that the solution is colourless to light yellow and
opalescent. The solution may develop a few fine translucent particles, as infliximab is a protein.
Do not use if opaque particles, discolouration, or other foreign particles are present.
3.
Dilute the total volume of the reconstituted Remicade solution dose to 250 ml with sodium
chloride 9 mg/ml (0.9%) solution for infusion. This can be accomplished by withdrawing a
volume of the sodium chloride 9 mg/ml (0.9%) solution for infusion from the 250-ml glass
bottle or infusion bag equal to the volume of reconstituted Remicade. Slowly add the total
volume of reconstituted Remicade solution to the 250-ml infusion bottle or bag. Gently mix.
4.
Administer the infusion solution over a period of not less than the infusion time recommended
for the specific indication. Use only an infusion set with an in-line, sterile, non-pyrogenic, low
protein-binding filter (pore size 1.2 micrometer or less). Since no preservative is present, it is
recommended that the administration of the solution for infusion is to be started as soon as
possible and within 3 hours of reconstitution and dilution. When reconstitution and dilution are
performed under aseptic conditions, Remicade infusion solution can be used within 24 hours if
stored at 2°C to 8°C. Do not store any unused portion of the infusion solution for reuse.
5.
No physical biochemical compatibility studies have been conducted to evaluate the co-
administration of Remicade with other agents. Do not infuse Remicade concomitantly in the
same intravenous line with other agents.
6.
Visually inspect Remicade for particulate matter or discolouration prior to administration. Do
not use if visibly opaque particles, discolouration or foreign particles are observed.
7.
Any unused product or waste material should be disposed of in accordance with local
requirements.
52
Source: European Medicines Agency
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