Remicade 100 mg powder for concentrate for solution for Infusion

Card updated following change of local representative of the Marketing Authorisation Holder to Janssen Sciences Ireland UC (update the date of revision and add Janssen internal code).

Change of local representative of the Marketing Authorisation Holder to Janssen Sciences Ireland UC.

Update to RMM document.

Update to section 4.8 of the SPC to include ‘weight increased’ as an adverse drug reaction. 

SPC document format updated to html

Addition of United Kingdom (Northern Ireland) details – details on how to report side effects from UK(NI) and local representative contact details for UK(NI) are added. 

Addition of United Kingdom (Northern Ireland) details – adding details on how to report side effects from UK(NI) and MAH for UK(NI).

Updates to sections 4.4, 4.5 and 4.6 of the SPC with regards to the administration of live vaccines to infants following in utero exposure to Remicade.

• Information in relation to breast-feeding /lactation while receiving Remicade has been added to the SPC.
•  

Dyslipidaemia is added to the side effects section (changes in cholesterol and fat levels in the blood).

Update to the ADR table of section 4.8 (SOC Neoplasms) of the SmPC with Kaposi’s Sarcoma

Change to section 4 - possible side effects;

Change to section 6 - date of revision

Section 4.8 of the SmPC has been updated to include cerebrovascular accidents as undesirable effect with unknown frequency. Administrative changes have also been implemented in section 4.1, 4.2 and 5.1.

Change to section 4.8 - Undesirable effects; Change to section 10 - Date of revision of the text

Change to section 4.8 - Undesirable effects; Change to section 10 - Date of revision of the text

Change to section 4.2 - Posology and method of administration; Change to section 4.4 - Special warnings and precautions for use; Change to section 4.8 - Undesirable effects; Change to section 5.1 - Pharmacodynamic properties; Change to section 5.2 - Pharmacokinetic properties

Change to section 4.2 - Posology and method of administration: editorial changes; Change to section 4.4 - Special warnings and precautions for use: update of the warning on colon cancer and dysplasia and updates to screening tests for tuberculosis to align with current medical practice; Change to Section 4.8 – Undesirable effects: editorial change

Section 4.4: A new heading for "Vaccinations" has been added

SPC change details:   Section 4.4 -  In three instances, the text has been revised from ‘Rare cases …’ and ‘Very rare cases …’ to ‘Cases’, Section 4.8 – the update is related to Cardiac adverse events such as myocardial ischaemia/myocardial infarction (time frame for their appearance has been deleted i.e. it use to be that these side effects appear during infurion and within 2 hours after infusion, now the time frame is not specified).

SPC change details:   Section 4.4 - The concurrent administration of live vaccines with Remicade is not recommended (for more details see section 4.4) and increased incidence of cervical cancer in women with rheumatoid arthritis treated with infliximab (for more details see section 4.4), Section 4.5 and 4.6 – live vaccine should not be given to infants after in utero exposure to infliximab for at least 6 months following birth (for more details see sections 4.5 and 4.6),  Section 4.8 -  Vaccine breakthrough infection (after in utero exposure to infliximab) and cervical cancer have been added.

change to Section 6.3 - Shelf life, change to section 6.4 Special precautions for storage and change to Section 10 - Date of revision of the text SPC change details:   Shelf life and storage conditions changed to include possibility to store the product before reconstitution below 25°C (not in refrigerator) for a single period for up to 6 months without exceeding the original expiry date of the product and text revision date from 24 July 2014 to 23 April 2015

Sections 4.4 & 4.8 - Updates to SPC section 4.4 (Warnings and Precautions for Use), section 4.8 (Adverse Events) & section 10 (Date of revision of text)
 

Section 4.4 Posology and method of administration:

‘Some cases of active tuberculosis have been reported in patients treated with Remicade during and after treatment for latent tuberculosis.’

Almost all patients had received treatment with AZA or 6-MP concomitantly with or immediately prior to a TNF-blocker. The vast majority of All Remicade cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority most 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.

Section 4.8 Undesirable Effects:

In addition, rare post‑marketing cases of hepatosplenic T‑cell lymphoma have been reported in patients with Crohn’s disease and ulcerative colitis treated with Remicade with the vast majority of cases occurring in Crohn’s disease and ulcerative colitis, the majority and most of whom were adolescent or young adult males (see section 4.4).

Wording added in section 4.4:

Live Vvaccinesations/therapeutic infectious agents

In patients receiving anti-TNF therapy, No limited 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. Use of live vaccines could result in clinical infections, including disseminated infections. It is recommended that live vaccines not be given concurrently with Remicade.

Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with Remicade.

Wording added in section 4.5:

It is recommended that therapeutic infectious agents not be given concurrently with Remicade (see section 4.4).

The following wording has been deleted from section 6.6 of the SmPC:

        ‘Do not use the vial if the vacuum is not present’

The changes made to the SmPC are as follows:

·        Update of section 4.2 of the SmPC to recommend that a continued therapy with a shortened interval should be carefully considered in paediatric Crohn's disease patients who show no evidence of additional therapeutic benefit after a change in the dosing interval. No data exist to establish a greater risk of adverse events in paediatric patients with Crohn’s disease at doses greater than 5 mg/kg, or at a dosing interval shorter than every 8 weeks, these recommendations are based on the general medical principle that continuing higher doses of any medication in the absence of therapeutic benefit is generally not desirable.

·        Warnings on concomitant use with other biologicals (worksharing with Simponi (II/041), revisions for Simponi will be communicated separately)

Data based on a summary of published information from studies where anti-TNF treatment has been combined with another biological DMARD has resulted in updates to sections 4.4 and 4.5 of the SmPC in order to add a warning and updated information regarding concomitant use of golimumab/infliximab with other biological therapeutics.

·        MCC and melanoma safety warning (worksharing with Simponi (II/042), revisions for Simponi will be communicated separately)

Following assessment melanoma is considered a drug class effect based on postmarketing data and the reporting rate associated with these data across TNF inhibitors, including infliximab and golimumab. The frequency category of melanoma is “rare” this has updated sections 4.4 and 4.8 of the SmPC to add a warning and safety information regarding cases of melanoma and MCC. In addition, Section 4.4, subsection Malignancies, of the SmPC has been updated to advise that periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

Update of section 5.2 of the SmPC to reflect pharmacokinetics data of infliximab in Children Aged 2 to <6 years with ulcerative colitis based on results of a pharmacokinetics modelling and simulation analysis:

Paediatric population

Population pharmacokinetic analysis based on data obtained from patients with ulcerative colitis (N=60), Crohn’s disease (N=112), juvenile rheumatoid arthritis (N=117) and Kawasaki disease (N=16) with an overall age range from 2 months to 17 years indicated that exposure to infliximab was dependent on body weight in a non-linear way. Following administration of 5 mg/kg Remicade every 8 weeks, the predicted median steady‑state infliximab exposure (area under concentration‑time curve at steady state, AUC_ss) in paediatric patients aged 6 years to 17 years was approximately 20% lower than the predicted median steady‑state drug exposure in adults. The median AUC_ss in paediatric patients aged 2 years to less than 6 years was predicted to be approximately 40% lower than that in adults, although the number of patients supporting this estimate is limited.

This has also affected wording in sections 4.1 and 4.2.

The MAH also took the opportunity to update the SmPC in line with the QRD template (order of text, new or revision to headings, standard terminology), correct grammatical errors and replace American spellings for English.
Sections 2, 4.4. 4.6, 4.8, 5.1, 6.4 and 6.6 are affected by these updates.

Expanding the use of Remicade to paediatric patients with ulcerative colitis, as follows:

Section 4.1, Therapeutic indications

Remicade is indicated for treatment of severely active ulcerative colitis, in paediatric patients aged 6 to 17 years, who have had an inadequate response to conventional therapy including corticosteroids and 6-MP or AZA, or who are intolerant to or have medical contraindications for such therapies.   

Section 4.2, Posology

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 do not support further infliximab treatment in paediatric patients not responding within the first 8 weeks of treatment (see section 5.1).

Remicade has not been studied in patients with ulcerative colitis below the age of 6 years.

In addition, information from the C0168T72 study was added to sections 4.8, 5.1 and 5.2 of the SmPC.

Shortened infusions across adult indications
In carefully selected adult patients who have tolerated at least 3 initial 2-hour infusions of Remicade (induction phase) and are receiving maintenance therapy, consideration may be given to administering subsequent infusions over a period of not less than 1 hour. If an infusion reaction occurs in association with a shortened infusion, a slower infusion rate may be considered for future infusions if treatment is to be continued. Shortened infusions at doses >6 mg/kg have not been studied (see section 4.8).

 The indication (section 4.1) will read:
Adult Crohn’s disease:

Remicade is indicated for:

·                treatment of moderately to severely active Crohn’s disease, in adult patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies.

·                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).

 This variation also affects sections 4.2, 4.8 and 5.1.

Section 4.4 of the EU Remicade SmPC has been extended to provide the medical practitioner and/or other healthcare providers with  up-to-date and relevant information regarding the safe and appropriate use of Remicade regading demyelinating disorders. As the SmPC was already quite extensively labeled for demyelinating disorders the actual changes of this variation for Remicade are relatively small. Addition of TNF-blocking agents, including infliximab, exclusion of rare cases and addition of a new sentence to consider Discontinuing Remicade if these disorders develop.

Following evaluation of safety information from an ongoing registry in Scandinavia on the collection of pregnancy data and an evaluation of pharmacovigilance data from the pharmacovigilance database section 4.6 of the SmPC has been updated, information on the number of exposed pregnancies has been updated and advice is given to physicians on the risks of infection and the timing of vaccinations in babies of mothers who received Remicade during their pregnancy. Section 4.6 now includes the following information:

 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.

 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)

 Section 4.4 on the SmPC under the heading 'Hepatitis B (HBV) reactivation' has been adapted in the following way:

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. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating Remicade therapy.

Based on an EMA request all information on deaths and infections in all our interventional, placebo-controlled clinical trials were delivered to the EMA. From this a request was received to look at RA trials only. Based on a pooled analysis of all clinical trials in RA which met the criteria, a higher incidence was found in serious infections in patients older than 65 years of age, in comparison to patients younger than 65 years of age and this was not as pronounced in the placebo/control group. This resulted in amendments to the SmPC as follows:

 4.2: the paragraph on elderly patients now includes 'For more information about the safety of Remicade in elderly patients see section 4.4 and 4.8'

4.4: Under a new sub heading 'Special Populations' the following information on infections in elderly patients has been added:

'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).'

4.8: Under a sub heading 'Additional Information on special populations' the following information on infections in elderly patients has been added:

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.

 For your information this safety change was a request for the class of TNF blockers and the original request from EMA was initiated due to findings in a clinical trial with Humira in RA. Humira already went through an update of their labeling and there are only minor differences between Remicade and Humira which resulted from negotiations we had with the rapporteur for Remicade.

 The EMA also requested to look at clinical trial data, post-marketing data and registry data and based on all available information it was decided to add sarcoid-like reactions to section 4.8 as a rare undesirable effect.

Class labelling changes affecting the SmPC in the following way:

·         Update of sections 4.4 and 4.8 of the SmPC to add viral infections

·         Update of section 4.4 of the SmPC to add:

- neutropenia with concurrent use of anakinra

-   information regarding the switching between biological DMARDs

-   information on haematologic reactions

Section 4.4, Malignancies & Lymphoproliferative disorders

1^st paragraph

From:

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. Furthermore, there is an increased background lymphoma risk in rheumatoid arthritis patients with longstanding, highly active, inflammatory disease, which complicates the risk estimation.

To:

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.

The following paragraph has been added to this section also:

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.

Section 4.4 - Infections, 

4th paragraph - the following has been added: "and of typical presentation of rare and unusual infections"

Section 4.8, Table 1

Infections and infestations

Not Known:                               "parasitic infections" has been added

Neoplasms benign, malignant and unspecified (including cysts and polyps), the following has been added to this section:

Rare:    Lymphoma

Not Known:  changed from:       Hepatosplenic T-cell lymphoma (primarily in adolescents and young adults with Crohn’s disease and ulcerative colitis), lymphoma (including non-Hodgkin’s lymphoma and Hodgkin’s disease).

                    Changed to:          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.

Skin disorders and subcutaneious tissue disorders

Not Known:  changed from:       Toxic epidermal necrolysis, Stevens-Johnson-Syndrome, psoriasis, including new onset psoriasis and pustular psoriasis (primarily palm & soles), erythema multiforme.

                     Changed to:         Toxic epidermal necrolysis, Stevens-Johnson-Syndrome, new onset or worsening psoriasis, including pustular psoriasis (primarily palm & soles), erythema multiforme.

Section 10

Date of revision of text updated



Section 4.1

Sections on Rheumatoid Arthritis & Adult Crohn’s disease

In the two bullet points, the word “adult” has been added before the word “patients” under both indications

Section on Ulcerative Colitis

Changed from:

Remicade is indicated for:

Treatment of moderately to severely active ulcerative colitis in patients who have had an inadequate response to conventional therapy including corticosteroids and 6-MP or AZA, or who are intolerant to or have medical contraindications for such therapies.

Changed to:

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.

Sections on Psoriatic Arthritis and Psoriasis

The word “adults” has been changed to “adult patients” in the first sentence under both indications

Section 4.2

The second & third paragraphs have been changed from:

Remicade is indicated for intravenous use in adults (³ 18 years) across all approved indications and in paediatric patients, aged 6 to 17 years, with Crohn’s disease (see section 5.1).

Due to insufficient data on safety and efficacy, Remicade is not recommended for use in any other paediatric indication (for juvenile rheumatoid arthritis, see section 4.8).

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).

Changed to:

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).

The section entitled Re-administration for Crohn’s Disease and rheumatoid arthritis the bracketed comment (see section 4.4 and 4.8: delayed hypersensitivity) has been changed to (see section 4.4 and 4.8)

At the end of each section on readministration in ulcerative colitits, ankylosing spondylitis and psoriatic arthritis, the following has been added - (see section 4.4 and 4.8

In the section on readministration for psoriasis a second paragraph has been added in relation to retreatment.

A new paragraph relating to readministration across all indications has been added.

A new section has been added Elderly patients (>65 years).

In the section on paediatric Crohn’s disease, at the end of the first paragraph, the following has been added – (see section 5.1).

The following has also been added to this section:

Remicade has not been studied in patients with Crohn’s disease below the age of 6 years.

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”).

A new section relating to impaired renal and/or hepatic function has been added.

Section 4.3

Paragraph 3 of this section has now become paragraph 1, with the other two paragraphs moving down accordingly.

Section 4.4

Infusion reactions and hypersensitivity – at the end of this section the bracketed comment has been changed from (see section 4.8: “Immunogenicity”) to (see section 4.8).

The third paragraph, 3^rd sentence has been changed from:

“Advise patients to seek immediate medical advise ….”

To:

“Patients should be advised to seek immediate medical advise …”

Section entitled Hepatitis B Reactivation has been renamed Hepatitis B (HBV) reactivation and the reference to “Remicade” in the fist sentence has been changed to “infliximab”.

A new section has been added providing information relating to Concurrent administration of TNF-alpha inhibitor and abatacept

In the section entitled Autoimmune processes, the bracketed comment has been changed from (see section 4.8: “Anti-nuclear antibodies (ANA)/Double-stranded DNA (dsDNA) antibodies”) to (see section 4.8)

In the section entitled Malignancies and lymphoproliferative disorders, in the 5^th paragraph which commences “Rare postmarketing cases of hepatosplenic ….”, “Remicade has been changed to “infliximab”, azathioprine has been abbreviated to aza and 6-mercaptopurine has been abbreviated to 6MP

The section entitled Paediatrics has been deleted.

In the section entitled Others, the 3^rd paragraph has been changed from:

There is limited safety experience of surgical procedures in Remicade treated patients. 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.

To:

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.

The fourth paragraph regarding patients who have undergone arthroplasty has been deleted.

Section 4.5

The 3^rd paragraph has been changed from:

The combination of Remicade and anakinra is not recommended (see section 4.4 - "Concurrent administration of TNF-alpha inhibitor and anakinra”).

To:

The combination of Remicade and anakinra or abatacept is not recommended (see section 4.4).

In the 5^th paragraph, the bracketed comment has changed from (see section 4.4 – “Vaccinations”) to  (see section 4.4)

Section 4.6

The following has been added to this section:

Fertility

There are insufficient preclinical data to draw conclusions on the effects of infliximab on fertility and general reproductive function (see section 5.3).

Section 4.7

Changed from:

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

To:

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).

Section 4.8

The frequency categories mentioned in the 2^nd paragraph have been changed from:

very common (³1/10); common (³1/100 to <1/10); uncommon (³1/1000 to <1/100); rare (³1/10,000 to <1/1,000); very rare (<1/10,000)

To:

very common (³1/10); common (³1/100 to <1/10); uncommon (³1/1,000 to <1/100); rare (³1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data)

The following sentence has also been changed:

“Therefore, the frequency of these adverse reactions is categorised as unknown.”

To:

“Therefore, the frequency of these adverse reactions is categorised as not known.”

In Table 1, all sections entitled “Unknown” have been changed to “Not known”

In Table 1, section on “Blood and lymphatic system disorders”, spelling of “leukopenia” has been changed to “leucopenia”

In Table 1, section on “Skin and subcutaneous tissue disorders” sub section “Not known” has been changed from:

Toxic epidermal necrolysis, Stevens-Johnson-Syndrome, psoriasis, including new onset and pustular (primarily palm & soles), erythema multiforme

To:

Toxic epidermal necrolysis, Stevens-Johnson-Syndrome, psoriasis, including new onset psoriasis and pustular psoriasis (primarily palm & soles), erythema multiforme.

Section entitled Infusion-related reactions – new paragraph added at end of section

In section entitled Delayed hypersensitivity, spelling of “edema” has been amended to “oedema”.

In section entitled Immunogenicity, the bracketed comment “(see section 4.4: "Infusion reactions and hypersensitivity")” has been moved to the end of the paragraph

In section entitled Infections, in the 3^rd paragraph the abbreviation “RA” has been expanded to “rheumatoid arthritis”

In section entitled Malignancies and lymphoproliferative disorders, in the 4^th paragraph the abbreviation “RA” has been expanded to “rheumatoid arthritis”

In section entitled Hepatobiliary events, the 2^nd sentence has been changed from:

Elevations of ALT ≥5 x ULN have been observed (see Table 2).

To:

Elevations of ALT ≥5 x Upper Limit of Normal (ULN) have been observed (see Table 2).

In Table 2, spelling of “Pediatric” has been changed to “Paediatric”

In the section entitled Juvenile Rheumatoid Arthritis, the abbreviation “JRA” has been expanded to “juvenile rheumatoid arthritis”.

In the section entitled Immunogenicity, the word “titers” has been changed to “titres”

In the section entitled Paediatric Crohn’s disease patients the word “leukopenia” has been changed to “leucopenia”

In the last paragraph in section 4.8, the bracketed comment has been changed from: “(see sections 4.4 and 4.8: ‘Malignancies and lymphoproliferative disorders’).” to “(see sections 4.4 and 4.8).”

Section 5.1

Pharmacotherapeutic group changed from:

“Selective immunosuppressive agent”

To:

“tumour necrosis factor alpha (TNFa) inhibitors”

In the section entitled Paediatric Crohn’s disease (6 to 17 years), in the 1^st sentence the bracketed comment “(median PCDAI of 40)” has been changed to “(median paediatric CDAI of 40)”

In the section entitled Ulcerative colitis, the abbreviation “UC” has been expanded to “ulcerative colitis”

Section 6.5

Changed from:

Remicade is supplied as a lyophilised powder in single-use glass (Type 1) vials with rubber stoppers and aluminium crimps protected by plastic caps. Remicade is available in packs of 1, 2, 3, 4 or 5 vials. Not all pack sizes may be marketed.

To:

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.

Section 6.6

Point 6 – the phrase “parenteral medicinal product” has been changed to “Remicade”

Point 7 – the semi-colon after “waste material” has been removed

Section 10

Date of revision of text updated.

Section 4.4

Infections

The following has been added:

Patients taking TNF-blockers are more susceptible to serious infections.

Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal infections, and other opportunistic infections have been observed in patients treated with infliximab. Some of these infections have been fatal.

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.

Malignancies and lymphoproliferative disorders

Rare postmarketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with TNF-blocking agents including Remicade.  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 Crohns disease or ulcerative colitis and the majority were reported in adolescent or young adult males.  All of these patients had received treatment with azathioprine or 6‑mercaptopurine 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).

Section 4.8

Table 1 Neoplasms benign, malignant and uspecified:

Hepatosplenic T-cell lymphoma (primarily in adolescents and young adults with Crohns disease and ulcerative colitis), lymphoma (including non-Hodgkins lymphoma and Hodgkins disease)

Malignancies and lymphoproliferative disorders

Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients with Crohns disease and ulcerative colitis treated with Remicade, the majority of whom were adolescent or young adult males (see section 4.4).

Section 6.5

Additional pack sizes added: 1, 2, 3, 4 or 5  vials.

Section 8

Two additional authorisation numbers (relating to additional pack sizes 4 & 5 vials)

Section 10

Date of revision of text updated

 The following sentence has been removed:

Cases of active tuberculosis including miliary tuberculosis and tuberculosis with extra pulmonary location have been reported in patients treated with Remicade.

And replaced with:

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.

Section 4.8

The following sentence has been added in the text immediately before Table 2:

Additional adverse reactions, some with fatal outcome, are reported from worldwide post-marketing experience and included in table 2.

Table 2, section relating to Respiratory, thoracic and mediastinal disorders, has been changed from:

To:

Section 10 date of revision of the text has been updated

Changed from: 

Each vial of Remicade contains 100 mg of infliximab, a chimeric IgG1 monoclonal antibody manufactured from a recombinant cell line cultured by continuous perfusion. After reconstitution each ml contains 10 mg of infliximab.  

To: 

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.  

Section 3 

The following sentence has been added: 

The powder is a freeze-dried white pellet. 

Section 4.1 

Section on Rheumatoid Arthritis, the first bullet point has been changed from: 

·                patients with active disease when the response to disease-modifying drugs, including methotrexate, has been inadequate. 

To: 

·                patients with active disease when the response to disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate, has been inadequate. 

Section on Ankylosing Spondylitis has been changed from: 

Treatment of ankylosing spondylitis, in patients who have severe axial symptoms, elevated serological markers of inflammatory activity and who have responded inadequately to conventional therapy. 

To: 

Treatment of severe, active ankylosing spondylitis, in adult patients who have responded inadequately to conventional therapy. 

Section on Psoriatic Arthritis has been changed from: 

Treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying anti-rheumatic drug therapy has been inadequate. 

To: 

Treatment of active and progressive psoriatic arthritis in adults when the response to previous DMARD therapy has been inadequate. 

The following sentence has also been added to this section: 

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). 

Section 4.2 

The following sentence has been moved to the beginning of this section: 

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. 

Sections entitled Severe, active Crohn’s disease and Fistulising, active Crohn’s disease: 

Various changes in this section relating to dosing and dosing strategies 

In the section entitled Re-administration for Crohn’s disease and rheumatoid arthritis references to “drug-free intervals” have been changed to “Remicade-free intervals” 

In the section entitled Re-administration for psoriasis, the word “infliximab” has been changed to “Remicade”. 

Section 4.3 

The third paragraph has been changed from: 

Remicade must not be given to patients with a history of hypersensitivity to infliximab (see section 4.8), to other murine proteins, or to any of the excipients. 

To: 

Patients with a history of hypersensitivity to infliximab (see section 4.8), to other murine proteins, or to any of the excipients. 

Section 4.4 

In the section relating to tuberculosis, the following has been added: 

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. 

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. 

Section 4.5 

The following paragraph has been added: 

It is recommended that live vaccines not be given concurrently with Remicade (see section 4.4 - “Vaccinations”).

Section 4.8 

Various changes to this first two paragraphs of this section and Tables 1 and 2. 

In the section entitled Malignancies and lymphoproliferative disorders the first paragraph has been changed from: 

In clinical studies with infliximab in which 5706 patients were treated, representing 4990 patient years, 5 cases of lymphomas and 24 non-lymphoma malignancies were detected as compared with no lymphomas and 1 non-lymphoma malignancy in 1600 placebo-treated patients representing 892 patient years. 

To: 

In clinical studies with infliximab in which 5780 patients were treated, representing 5494 patient years, 5 cases of lymphomas and 26 non-lymphoma malignancies were detected as compared with no lymphomas and 1 non-lymphoma malignancy in 1600 placebo-treated patients representing 941 patient years. 

Section 4.9 

The first sentence “There is no clinical experience of overdose” has been changed to “No case of overdose has been reported” 

Section 5.1 

The section entitled Maintenance treatment in severe active Crohn’s disease has been changed including new tables 6 and 7, all following tables have now also been renumbered 

The section entitled Ankylosing Spondylitis has been changed 

The section entitled Psoriatic Arthritis has had the following paragraph added: 

Radiographic changes were assessed in IMPACT2. 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. 

Section 6.3 

“Room temperature” has been changed to “25°C” 

Section 6.4 

The following sentence has been added: 

            For storage conditions of the reconstituted medicinal product, see section 6.3 

Section 6.6, point 7 

Changed from: 

Discard any unused portion of the solution. 

To: 

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

Section 10 

Date of revision of text changed from 24 July 2007 

To: 

30 November 2007

 The following sentence has been added:

 Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu

Section 4.4, information regarding reactivation of Hepatitis B has been changed from:

Reactivation of hepatitis B occurred in patients receiving Remicade who are chronic carriers of this virus (i.e. surface antigen positive). Chronic carriers of hepatitis B should be appropriately evaluated and monitored prior to the initiation of and during treatment with Remicade.

To:

Hepatitis B Reactivation

Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including Remicade, who are chronic carriers of this virus. Some cases have had fatal outcome. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating Remicade therapy.  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.

Section 4.8.  Table 2, the following has been added under ¡°Skin and subcutaneous tissue disorders¡±:

            Very rare:          Psoriasis, including new onset and pustular (primarily palmar/plantar)

The section sub-headed Hepatobiliary events: has been changed from:

Hepatobiliary events: In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving Remicade without progression to severe hepatic injury. 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 medications. ALT elevations ¡Ý 5 times the upper limit of normal were observed in 1% of patients receiving Remicade. ALT elevations ¡Ý 3 times the upper limit of normal were observed across all approved indications at the following frequencies (placebo/infliximab): rheumatoid arthritis 3.2%/3.9%; Crohn's disease 3.5%/5.1%; ankylosing spondylitis 0.0%/5.9%; psoriatic arthritis 0.0%/6.8%; psoriasis 0.0%/10.4%. 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)

To:

Hepatobiliary events: In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving Remicade without progression to severe hepatic injury. Elevations of ALT ¡Ý5 x ULN have been observed (see Table 3). 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 medications. 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)

A new Table 3 has been added entitled Proportion of patients with increased ALT activity in clinical trials

Section 5, Tables 3, 4, 5, 6 and 7 have been renumbered as Tables 4, 5, 6, 7 and 8 all subsequent references to those table numbers in the text of section 5 have also been amended.

Under the sub-heading Psoriasis, in paragraph 4 (EXPRESS evaluated ¡­.) the following sentence has been added:

            Nail psoriasis was assessed using the Nail Psoriasis Severity Index (NAPSI)

And newly renumbered Table 8 (was table 7) has new data included to reflect the nail psoriasis update

Section 10 ¨C revised date

 Heading Crohn’s disease:, changed to Adult Crohn’s disease

 The following indication has been added:

           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.

 Section 4.2

 The first paragraph has been changed from:

 To:

The following sentences has been moved from the end of Section 4.2 and added after paragraph 4:

For preparation and administration instructions, see section 6.6

 The following heading has been added:

                 Adults (­> 18 years).

At the start of Section 4.2, the following has been added:

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.

 Section 4.4

 In the section entitled Infections, the following sentence has been added after the paragraph commencing “Opportunistic infections reported …”

 In the section entitled Vaccinations, the following has been added: 

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.

 The section entitled “Paediatrics” has been changed from: 

Remicade is not recommended for use in children <17 years due to insufficient data on safety and efficacy (for juvenile RA see Section 4.8)

 In the section entitled Others, the following paragraph has been deleted:

 Section 4.8

 The following paragraph has been changed from:

 To:

 The following has been added before the section entitled Juvenile Rheumatoid Arthritis patients:

                 Additional information on special populations

Paediatric Crohn’s disease patients:

The following adverse events were reported more commonly in paediatric Crohn’s disease patients in the REACH trial (see section 5.1) than in adult Crohn’s disease patients: anaemia (10.7%), blood in stool (9.7%), leukopenia (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 trial, 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 autoantibodies (see sections 4.4 and 4.8: “Malignancies and lymphoproliferative disorders”).

 Section 5.1

 The heading Crohn’s disease has been changed to Adult Crohn’s disease.

 The following information has been added to this section:

                 Paediatric Crohn’s disease (6 to17 years)

In the REACH trial, 112 patients (6 to 17 years, median age 13.0 years) with moderate to severe, active Crohn’s disease (median PCDAI 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.

 Section 5.2

 The following has been added after the third paragraph in this section:

 Section 10

 Updated date of revision of text

Section 4.2 – second paragraph changed from:

Remicade treatment is to be administered under the supervision and monitoring of specialised physicians experienced in the diagnosis and treatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosing spondylitis, psoriatic arthritis or psoriasis. Patients treated with Remicade should be given the package leaflet and the special Alert card.

To:

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.

Section entitled Rheumatoid Arthritis, the following sentence added at end of 2^nd paragraph:

“Shortened infusions at doses >6mg/kg have not been studied.”

The following paragraph has been changed from:

Available data suggest that the clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.

To:

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 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.

Section 5.1

The following paragraph has been added after Table 4:

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.

Section 10 Date of revision of text updated

Section 4.2, Paragraph 1

Changed from:

Remicade is for intravenous use in adults and has not been studied in children (0‑17 years).

Changed to:

Remicade is indicated for intravenous use in adults (³ 18 years) across all approved indications. Remicade is not recommended for use in children ≤ 17 years, since efficacy has not been established in this age group (see section 4.8).

Paragraph 3, Changed from:

Changed from:

The recommended infusion time is 2 hours.

Changed to:

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.

Changed from:

Rheumatoid arthritis

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.

Remicade must be given concomitantly with methotrexate.

Available data suggest that the clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.

Changed to:

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.

Remicade must be given concomitantly with methotrexate.

Available data suggest that the clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.

Section 4.4, the following has been added in respect of paediatric patients:

Paediatrics

Remicade is not recommended for use in children ≤ 17 years due to insufficient data on safety and efficacy (for juvenile RA see Section 4.8)

Section 4.8:

Changed from:

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

Changed to:

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 1040) received at least one shortened infusion of 90 minutes or less and 44% of the patients (454 out of 1040) 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.

The following has been added in respect of paediatric patients:

Juvenile Rheumatoid Arthritis patients: Remicade was studied in a trial in 120 patients (age range: 4-17 years old) with active JRA despite MTX. 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 MTX.

Infusion reactions

Infusion reactions occurred in 35 % of patients with JRA 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.

Immunogenicity

Antibodies to infliximab developed in 38 % of patients receiving 3 mg/kg compared with 12% of patients receiving 6 mg/kg. The antibody titers 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.

Section 6.6, No.4:

Changed from:

Administer the infusion solution over a period of not less than 2 hours (at not more than 2 ml/min).

Changed to:

Administer the infusion solution over a period of not less than the infusion time recommended for the specific indication.

Section 10 – Date of revision of text updated

Change highlighted

Section 4.1 Therapeutic Indications:

Crohn's disease:

Remicade is indicated for:

• treatment of severe, active Crohn's disease, in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; .....

Section 4.4 Special warnings and special precautions for use:

Malignancies & Lymphoproliferative disorders - changed from:

In the controlled portions of clinical trials of TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. However, the occurrence was rare, and the follow up period of placebo patients was shorter than for patients receiving TNF-blocking therapy. Furthermore, there is an increased background lymphoma risk in rheumatoid arthritis patients with longstanding, highly active, inflammatory disease, which complicates the risk estimation.
 

In an exploratory clinical trial 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. No studies have been conducted that include patients with a history of malignancy or that continue treatment in patients who develop malignancy while receiving Remicade. Thus additional caution should be exercised in considering Remicade treatment of these patients as well as in 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).

To:

In the controlled portions of clinical trials 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 trials 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. Furthermore, there is an increased background lymphoma risk in rheumatoid arthritis patients with longstanding, highly active, inflammatory disease, which complicates the risk estimation.

In an exploratory clinical trial 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.

Others changed from:

Treatment of patients with intestinal strictures due to Crohn's disease is not recommended since the risk/benefit relationship in this patient population has not been established.

To:

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 suggests that infliximab does not worsen or cause strictures.

Section 4.8 Undesirable effects:

The following has been added to Table 2:

Malignancies & lymphoproliferative disorders changed from:

In clinical studies with infliximab and during long-term follow-up of 4 years, representing 8800 patient years, 8 cases of lymphomas and 43 other malignancies were detected as compared with 9 malignancies and 0 lymphoma in placebo-treated patients observed during 1274 patient years. The overall rate of malignancies in these patients was similar to that expected for an age-, gender- and race-matched general population. From August 1998 to August 2004, 1367 cases of suspected malignancies have been reported from post-marketing, clinical trials and registries (229 in Crohn’s disease patients, 942 in rheumatoid arthritis patients and 196 in patients with other or unknown indications). Among those there were 242 lymphoma cases. During this period, the estimated exposure is 1,350,000 patient years (see section 4.4: Special Warnings and Special Precautions for Use - "Malignancies").

To:

In clinical studies with infliximab in which 5706 patients were treated, representing 4990 patient years, 5 cases of lymphomas and 24 non-lymphoma malignancies were detected as compared with no lymphomas and 1 non-lymphoma malignancy in 1600 placebo-treated patients representing 892 patient years.

In long-term safety follow-up of clinical studies with infliximab of up to 5 years, representing 6234 patients-years (3210 patients), 5 cases of lymphoma and 38 cases of non-lymphoma malignancies were reported.

From August 1998 to August 2005, 1909 cases of suspected malignancies have been reported from post-marketing, clinical trials and registries (321 in Crohn’s disease patients, 1302 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: Special Warnings and Special Precautions for Use - "Malignancies").

Section 10 - Date of Revision of the text - date updated

Change highlighted

 Section 4.1 Therapeutic Indications:

 Crohn's disease:

Remicade is indicated for:

• treatment of severe, active Crohn's disease, in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; .....

Section 4.4 Special warnings and special precautions for use:

 Malignancies & Lymphoproliferative disorders - changed from:

 In the controlled portions of clinical trials of TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. However, the occurrence was rare, and the follow up period of placebo patients was shorter than for patients receiving TNF-blocking therapy. Furthermore, there is an increased background lymphoma risk in rheumatoid arthritis patients with longstanding, highly active, inflammatory disease, which complicates the risk estimation.

In an exploratory clinical trial 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. No studies have been conducted that include patients with a history of malignancy or that continue treatment in patients who develop malignancy while receiving Remicade. Thus additional caution should be exercised in considering Remicade treatment of these patients as well as in 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).  

To:

In the controlled portions of clinical trials 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 trials 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. Furthermore, there is an increased background lymphoma risk in rheumatoid arthritis patients with longstanding, highly active, inflammatory disease, which complicates the risk estimation.

In an exploratory clinical trial 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.

Others changed from: 

Treatment of patients with intestinal strictures due to Crohn's disease is not recommended since the risk/benefit relationship in this patient population has not been established.

To: 

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 suggests that infliximab does not worsen or cause strictures.

Section 4.8 Undesirable effects: 

The following has been added to Table 2:

Malignancies & lymphoproliferative disorders changed from:

In clinical studies with infliximab and during long-term follow-up of 4 years, representing 8800 patient years, 8 cases of lymphomas and 43 other malignancies were detected as compared with 9 malignancies and 0 lymphoma in placebo-treated patients observed during 1274 patient years. The overall rate of malignancies in these patients was similar to that expected for an age-, gender- and race-matched general population. From August 1998 to August 2004, 1367 cases of suspected malignancies have been reported from post-marketing, clinical trials and registries (229 in Crohn’s disease patients, 942 in rheumatoid arthritis patients and 196 in patients with other or unknown indications). Among those there were 242 lymphoma cases. During this period, the estimated exposure is 1,350,000 patient years (see section 4.4: Special Warnings and Special Precautions for Use - "Malignancies").

To:

In clinical studies with infliximab in which 5706 patients were treated, representing 4990 patient years, 5 cases of lymphomas and 24 non-lymphoma malignancies were detected as compared with no lymphomas and 1 non-lymphoma malignancy in 1600 placebo-treated patients representing 892 patient years.

In long-term safety follow-up of clinical studies with infliximab of up to 5 years, representing 6234 patients-years (3210 patients), 5 cases of lymphoma and 38 cases of non-lymphoma malignancies were reported.

From August 1998 to August 2005, 1909 cases of suspected malignancies have been reported from post-marketing, clinical trials and registries (321 in Crohn’s disease patients, 1302 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: Special Warnings and Special Precautions for Use - "Malignancies").

Section 10 - Date of Revision of the text - date updated 

Section 4.1

Psoriatic Arthritis changed from:

Psoriatic arthritis:

Remicade, in combination with methotrexate, is indicated for:

Treatment of active and progressive psoriatic arthritis in patients who have responded inadequately to disease-modifying anti-rheumatic drugs.

To:

Treatment of active and progressive psoriatic arthritis in patients who have responded inadequately to disease-modifying anti-rheumatic drugs.

Remicade should be administered

- in combination with methotrexate

- or alone in patients who show intolerance to methotrexate or for whom methotrexate is contraindicated

Section 4.2

Psoriatic Arthritis changed from:

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. Efficacy and safety have been demonstrated in combination with methotrexate.

To:

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.

Section 4.4

Infections the following has been added as the 2^nd paragraph:

Caution should be exercised when considering the use of Remicade in patients with chronic infection or a history of recurrent infections, including use of concomitant immunosuppressive medications. Patients should be advised of and avoid exposure to potential risk factors for infection as appropriate.

Fourth paragraph changed from:

It should be noted that suppression of TNF_a may also mask symptoms of infection such as fever.

To:

It should be noted that suppression of TNF_a may mask symptoms of infection such as fever. Early recognition of atypical clinical presentations of serious infections is critical in order to minimize delays in diagnosis and treatment.

Fifth paragraph changed from:

Cases of active tuberculosis including miliary tuberculosis and tuberculosis with extrapulmonary location have been reported in patients treated with Remicade. Some of these cases had a fatal outcome

To:

Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal infections, and other opportunistic infections have been observed in patients treated with infliximab. Some of these infections have been fatal.

The following paragraph has been added:

Opportunistic infections reported in patients on Remicade have included, but are not limited to pneumocystosis, histoplasmosis, cytomegalovirus infection, atypical mycobacterial infections, listeriosis and aspergillosis.

The following paragraphs have been changed from:

If inactive (latent) tuberculosis is diagnosed, prophylactic anti-tuberculosis therapy must be started before the initiation of Remicade, and in accordance with local recommendations. In this situation, the benefit/ risk balance of Remicade therapy should be very carefully considered.  

To:

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 this situation, the benefit/ risk balance of Remicade therapy should be very carefully considered.  

From:

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).

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.

To:

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.

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).

In the Section on Malignancies and Lymphoproliferative Disorders the following paragraph has been added:

Rare postmarketing cases of hepatosplenic T-cell lymphoma have been reported in adolescent and young adult patients with Crohn’s disease treated with Remicade. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. All of these hepatosplenic T-cell lymphomas with Remicade have occurred in patients on concomitant treatment with azathioprine or 6-mercaptopurine. 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).

Section 4.5

The first line of the first paragraph has been changed from:

In rheumatoid arthritis and Crohn’s disease patients, there are indications that concomitant use …

To:

In rheumatoid arthritis, psoriatic arthritis and Crohn’s disease patients, there are indications that concomitant use …

Section 4.8

In the section on Immunogenicity the 2^nd paragraph has been changed from:

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.

To:

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).

In the section on Infections, the following has been added as the 1^st paragraph:

Infections: Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal infections, and other opportunistic infections have been observed in patients receiving Remicade.  Some of these infections have been fatal. Opportunistic infections reported in patients on Remicade have included, but are not limited to pneumocystosis, histoplasmosis, cytomegalovirus infection, atypical mycobacterial infections, listeriosis and aspergillosis (see section 4.4).

In the section on Malignancies and lymphoproliferative disorders the following paragraph has been added:

Six cases of a rare type of hepatosplenic T-cell lymphoma have been reported in adolescent and young adult patients with Crohn’s disease treated with Remicade in the United States (see section 4.4). It is estimated that approximately 270,000 Crohn’s disease patients have been exposed to infliximab, and in the United States, approximately 10,000 patients with Crohn¡¯s disease below 18 years of age.

In the section on Hepatobiliary events, the penultimate sentence has been changed from:

ALT elevations >3 times the upper limit of normal were observed across all approved indications at the following frequencies (placebo/infliximab): rheumatoid arthritis 3.2%/3.9%; Crohn's disease 3.5%/5.1%; ankylosing spondylitis 0.0%/5.9%; psoriatic arthritis 0.0%/5.4%; psoriasis 0.0%/10.4%

To:

ALT elevations >3 times the upper limit of normal were observed across all approved indications at the following frequencies (placebo/infliximab): rheumatoid arthritis 3.2%/3.9%; Crohn's disease 3.5%/5.1%; ankylosing spondylitis 0.0%/5.9%; psoriatic arthritis 0.0%/6.8%; psoriasis 0.0%/10.4%.

Section 5.1

The following sentence has been added at the end of the 3^rd paragraph:

In psoriatic arthritis, short term treatment with Remicade reduced the number of T-cells and blood vessels in the synovium and psoriatic skin.

In the Clinical Efficacy section, the section, Psoriatic Arthritis has been changed from:

Psoriatic Arthritis

Efficacy and safety were studied in a double-blind, placebo-controlled, multicenter study evaluating infliximab in 104 patients with active polyarticular psoriatic arthritis. In total 74 subjects were on at least one concomitant DMARD, and among those 58 patients were treated with methotrexate. 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.

Treatment with infliximab resulted in improvement in signs and symptoms, as assessed by the ACR criteria, with 65% of infliximab-treated patients achieving ACR 20 at week 16, compared with 10% of placebo-treated patients (p<0.01). Improvement (ACR 20 and 50) was observed as early as week 2 and was maintained through week 50 (ACR 20, 50, and 70). 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.

Infliximab-treated patients also demonstrated improvement in physical function as assessed by HAQ (mean change from baseline to week 16 of 0.6 vs. 0 for placebo-treated patients).

To:

Psoriatic Arthritis

Efficacy and safety were assessed in two multicenter, double-blind, placebo-controlled studies in patients with active psoriatic arthritis.

In the first 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 trial (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 6 below:

Table 6: Effects on ACR and  PASI in IMPACT and 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.

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.

Under the Psoriasis section, Table 6 now becomes Table 7

Section 10 updated date of revision of text