Monoclonal antibodies (selective immunosuppressants).

Infliximab - Crohn's disease

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.

Powder for concentrate for solution for infusion. The powder is a freeze-dried white pellet.

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:

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

• 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.

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

Due to insufficient data on safety and efficacy, Remicade is not recommended for use in any other paediatric indication.

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 12 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.

During Remicade treatment, other concomitant therapies, e.g., corticosteroids and immunosuppressants should be optimised.

Adults ( 18 years)

Rheumatoid arthritis

Patients not previously treated with Remicade: 3 mg/kg given as an intravenous infusion over a 2hour 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 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 2hour 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 recu.

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. 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 2hour 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.

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. 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 2hour period followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.

Psoriasis

5 mg/kg given as an intravenous infusion over a 2hour 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. 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.

Re-administration for ankylosing spondylitis

The safety and efficacy of re-administration, other than every 6 to 8 weeks, has not been established.

Re-administration for psoriatic arthritis

The safety and efficacy of re-administration, other than every 8 weeks, has not been established.

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.

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.

Children under 17 years, not recommended.  recommended.

Patients with tuberculosis or other severe infections such as sepsis, abscesses, and opportunistic infections.

Patients with moderate or severe heart failure (NYHA class III/IV).

Patients with a history of hypersensitivity to infliximab, to other murine proteins, or to any of the excipients.

Infusion reactions and hypersensitivity

Infliximab has been associated with acute infusion-related reactions, including anaphylactic shock, and delayed hypersensitivity reactions.

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.

In clinical studies, delayed hypersensitivity reactions have been reported. Available data suggest an increased risk for delayed hypersensitivity with increasing Remicade-free interval. Advise patients to seek immediate medical advice if they experience any delayed adverse event. 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.

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 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 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.

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.

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

In clinical studies, infections have been reported more frequently in paediatric patient populations than in adult patient populations.

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.

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.

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.

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.

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 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.

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.

Neurological events

Infliximab and other agents that inhibit TNF_α have been associated in rare cases with optic neuritis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system 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 Remicade treatment should be carefully considered before initiation of Remicade therapy.

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. 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 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. 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.

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 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 azathioprine or 6mercaptopurine 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.

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.

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

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.

Paediatrics

Due to insufficient data on safety and efficacy, Remicade is not recommended for use in children 17 years, except in Crohn's disease. Remicade has not been studied in patients with Crohn's disease below the age of 6 years.

Others

The pharmacokinetics of infliximab in elderly patients has not been studied. Studies have not been performed in patients with liver or renal disease.

There are insufficient preclinical data to draw conclusions on the effects of infliximab on fertility and general reproductive function.

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.

There is limited safety experience of Remicade treatment in patients who have undergone arthroplasty.

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.

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 is not recommended.

Nothing is known regarding possible interactions between infliximab and other active substances.

It is recommended that live vaccines not be given concurrently with Remicade.

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 (1/1000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000). 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 unknown. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1

Undesirable Effects in Clinical Studies and from Post-Marketing Experience

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.

In post-marketing experience, cases of anaphylactic-like reactions, including laryngeal/pharyngeal oedema and severe bronchospasm, and seizure have been associated with Remicade administration.

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 edema, 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.

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.

In clinical studies 36% of infliximab-treated patients were treated for infections compared with 25% of placebo-treated patients.

In RA 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.

In postmarketing 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 infection. Cases of tuberculosis, sometimes fatal, including miliary tuberculosis and tuberculosis with extrapulmonary location have been reported.

Malignancies and lymphoproliferative disorders: 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.

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 studies 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.

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 RA 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.

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 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

Table 2: Proportion of patients with increased ALT activity in Clinical Studies

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

Paediatric population

Juvenile Rheumatoid Arthritis patients:

Remicade was studied in a clinical study in 120 patients (age range: 4-17 years old) with active JRA 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 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.

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%), 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 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 autoantibodies.

Schering-Plough

(POM)

01 July 2009