Remsima SC (Celltrion, PM 00086235) Product Monograph

1. Indications

REMSIMA SC (infliximab injection) is indicated for:

• use in combination with methotrexate for the reduction in signs and symptoms, inhibition of the progression of structural damage and improvement in physical function in adult patients with moderately to severely active rheumatoid arthritis.
• maintenance treatment of adults with moderately to severely active Crohn’s disease who have had an inadequate response or were intolerant to conventional therapy. REMSIMA SC should only be used as maintenance therapy after the completion of an induction period with intravenous infliximab.
• maintenance treatment of adults with moderately to severely active ulcerative colitis who have had an inadequate response or were intolerant to conventional therapy. REMSIMA SC should only be used as maintenance therapy after the completion of an induction period with intravenous infliximab.

REMSIMA SC should be used by health professionals who have sufficient knowledge of rheumatoid arthritis, Crohn’s disease and/or ulcerative colitis, and who have fully familiarized themselves with the efficacy/safety profile of REMSIMA SC.

REMSIMA SC is not intended for use as an induction regimen in patients with Crohn’s disease or ulcerative colitis.

1.1. Pediatrics

No data on the safety and efficacy of REMSIMA SC in children aged below 18 years of age are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2. Geriatrics

Clinical studies with REMSIMA SC did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Geriatric patients treated with intravenous infliximab had similar efficacy and safety profiles to younger patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly (see 8 Adverse Reactions, Infections).

2. Contraindications

REMSIMA SC is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition and Packaging.

• Patients with severe infections such as sepsis, abscesses, tuberculosis and opportunistic infections (see 7 Warnings and Precautions, Infections).
• Patients with moderate or severe (NYHA Class III/IV) congestive heart failure (see 7 Warnings and Precautions, Cardiovascular and 8 Adverse Reactions, Congestive Heart Failure).
• Patients with history of hypersensitivity to infliximab, to other murine proteins, or to any excipients. For a complete listing, see 6 Dosage Forms, Strengths, Composition and Packaging section of the product monograph.

3. Serious Warnings and Precautions Box

4. Dosage and Administration

4.1. Dosing Considerations

It is important to check the product labels to ensure that the correct formulation of infliximab (intravenous or subcutaneous) is being administered to the patient, as prescribed. REMSIMA SC is not intended for intravenous administration and should be administered via a subcutaneous injection only, see 4.4 Administration.

4.2. Recommended Dose and Dosage Adjustment

Rheumatoid Arthritis

For patients initiating treatment with infliximab:

Treatment with REMSIMA SC administered subcutaneously in adult patients with moderately to severely active rheumatoid arthritis should be initiated with loading doses of infliximab which may be intravenous or subcutaneous. When subcutaneous loading is used, REMSIMA SC 120 mg should be given as a subcutaneous injection followed by additional subcutaneous injections at 1, 2, 3 and 4 weeks after the first injection, then every 2 weeks thereafter. If intravenous loading doses of infliximab are given to initiate treatment, 2 intravenous infusions of infliximab 3 mg/kg should be given 2 weeks apart. The first treatment with REMSIMA SC should be initiated as maintenance therapy 4 weeks after the second intravenous administration, see 4.4 Administration. The recommended maintenance dose for REMSIMA SC is 120 mg once every 2 weeks. REMSIMA SC should be given in combination with methotrexate.

Crohn’s Disease and Ulcerative Colitis

For patients who have completed an induction regimen with intravenously administered infliximab:

The recommended maintenance dosing regimen of REMSIMA SC is 120 mg (given as one subcutaneous injection) once every 2 weeks, starting 4 weeks following completion of an induction regimen.

For patients already receiving intravenous infliximab maintenance therapy

For patients who have been on maintenance therapy with intravenous infliximab and who are switching to REMSIMA SC maintenance therapy, the first dose of REMSIMA SC may be administered 8 weeks after the last infliximab intravenous infusion.

There is insufficient information regarding the switching of patients who received the intravenous infusions of infliximab higher than 3 mg/kg for rheumatoid arthritis or 5 mg/kg for Crohn’s disease or ulcerative colitis every 8 weeks to REMSIMA SC.

Information regarding switching patients from the subcutaneous formulation to intravenous infliximab is not available.

Pediatrics

Health Canada has not authorized an indication for pediatric use (see 1 Indications).

4.4. Administration

REMSIMA SC 120 mg solution for subcutaneous injection is provided with a pre-filled syringe (with or without needle guard) or in a pre-filled pen, and administered by subcutaneous (under the skin) injection only (see Patient Medication Information).

Dose-induction for initiation of infliximab therapy:

Rheumatoid Arthritis

For patients beginning infliximab therapy, initial induction doses may be given intravenously or subcutaneously. When subcutaneous loading is used, REMSIMA SC 120 mg should be given as a subcutaneous injection followed by additional subcutaneous injections at 1, 2, 3 and 4 weeks after the first injection. If intravenous loading doses of infliximab are given to initiate treatment, 2 intravenous infusions of infliximab 3 mg/kg should be given 2 weeks apart. See detailed instructions in the appropriate labelling for the selected intravenous infliximab preparation.

Ulcerative Colitis and Crohn’s Disease

For patients beginning infliximab therapy, induction doses should be given intravenously. See detailed instructions in the appropriate labelling for the selected intravenous infliximab preparation.

REMSIMA SC maintenance therapy:

Rheumatoid Arthritis, Ulcerative Colitis, and Crohn’s Disease

• The first maintenance dose of REMSIMA SC may be administered under the supervision of the health professional 4 weeks after last IV induction dose (i.e. at Week 6 following two IV infusion doses at Weeks 0 & 2 for rheumatoid arthritis; at Week 10 following three IV infusion doses at

  • Weeks 0, 2 & 6 for ulcerative colitis or Crohn’s disease) or 2 weeks after five SC injection doses at Weeks 0, 1, 2, 3 & 4 for rheumatoid arthritis.
• The first maintenance dose of REMSIMA SC may also be administered under the supervision of a health professional 8 weeks after the most recent IV infusion for patients already receiving infliximab maintenance therapy.
• The health professional should ensure appropriate follow-up of patients for any systemic injection reaction(s) and localized injection site reaction(s).
• For subsequent REMSIMA SC injections and after proper training in subcutaneous injection technique, patients may self-inject with REMSIMA SC if their physician determines that it is appropriate. Adequate medical follow-up should be provided by the physician as necessary. Suitability of the patient for subcutaneous home use should be assessed and patients should be advised to inform their healthcare professional if they experience symptoms of an allergic reaction before administering the next dose. Patients should seek immediate medical attention if developing symptoms of serious allergic reactions. REMSIMA SC should be discontinued in patients who have experienced a serious systemic allergic or hypersensitivity reaction.
• REMSIMA SC should be refrigerated at 2 to 8oC. Do not freeze. REMSIMA SC may be stored at temperatures up to a maximum of 25°C for a period of up to 28 days. REMSIMA SC must be discarded if not used within the 28-day period (See 11 Storage, Stability, and Disposal).

4.5. Missed Dose

Missed dose for up to 7 days

If the patient misses a dose of REMSIMA SC for up to 7 days after the original scheduled dose, the missed dose should be taken immediately. The next dose should be administered as per the originally planned date and thereafter on the original bi-weekly schedule.

Missed dose for 8 days or more

If the patient misses a dose of REMSIMA SC for 8 days or more after the original scheduled dose, the missed dose should not be taken. The next dose should be administered as per the next originally planned date and thereafter on the original bi-weekly schedule.

5. Overdose

Repeated doses of subcutaneous infliximab up to 240 mg have been administered without any direct toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects. Appropriate symptomatic treatment should be instituted immediately.

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table – Dosage Forms, Strengths, and Composition

REMSIMA SC (infliximab injection) consists of a chimeric immunoglobin G1 (IgG1) monoclonal antibody that binds with high affinity to the human tumor necrosis factor alpha (TNFα).

The REMSIMA SC drug product is formulated as a clear to opalescent, colorless to pale brown solution which is supplied as a single use pre-filled syringe or pre-filled pen. Each syringe or pen is designed to deliver a single dose of 120 mg infliximab active substance. The components of a single syringe or pen of the drug product REMSIMA SC are: infliximab, acetic acid, sodium acetate trihydrate, sorbitol, polysorbate 80, water for injection.

The pre-filled pen (27G needle and 29G needle presentations), the pre-filled syringe and pre-filled syringe with needle guard presentations are available in 1-pack, 2-pack and 4-pack formats.

7. Warnings and Precautions

See 3 Serious Warnings and Precautions Box

General

To help ensure the traceability of biologic products, health professionals, caregivers and patients should recognize the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Carcinogenesis and Mutagenesis

Lymphoma

Lymphomas have been observed in patients treated with TNF-blocking agents, including infliximab. In clinical trials, patients treated with infliximab had a higher incidence of lymphoma than the expected rate in the general population. Patients with rheumatoid arthritis and Crohn’s disease, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) for the development of lymphoma than the general population, even in the absence of TNF-blocking therapy. The role of TNF-blockers in the development of malignancy is not known.

Hepatosplenic T-cell lymphoma

Post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with TNF-blockers including infliximab. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Almost all patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with or immediately prior to a TNF-blocker. The vast majority of infliximab cases have occurred in patients with Crohn’s disease or ulcerative colitis and most were reported in adolescent or young adult males. Cases of hepatosplenic T-cell lymphoma have also occurred in Crohn’s disease and ulcerative colitis patients receiving azathioprine or 6-mercaptopurine who were not treated with infliximab. Before initiating or continuing REMSIMA SC therapy in a patient who is receiving an immunosuppressant such as azathioprine or 6-mercaptopurine, carefully assess the need for continuing the immunosuppressant therapy in light of the potential risks of concomitant treatment. The causal relationship of hepatosplenic T-cell lymphoma to infliximab therapy remains unclear.

Leukemia

Cases of acute and chronic leukemia have been reported with post-marketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF-blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.

Non-lymphoma malignancy

In the controlled portions of clinical trials of some TNF-blocking agents, including infliximab, more malignancies (excluding lymphoma and non-melanoma skin cancer [NMSC]) have been observed in patients receiving those TNF-blockers compared with control patients (see 8 Adverse Reactions, Malignancies/Lymphoproliferative Disease). The rate of non-lymphoma malignancies among infliximab-treated patients was similar to that expected in the general population whereas the rate among control patients was lower than expected.

In an exploratory clinical trial evaluating the use of infliximab in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking.

Cervical cancer

A population-based retrospective cohort study using data from Swedish national health registries found an increased incidence of cervical cancer in women with rheumatoid arthritis treated with infliximab compared to biologics-naïve patients or the general population, including those over 60 years of age. A causal relationship between infliximab and cervical cancer cannot be excluded. Periodic screening should continue in women treated with REMSIMA SC, including those over 60 years of age.

Skin cancers

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocker therapy, including infliximab. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

The potential role of TNF-blocking therapy in the development of malignancies is not known. 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 (see 8 Adverse Reactions, Malignancies/Lymphoproliferative Disease).

Long-term studies in animals have not been performed to evaluate the carcinogenic potential. No clastogenic or mutagenic effects of infliximab were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively. Chromosomal aberrations were not observed in an assay performed using human lymphocytes. Tumorigenicity studies in mice deficient in TNFα demonstrated no increase in tumors when challenged with known tumor initiators and/or promoters.

Cardiovascular

REMSIMA SC should be used with caution in patients with mild heart failure (NYHA Class I/II). Patients should be closely monitored, and REMSIMA SC must not be continued in patients who develop new or worsening symptoms of heart failure (see 2 Contraindications and 8 Adverse Reactions, Congestive Heart Failure).

The results of a randomized study evaluating the use of infliximab in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg intravenous infliximab, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 mg/kg.

Driving and Operating Machinery

REMSIMA SC may have a minor influence on the ability to drive and use machines. Dizziness may occur following administration of REMSIMA SC.

Hematologic

There have been reports of pancytopenia, leukopenia, neutropenia, and thrombocytopenia in patients receiving TNF-blockers, including infliximab. Caution should be exercised in patients treated with REMSIMA SC who have a current or past history of significant cytopenia. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. persistent fever, bruising, bleeding, pallor). Discontinuation of REMSIMA SC therapy should be considered in patients with confirmed significant hematologic abnormalities.

Hepatic/Biliary/Pancreatic

Cases of jaundice and non-infectious hepatitis, some with features of autoimmune hepatitis, have been observed in the post-marketing experience with infliximab. Isolated cases of liver failure resulting in liver transplantation or death have occurred. A causal relationship between infliximab and these events has not been established. In clinical trials of Crohn’s disease and ulcerative colitis patients, three patients treated with REMSIMA SC had drug induced livery injury based on hepatic transaminase elevations, including one subject with accompanying bilirubin elevation (See 8 Adverse Reactions, Hepatobiliary Events). 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, REMSIMA SC should be discontinued immediately, and a thorough investigation of the abnormality should be undertaken. As also observed with the use of other immunosuppressive drugs, reactivation of hepatitis B has occurred very rarely in patients receiving infliximab who are chronic carriers of this virus (i.e., surface antigen positive). Patients should be tested for hepatitis B virus (HBV) infection before initiating treatment with immunosuppressants, including REMSIMA SC. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Chronic carriers of hepatitis B should be appropriately evaluated prior to the initiation of REMSIMA SC therapy and monitored closely during treatment and for several months following discontinuation of therapy.

Immune

Hypersensitivity Reactions

Infliximab has been associated with hypersensitivity reactions that vary in their time of onset. Hypersensitivity reactions, which include urticaria, dyspnea, and/or bronchospasm, laryngeal edema and hypotension, have occurred during or within 2 hours of intravenous infliximab infusion. However, in some cases, serum sickness-like reactions have been observed in Crohn’s disease and rheumatoid arthritis patients 3 to 12 days after infliximab therapy was reinstituted following an extended period without infliximab treatment. Symptoms associated with these reactions include fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema and/or dysphagia. These reactions were associated with marked increase in antibodies to infliximab, loss of detectable serum concentrations of infliximab, and possible loss of drug efficacy. REMSIMA SC should be discontinued for severe reactions. Medications for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids and/or epinephrine) should be available for immediate use in the event of a reaction (see 8 Adverse Reactions, Hypersensitivity Reactions).

Delayed Hypersensitivity Reactions

In clinical studies, delayed hypersensitivity reactions have been reported. Available data suggest an increased risk for delayed hypersensitivity with increasing infliximab-free interval. Patients should be advised to seek immediate medical advice if they experience any delayed adverse reaction. If patients are re-treated after a prolonged period, they must be closely monitored for signs and symptoms of delayed hypersensitivity.

Hypersensitivity Reactions following Readministration of Infliximab

In a rheumatoid arthritis clinical trial where subjects were receiving low dose methotrexate resulted in a higher incidence of serious and severe infusion reactions during the reinduction regimen than had been observed in rheumatoid arthritis and Crohn’s disease trials in which a period of no drug treatment was followed by regular maintenance therapy without reinduction. Most of these reactions occurred during the second reinduction infusion at Week 2. The serious infusion reactions included anaphylaxis, urticaria, facial edema, chills and itching. Retreatment with a reinduction regimen after a period of no treatment is not recommended. There are no data on readministration in patients treated with REMSIMA SC maintenance therapy.

Autoimmunity

Treatment with infliximab may result in the formation of autoantibodies and in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with infliximab, treatment should be discontinued (see 8 Adverse Reactions, Autoantibodies/Lupus-like Syndrome).

Immunogenicity

Treatment with infliximab can be associated with the development of antibodies to infliximab (see 8 Adverse Reactions, Hypersensitivity Reactions).

In a Phase III study of rheumatoid arthritis (CT-P13 3.5 Part 2) in patients who received concomitant MTX, anti-infliximab antibodies occurred at Week 30 in 48.4% and 57.1% following the subcutaneous infliximab and intravenous infliximab, respectively.

In Phase III ulcerative colitis (CT-P13 3.7), 62.7% subjects treated with REMSIMA SC developed anti-drug antibodies to subcutaneous infliximab, and in Phase III Crohn’s disease clinical study (CT-P13 3.8), 65.1% subjects treated with REMSIMA SC developed anti-drug antibodies to subcutaneous infliximab.

Patients with rheumatoid arthritis, ulcerative colitis and Crohn’s disease who were antibody-positive were more likely to have higher rates of clearance than patients who were antibody-negative.

Immunogenicity tests are generally product-specific. Comparison of antibody rates to those from other products, or comparison of the incidence of antibodies between different tests without cross-validation is not appropriate.

Vaccinations

It is recommended that all patients, if possible, be brought up to date with all vaccinations in agreement with current vaccination guidelines prior to initiating REMSIMA SC therapy.

Live Vaccines/Therapeutic Infectious Agents

In patients receiving anti-TNF therapy, limited data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines can result in clinical infections, including disseminated infections. The concurrent administration of live vaccines with REMSIMA SC is not recommended.

Infant exposure in utero

Fatal outcome due to disseminated Bacille Calmette-Guérin (BCG) infection has been reported in an infant who received BCG vaccine after in utero exposure to infliximab. A twelve month waiting period following birth is recommended before the administration of live vaccines to infants exposed in utero to infliximab. Administration of the live vaccine prior to 12 months of age might be considered if infliximab exposure was limited to the first trimester of pregnancy, or if infant infliximab serum levels are undetectable, or if there is a clear clinical benefit for the individual infant (see 7 Warnings and Precautions, Special Populations, Pregnancy).

Infant exposure via breast milk

Administration of a live vaccine to a breastfed infant while the mother is receiving infliximab is not recommended unless infant infliximab serum levels are undetectable (see 7 Warnings and Precautions, Special Populations, Breastfeeding).

Therapeutic Infectious Agents

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 REMSIMA SC.

Non-Live Vaccines

In a subset of patients from a study of intravenous infliximab in RA patients, a similar proportion of patients in each treatment group mounted an effective two-fold increase in titers to a polyvalent pneumococcal vaccine indicating that infliximab did not interfere with T-cell independent humoral immune responses.

Infections

Serious infections due to bacterial (including sepsis and pneumonia), invasive fungal, viral, and other opportunistic pathogens, have been reported in patients receiving TNF-blocking agents. Some of these infections have been fatal. Many of the serious infections in patients treated with infliximab have occurred in patients on concomitant immunosuppressive therapy that, in addition to their underlying disease, could predispose them to infections.

REMSIMA SC should not be given to patients with a clinically important active infection, including tuberculosis. Caution should be exercised when considering the use of REMSIMA SC in patients with a chronic infection or a history of recurrent infection. Patients should be monitored for signs and symptoms of infection while on or after treatment with REMSIMA SC. New infections should be closely monitored. If a patient develops a serious infection, REMSIMA SC therapy should be discontinued (see 8 Adverse Reactions, Infections).

Cases of histoplasmosis, coccidioidomycosis, blastomycosis, listeriosis, pneumocystosis, and tuberculosis have been observed in patients receiving infliximab. For patients who have resided in or travelled to regions where histoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefits and risks of REMSIMA SC treatment should be carefully considered before initiation or continuation of REMSIMA SC therapy.

Invasive Fungal Infections

In patients treated with REMSIMA SC, an invasive fungal infection such as aspergillosis, candidiasis, pneumocystosis, histoplasmosis, coccidioidomycosis or blastomycosis should be suspected if they develop a serious systemic illness. Invasive fungal infections may present as disseminated rather than localized disease, and antigen and antibody testing may be negative in some patients with active infection. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. The decision to administer empiric antifungal therapy should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.

Tuberculosis

Cases of active tuberculosis have occurred in patients treated with infliximab during and after treatment for latent tuberculosis. Patients receiving REMSIMA SC should be monitored closely for signs and symptoms of active tuberculosis during and after treatment, including patients who tested negative for latent tuberculosis infection. The possibility of undetected latent tuberculosis should be considered, especially in patients who have immigrated from or traveled to countries with a high prevalence of tuberculosis or had close contact with a person with active tuberculosis. All patients treated with REMSIMA SC should have a thorough history taken prior to initiating therapy. Some patients who have previously received treatment for latent or active tuberculosis have developed active tuberculosis while being treated with infliximab. Anti-tuberculosis therapy should be considered prior to initiation of REMSIMA SC in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Anti-tuberculosis therapy prior to initiating REMSIMA SC should also be considered in patients who have several or highly significant risk factors for tuberculosis infection and have a negative test for latent tuberculosis. The decision to initiate anti-tuberculosis therapy in these patients should only be made following consultation with a physician with expertise in the treatment of tuberculosis and taking into account both the risk for latent tuberculosis infection and the risks of anti-tuberculosis therapy.

Opportunistic Infections

Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF-blockers, including infliximab. Patients have frequently presented with disseminated rather than localized disease.

Concurrent Administration of TNF-alpha Inhibitor and Anakinra

Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNFα-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 TNFα-blocking agents. Therefore, the combination of REMSIMA SC and anakinra is not recommended.

Concurrent Administration of REMSIMA SC with Abatacept

In clinical studies, concurrent administration of TNF-blocking agents and abatacept has been associated with an increased risk of infections including serious infections compared with TNF- blocking agents alone, without increased clinical benefit. Because of the nature of the adverse events seen with the combination of TNF-blocking agents and abatacept therapy, the combination of REMSIMA SC and abatacept is not recommended.

Concurrent Administration with other Biological Therapeutics

There is insufficient information regarding the concomitant use of REMSIMA SC with other biological therapeutics used to treat the same conditions as REMSIMA SC. The concomitant use of REMSIMA SC with these biologics is not recommended because of the possibility of an increased risk of infection.

Switching between Biological Therapeutics

When switching from one biologic to another, patients should continue to be monitored, since overlapping biological activity may further increase the risk of infection.

Neurologic

Infliximab and other agents that inhibit TNF have been associated with seizure, and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of REMSIMA SC in patients with these neurological disorders, and should consider discontinuation of REMSIMA SC if these disorders develop.

Health professional should alert patients to the presence of the Patient Package Insert, provide this information to them, and ensure full understanding of the content.

Perioperative Considerations

There is limited safety experience of infliximab in patients who have undergone surgical procedures, including arthroplasty. The long half-life of infliximab should be taken in to consideration if a surgical procedure is planned. A patient who requires surgery while on REMSIMA SC should be closely monitored for infections, and appropriate actions should be taken.

Reproductive Health

• Fertility

  Women of childbearing potential must use adequate contraception to prevent pregnancy and continue to do so for at least 6 months after the last REMSIMA SC treatment.

  It is not known whether infliximab can affect reproductive potential.

7.1. Special Populations

7.1.1. Pregnancy

It is not known whether REMSIMA SC can cause fetal harm when administered to a pregnant woman. As with other IgG antibodies, infliximab crosses the placenta. Infliximab has been detected in the serum of infants up to 12 months following birth. The clinical significance of low serum levels of infliximab on the immune status in infants is unknown. After in utero exposure to infliximab, infants may be at increased risk of infection, including disseminated infection that can become fatal (see 7 Warnings and Precautions, Immune, Live Vaccines/Therapeutic Infectious Agents and Non-Live Vaccines).

7.1.2. Breastfeeding

Infliximab has been detected at low levels in human milk and in infant serum via breast milk. While systemic exposure in a breastfed infant is expected to be low because infliximab is largely degraded in the gastrointestinal tract, the administration of live vaccines to a breastfed infant when the mother is receiving infliximab is not recommended unless infant infliximab serum levels are undetectable. Limited data from published literature reported that infants exposed to infliximab through breast milk had no increase in rates of infections and developed normally. The consideration of REMSIMA SC use during breast-feeding should take into account the importance of the drug to the mother and health benefits of breast-feeding for the infant.

7.1.3. Pediatrics

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4. Geriatrics

Specific studies of subcutaneous infliximab in elderly patients have not been conducted. No major age-related differences in clearance or volume of distribution were observed in clinical studies with intravenous infliximab and this suggests that the use in geriatric population is associated with no overall differences in safety and efficacy and the same is expected for subcutaneous infliximab. Studies with intravenous infliximab indicated a potentially greater risk of serious infections in patients 65 years and older; there are inadequate data to determine whether the use of REMSIMA SC is associated with differences in safety profile in older adults.

8. Adverse Reactions

8.1. Adverse Reaction Overview

The most common adverse drug reactions reported from both clinical trials and post-marketing reports are infections, allergic reactions and infusion-related reactions. Less common adverse drug reactions from these sources, which may be serious and clinically relevant include hepatobiliary events (see 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic), demyelinating disorders (see 7 Warnings and Precautions, Neurologic), and lymphoma (see 7 Warnings and Precautions, Carcinogenesis and Mutagenesis).

8.2. Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The safety profile of subcutaneous infliximab was evaluated in a Phase I/III parallel group study in patients with active rheumatoid arthritis and Phase III placebo-controlled studies in patients with active ulcerative colitis and Crohn’s disease. The safety population consisted of 168 patients in the subcutaneous infliximab group and 175 patients in the intravenous infliximab group for rheumatoid arthritis; 296 patients in the subcutaneous infliximab group for ulcerative colitis and 238 patients in the subcutaneous infliximab group for Crohn’s disease. For study details, see PART II, Clinical Trials.

Rheumatoid Arthritis

Overall, treatment-emergent adverse events (TEAEs) were reported in 62% of patients (60% of subcutaneous infliximab-treated patients vs 65% of intravenous infliximab-treated patients) and treatment-emergent serious adverse events (TESAEs) were reported in 6% of patients (5% of subcutaneous infliximab-treated patients vs 8% of intravenous infliximab-treated patients).

Study CT-P13 3.5 Part 2 was a randomised, parallel-group, multi-dose, 64-week study to evaluate efficacy, PK and safety of subcutaneous infliximab in RA patients. The study was conducted to establish therapeutic non-inferiority of subcutaneous infliximab compared with intravenous infliximab in 343 RA patients.

Table 1 – Number of RA Patients with 1 or More Treatment-Emergent Adverse Events (Frequency of at Least 3 Patients Overall) during the Maintenance Phase of RA trial (Study CT-P13 3.5 Part 2)

Ulcerative Colitis

In UC, TEAEs were reported in 67.6% of subcutaneous infliximab-treated patients and 59.3% of placebo-treated patients. Treatment-emergent serious adverse events (TESAEs) were reported in 6.4% of subcutaneous infliximab-treated patients vs 2.9% of placebo-treated patients.

Table 2 – Number of UC Patients with 1 or More Treatment-Emergent Adverse Events (Frequency of at least 2% of subcutaneous infliximab treated patients and at a higher rate than placebo) during the Maintenance Phase of UC trial (Study CT-P13 3.7)

Crohn’s Disease

In CD, TEAEs were reported in 72.3%% of subcutaneous infliximab-treated patients and 61.9% of placebo-treated patients. Treatment-emergent serious adverse events (TESAEs) were reported in 6.7% of subcutaneous infliximab-treated patients vs 7.6% of placebo-treated patients.

Table 3 – Number of CD Patients with 1 or More Treatment-Emergent Adverse Events (Frequency of at least 2% of subcutaneous infliximab treated patients and at a higher rate than placebo) during the Maintenance Phase of CD trial (Study CT-P13 3.8)

Subcutaneous Infliximab

Hypersensitivity Reactions

Systemic Injection Reaction/ Localized Injection Site Reaction

The incidence of systemic injection reactions (e.g. rash, pruritus, flushing and edema) was 1.2 per 100 patient-years in the subcutaneous infliximab group (from Week 6) and 2.1 per 100 patient-years in the intravenous infliximab group who switched to subcutaneous infliximab administration (from Week 30) for rheumatoid arthritis; and 5.20 per 100 patient-years in the subcutaneous infliximab group (from Week 10) and 5.34 per 100 patient-years in the placebo group (from Week 10) for UC; and 1.57 per 100 patient-years in the subcutaneous infliximab group (from Week 10) and 1.69 per 100 patient-years in the placebo group (from Week 10) for CD. Most systemic injection reactions were mild to moderate.

The incidence of localized injection site reactions (e.g. injection site erythema, pain, pruritus and swelling) was 17.6 per 100 patient-years in the subcutaneous infliximab group (from Week 6) and 21.4 per 100 patient-years in those who switched to subcutaneous infliximab administration (from Week 30) for rheumatoid arthritis; and 4.33 per 100 patient-years in the subcutaneous infliximab group (from Week 10) and 4.0 per 100 patient-years in the placebo group (from Week 10) for UC; and 7.31 per 100 patient-years in the subcutaneous infliximab group (from Week 10) and 1.69 per 100 patient-years in the placebo-group (from Week 10) for CD. Most of these reactions were mild to moderate.

Infections

In subcutaneous infliximab RA studies, infections were reported in 30% of subcutaneous infliximab-treated patients and in 33% of intravenous infliximab-treated patients.

In the maintenance period of Study CT-P13 3.5 Part 2, 29% of subcutaneous infliximab-treated RA patients had infections reported vs. 34% of intravenous infliximab-treated RA patients (up to 64 weeks of follow-up). The infections most frequently reported in the RA study were viral upper respiratory tract infection, upper respiratory tract infection and latent tuberculosis. No increased risk of serious infections was observed with subcutaneous infliximab compared with intravenous infliximab.

In the maintenance period of Studies CT-P13 3.7, 28.0% of subcutaneous infliximab-treated UC patients had infections reported vs. 25.7% of placebo-controlled UC patients. The infections most frequently reported in the UC study were COVID-19, upper respiratory tract infection, nasopharyngitis, urinary tract infection, pharyngitis and oral herpes.

In the maintenance period of Studies CT-P13 3.8, 31.1% of subcutaneous infliximab-treated CD patients had infections reported vs. 18.1% of placebo-controlled CD patients. The infections most frequently reported in the CD study were COVID-19, urinary tract infection, oral herpes, and nasopharyngitis .

In subcutaneous infliximab studies, latent tuberculosis was reported in 4% of RA patients,0.7% of UC patients, and none of CD patients.

Hepatobiliary Events

In subcutaneous infliximab clinical trials, hepatobiliary disorders were reported in 1% of subcutaneous infliximab-treated patients and in 2% of intravenous infliximab-treated patients in RA study; and in 1.7% of subcutaneous infliximab-treated patients and in 0.7% in placebo-treated patients in UC; and in 2.9% of subcutaneous infliximab-treated patients and in 1.9% in placebo-treated patients in CD studies.

In Study CT-P13 3.5 Part 2, there was one subcutaneous infliximab-treated RA patient with cholecystitis chronic and four intravenous infliximab-treated RA patients with chronic hepatitis, hepatic steatosis, hepatomegaly and liver disorders (up to 64 weeks of follow-up).

In Studies CT-P13 3.7 and CT-P13 3.8, abnormal hepatic function, cholelithiasis, hepatic steatosis, hepatitis, hepatotoxicity, hyperbilirubinemia and non-alcoholic fatty liver were reported in subcutaneous infliximab-treated UC or CD patients.

Mild or moderate elevations of ALT and AST have been observed in patients receiving subcutaneous infliximab or intravenous infliximab without progression to severe hepatic injury. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved in most patients without discontinuation of infliximab treatment. However, three cases of drug induced liver injury were noted in REMSIMA SC-treated patients that led to study drug discontinuation.

• In two patients in Study CT-P13 3.7, ALT and AST levels started rising 7 to 12 months after starting REMSIMA SC, reaching peak values of 4 to 11 x ULN for ALT, and 2 to 7x ULN for AST. In both patients, total bilirubin levels remained below 2 x ULN
• In one patient in Study CT-P13 3.8, ALT and AST started rising within a month after starting REMSIMA SC, reaching peak values of 18 x ULN for ALT and 14 x ULN for AST. At approximately 5 months, total bilirubin levels also increased to a peak value of 2.5 x ULN.

Malignancies/Lymphoproliferative Disease

The potential role of TNF-blocking therapy in the development of malignancies is not known. Rates in clinical trials for infliximab cannot be compared to rates in clinical trials of other TNF-blockers and may not predict rates observed in a broader patient population. Caution should be exercised in considering infliximab treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving infliximab.

In subcutaneous infliximab clinical studies, one RA patient developed malignant ovarian cyst amongst 168 RA patients administered with subcutaneous infliximab, which is at a rate of 0.586 cases per 100 patient-years; and one IBD patient developed prostate cancer amongst 534 IBD patients administered with subcutaneous infliximab, which is at a rate of 0.27 per 100 patient-years. In another clinical trial in patients with CD, one malignancy (non-small cell lung cancer) was reported in a REMSIMA-SC treated patient.

Congestive Heart Failure

In subcutaneous infliximab clinical trials, no mortality related to congestive heart failure was reported. There was one case of moderate cardiac failure in one UC patient, who was administered with subcutaneous infliximab. There is no experience with REMSIMA SC in patients with NYHA Class III or IV heart failure, severe uncontrolled cardiac disease, or history of myocardial infarction.

Intravenous Infliximab

The following information reflects the use of intravenous infliximab in clinical trials. There are inadequate data to determine whether these findings apply to the use of subcutaneous infliximab, therefore these should be considered as potential risks.

Autoantibodies/Lupus-like Syndrome

Approximately 55% of 1598 intravenous infliximab-treated patients in clinical trials (primarily RA and CD) who were antinuclear antibody (ANA) negative at baseline developed a positive ANA during the trial compared with approximately 20% of 265 placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately 19% of 2116 intravenous infliximab-treated patients compared with 0% of 422 placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon.

In a study of intravenous infliximab in RA patients through Week 102, 62% of intravenous infliximab-treated patients developed antinuclear antibodies (ANA) between screening and last evaluation, compared with 27% of placebo-treated patients. In another study of intravenous infliximab in RA patients through Week 58, 66% of intravenous infliximab-treated patients developed antinuclear antibodies (ANA) between screening and last evaluation, compared with 21% of placebo-treated patients. In both RA studies, anti-dsDNA antibodies developed in approximately 15% of intravenous infliximab-treated patients, compared to none of the placebo-treated patients. No association was seen between intravenous infliximab dose/schedule and development of ANA or anti-dsDNA antibodies.

Of Crohn’s disease patients treated with intravenous infliximab who were evaluated for antinuclear antibodies (ANA), 40% developed ANA between screening and last evaluation. Anti-dsDNA antibodies developed in approximately 20% of Crohn’s disease patients treated with intravenous infliximab. The development of anti-dsDNA antibodies was not related to either the dose or duration of intravenous infliximab treatment. However, baseline therapy with an immunosuppressant in Crohn’s disease patients was associated with reduced development of anti-dsDNA antibodies (3% compared to 21% in patients not receiving any immunosuppressant). Crohn’s disease patients were approximately 2 times more likely to develop anti-dsDNA antibodies if they were ANA-positive at study entry.

In clinical studies, 6 patients were diagnosed with a possible lupus-like syndrome, four with Crohn’s disease and two with rheumatoid arthritis. All patients improved following discontinuation of therapy and/or appropriate medical treatment. No patients had renal involvement. The lupus-like syndrome in one patient with rheumatoid arthritis remained ongoing at the end of the study. One case of a lupus-like reaction has been observed in a Crohn’s disease patient in up to three years of long-term follow-up (see 7 Warnings and Precautions, Immune, Autoimmunity).

Hepatobiliary Events

In post-marketing surveillance, cases of jaundice and hepatitis, some with features of autoimmune hepatitis, have been reported in patients receiving intravenous infliximab (see 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic).

In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving intravenous infliximab without progression to severe hepatic injury. Elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving intravenous infliximab than in controls, both when intravenous infliximab 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 intravenous infliximab, or modification of concomitant medications.

Malignancies/Lymphoproliferative Disease

The potential role of TNF-blocking therapy in the development of malignancies is not known. Rates in clinical trials for infliximab cannot be compared to rates in clinical trials of other TNF-blockers and may not predict rates observed in a broader patient population. Caution should be exercised in considering infliximab treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving infliximab.

In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF-blocker compared with control patients. In the controlled and open-label portions of intravenous infliximab clinical trials, 5 patients developed lymphomas among 5780 patients treated with intravenous infliximab (median duration of follow-up 1.0 years) vs. 0 lymphomas in 1600 control patients (median duration of follow-up 0.4 years). In rheumatoid arthritis patients, 2 lymphomas were observed for a rate of 0.08 cases per 100 patient-years of follow-up, which is approximately 3-fold higher than expected in the general population. In the combined clinical trial population for rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, psoriasis, ankylosing spondylitis, and ulcerative colitis, 5 lymphomas were observed for a rate of 0.09 cases per 100 patient-years of follow-up, which is approximately 4-fold higher than expected in the general population. Patients with Crohn’s disease or rheumatoid arthritis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several-fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy.

In the controlled portions of clinical trials of some TNF-blocking agents including intravenous infliximab, more cases of non-lymphoma malignancies have been observed in patients receiving those TNF-blockers compared with control patients. During the controlled portions of intravenous infliximab trials in patients with moderately to severely active rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, psoriasis, ankylosing spondylitis, and ulcerative colitis, 14 patients were diagnosed with non-lymphoma malignancies among 4019 intravenous infliximab-treated patients vs. 1 among 1597 control patients (at a rate of 0.52/100 patient-years among intravenous infliximab-treated patients vs. a rate of 0.11/100 patient-years among control patients), with median duration of follow-up 0.5 years for intravenous infliximab-treated patients and 0.4 years for control patients. Of these, the most common malignancies were breast, colorectal, and melanoma. The rate of non-lymphoma malignancies among intravenous infliximab-treated patients was similar to that expected in the general population whereas the rate in control patients was lower than expected.

A population-based retrospective cohort study found an increased incidence of cervical cancer in women with rheumatoid arthritis treated with intravenous infliximab compared to biologics-naïve patients or the general population, including those over 60 years of age.

Congestive Heart Failure

In a phase II study evaluating intravenous infliximab in NYHA Class III/IV CHF patients (left ventricular ejection fraction ≤35%), higher incidences of mortality and hospitalization due to worsening heart failure were seen in intravenous infliximab-treated patients, especially those treated with 10 mg/kg. One hundred and fifty patients were treated with 3 infusions of intravenous infliximab 5 mg/kg, 10 mg/kg, or placebo over 6 weeks. At 28 weeks, 4 of 101 patients treated with intravenous infliximab (1 at 5 mg/kg and 3 at 10 mg/kg) died compared with no deaths among the 49 placebo-treated patients. In follow-up, at 38 weeks, 9 patients treated with intravenous infliximab (2 at 5 mg/kg and 7 at 10 mg/kg) died compared with one death among the placebo-treated patients. At 28 weeks, 14 of 101 patients treated with intravenous infliximab (3 at 5 mg/kg and 11 at 10 mg/kg) were hospitalized for worsening CHF compared with 5 of the 49 placebo-treated patients (see 2 Contraindications and 7 Warnings and Precautions, Cardiovascular).

There have also been 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.

8.3. Less Common Clinical Trial Adverse Reactions

Subcutaneous Infliximab

Other medically relevant adverse events occurring in less than 2% patients overall in patients treated with REMSIMA SC for any indication (RA, UC, CD) were as follows, presented by body system:

Blood and lymphatic system disorders: eosinophilia, haemorrhagic anaemia, hypereosinophilic syndrome, iron deficiency anaemia, leukocytosis, leukopenia, lymphadenopathy, lymphadenopathy mediastinal, lymphopenia, monocytosis, polycythaemia, thrombocytopenia, thrombocytosis

Cardiac disorders: aortic valve incompetence, arrhythmia, atrial fibrillation, atrioventricular block second degree, bundle branch block right, cardiac arrest, cardiac failure, left atrial enlargement, left ventricular hypertrophy, mitral valve incompetence, myocardial infarction, palpitations, subendocardial ischaemia, supraventricular tachycardia, tachycardia, tricuspid valve incompetence, ventricular extrasystoles

Congenital, familial and genetic disorders: hereditary haemochromatosis

Ear and labyrinth disorders: ear pain, tinnitus, vertigo, vertigo positional

Endocrine disorders: cushingoid

Eye disorders: chalazion, conjunctival haemorrhage, eye pain, eye pruritus, swelling of eyelid, xerophthalmia

Gastrointestinal disorders: abdominal distension, abdominal pain lower, abdominal pain upper, anal fissure, anal ulcer, aphthous ulcer, chronic gastritis, colitis, constipation, dry mouth, duodenal ulcer haemorrhage, duodenal ulcer perforation, dyspepsia, flatulence, food poisoning, frequent bowel movements, gastrointestinal inflammation, gastrooesophageal reflux disease, gingival bleeding, glossodynia, haematochezia, haemorrhoidal haemorrhage, haemorrhoids, inguinal hernia, intestinal metaplasia, large intestinal stenosis, large intestine polyp, lip pruritus, lower gastrointestinal haemorrhage, nausea, peritoneal adhesions, proctalgia, pseudopolyposis, rectal haemorrhage, subileus, toothache, vomiting

General disorders and administration site conditions: accidental death, adverse drug reaction, asthenia, chest discomfort, chest pain, chills, cyst, enanthema, fatigue, hyperthermia, inflammation, injection site pain, injection site paraesthesia, malaise, mucosal inflammation, non-cardiac chest pain, oedema, oedema peripheral, peripheral swelling, pyrexia, soft tissue inflammation, sudden death, swelling face, vaccination site pain

Hepatobiliary disorders: cholecystitis chronic, cholelithiasis, chronic hepatitis, hepatic function abnormal, hepatic steatosis, hepatitis, hepatomegaly, hepatotoxicity, hyperbilirubinaemia, liver disorder, non-alcoholic fatty liver

Immune system disorders: infusion related hypersensitivity reaction

Infections and infestations: abscess intestinal, abscess limb, abscess rupture, acute sinusitis, adenoviral upper respiratory infection, anal abscess, appendicitis, arthritis bacterial, ascariasis, asymptomatic bacteriuria, bartholinitis, bronchiolitis, bronchitis, bronchitis haemophilus, COVID-19 pneumonia, candida infection, cellulitis, chronic sinusitis, conjunctivitis, conjunctivitis bacterial, cystitis, ear infection, folliculitis, furuncle, gastroenteritis, gastroenteritis viral, gastrointestinal viral infection, gingivitis, herpes dermatitis, herpes simplex, herpes zoster, impetigo, infected fistula, influenza, latent tuberculosis, lower respiratory tract infection, nasal herpes, nasopharyngitis, onychomycosis, oral bacterial infection, oral candidiasis, orchitis, otitis externa, otitis media, paronychia, periodontitis, peritonitis, pertussis, pharyngitis, pharyngitis streptococcal, pharyngotonsillitis, pilonidal disease, pneumonia, pulpitis dental, pustule, pyelonephritis, pyelonephritis chronic, pyoderma, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinovirus infection, salpingitis, salpingo-oophoritis, sinusitis, skin bacterial infection, streptococcal impetigo, tinea versicolour, tonsillitis, tooth infection, tracheobronchitis, vaginal infection, varicella, viral upper respiratory tract infection

Injury, poisoning and procedural complications: administration related reaction, animal bite, bone contusion, burns second degree, clavicle fracture, contusion, fall, foot fracture, gastrointestinal stoma complication, heat stroke, hip fracture, joint injury, ligament sprain, skin laceration, sunburn, synovial rupture, thermal burn, wrong technique in product usage process

Investigations: aspartate aminotransferase increased, bilirubin conjugated increased, blood alkaline phosphatase increased, blood bilirubin increased, blood creatine phosphokinase MB increased, blood lactate dehydrogenase increased, blood pressure abnormal, blood pressure increased, blood triglycerides increased, blood urea increased, body temperature increased, c-reactive protein increased, coronavirus test positive, creatinine renal clearance decreased, creatinine renal clearance increased, faecal calprotectin increased, gamma-glutamyltransferase increased, haemoglobin decreased, heart rate increased, hepatic enzyme increased, interferon gamma release assay positive, liver function test increased, mycobacterium tuberculosis complex test positive, neutrophil count decreased, platelet count increased, transaminases increased, weight decreased, weight increased, white blood cell count decreased, white blood cells urine positive

Metabolism and nutrition disorders: diabetes mellitus, glucose tolerance impaired, gout, hypercholesterolaemia, hyperkalaemia, hyperlipidaemia, hyperphosphataemia, hypertriglyceridaemia, hyperalbuminaemia, hypoferritinaemia, hypokalemia, hypophosphataemia, iron deficiency, type 2 diabetes mellitus, vitamin D deficiency

Musculoskeletal and connective tissue disorders: arthritis, arthritis enteropathic, arthropathy, back pain, bursitis, connective tissue inflammation, costochondritis, exostosis, fistula, intervertebral disc compression, intervertebral disc degeneration, intervertebral disc disorder, intervertebral disc protrusion, joint swelling, musculoskeletal pain, myalgia, osteoporosis, pain in extremity, rheumatoid arthritis, rotator cuff syndrome, scleroderma, spinal osteoarthritis, spinal pain, spondyloarthropathy, tenosynovitis

Neoplasms benign, malignant and unspecified (incl cysts and polyps): colorectal adenoma, haemangioma, large intestine benign neoplasm, malignant ovarian cyst, prostate cancer, skin papilloma, uterine leiomyoma

Nervous system disorders: altered state of consciousness, autonomic nervous system imbalance, carotid artery stenosis, cerebral infarction, dementia Alzheimer's type, dizziness, hypoaesthesia, neurovascular conflict, paresthesia, parosmia, sciatica, somnolence, syncope, vertebrobasilar insufficiency

Product issues: device loosening

Psychiatric disorders: anxiety, depression, irritability, mixed anxiety and depressive disorder, stress

Renal and urinary disorders: calculus urinary, chronic kidney disease, dysuria, haematuria, leukocyturia, nephrolithiasis, proteinuria, renal amyloidosis, renal colic, urinary incontinence, urinary tract pain, urine odour abnormal

Reproductive system and breast disorders: amenorrhoea, balanoposthitis, benign prostatic hyperplasia, breast pain, dysmenorrhoea, endometrial hyperplasia, gynaecomastia, menstruation delayed, nipple pain, prostatitis, uterine haemorrhage, vulvovaginal inflammation

Respiratory, thoracic and mediastinal disorders: acute respiratory failure, asthma, bronchiectasis, cough, dyspnoea, epistaxis, haemoptysis, hiccups, increased bronchial secretion, nasal congestion, nasal dryness, oropharyngeal pain, productive cough, pulmonary mass, rhinorrhoea

Skin and subcutaneous tissue disorders: acne, acne fulminanas, alopecia, alopecia areata, angioedema, blister, cutaneous vasculitis, dermatitis, dermatitis allergic, dermatitis atopic, dermatitis contact, drug eruption, dry skin, ecchymosis, eczema, erythema, hyperhidrosis, intertrigo, night sweats, pruritus, psoriasis, pustular psoriasis, rash, rash erythematous, rash papular, seborrhoeic dermatitis, skin discolouration, skin disorder, skin exfoliation, skin lesion, skin lesion inflammation, target skin lesion, urticaria

Surgical and medical procedures: tooth extraction

Vascular disorders: deep vein thrombosis, flushing, haematoma, hot flush, hypotension, phlebitis, phlebitis superficial, varicose vein

Intravenous Infliximab

Other medically relevant adverse events occurring at a frequency <1% in patients treated with intravenous infliximab were as follows, presented by body system:

Administration / application site: injection site inflammation, injection site ecchymosis, injection site swelling, injection site infection

Autonomic Nervous System: fecal incontinence

Body as a whole: anaphylactoid reaction, diaphragmatic hernia, generalized edema, surgical/procedural sequela, substernal chest pain, rigors

Blood: pancytopenia, splenomegaly

Cardiovascular: circulatory failure, hypotension postural, pallor

Collagen: LE syndrome, anti-DNA antibodies, positive antinuclear factor test, anticardiolipin antibodies

Ear and Hearing: otitis externa

Endocrine: adrenal insufficiency, hypothyroidism

Eye and Vision: lacrimation abnormal, iritis, scleritis, eye pain, glaucoma

Gastrointestinal: ileus, intestinal stenosis, pancreatitis, peritonitis, rectal hemorrhage, appetite increased, anal fistula, diarrhea bloody, gastritis, intestinal obstruction, intestinal perforation

Central & Peripheral Nervous: meningitis, neuritis, optic neuritis, peripheral neuropathy, neuralgia, ataxia, dysesthesia, tremor, hyperkinesia

Heart Rate and Rhythm: arrhythmia, bradycardia, cardiac arrest, palpitations

Liver and Biliary: cholelithiasis, hepatitis, bilirubinemia, cholecystitis, hepatocellular damage, elevated GGT, fatty liver, hepatomegaly

Metabolic and Nutritional: hypercholesterolemia

Musculoskeletal: intervertebral disk herniation, tendon disorder, joint stiffness

Myo-, Endo-, Pericardial and Coronary Valve: myocardial infarction, mitral insufficiency, heart murmur, cardiac failure

Platelet, Bleeding and Clotting: thrombocytopenia

Neoplasms: adenocarcinoma, basal cell carcinoma, breast cancer, lymphoma, malignant melanoma, squamous cell carcinoma, bladder carcinoma, rectal carcinoma, uterine cancer, pulmonary carcinoma

Psychiatric: confusion, suicide attempt, irritability, nervousness, amnesia

Red Blood Cell: iron deficiency anemia, hemolytic anemia

Reproductive: menstrual irregularity, dysmenorrhea, menorrhagia, breast fibroadenosis, amenorrhea, female breast pain

Resistance Mechanism: sepsis, serum sickness, tuberculosis, fungal infection, viral infection, sarcoid-like reaction

Respiratory: Adult respiratory distress syndrome, respiratory tract infection, pleural effusion, lobar pneumonia, pulmonary edema, respiratory insufficiency, bronchospasm, asthma, hemoptysis, epistaxis, laryngitis

Skin and Appendages: erythema nodosum, rash maculopapular, rash pustular, photosensitivity reaction, edema periorbital, fascitis

Special Senses, Other: taste perversion, taste loss

Urinary: renal failure, dysuria, renal calculus, pyelonephritis

Vascular (Extracardiac): brain infarction, thrombophlebitis, vasculitis, brain ischemia, pulmonary embolism

White Cell and Reticuloendothelial: neutropenia, neutrophilia, lymphocytosis

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data

Hematologic adverse reactions observed in clinical trials in more than 1 patient include: anemia, iron deficiency anemia, leukocytosis, leukopenia, lymphadenopathy, lymphopenia, neutropenia, thrombocytopenia, thrombocytosis.

The proportion of patients with abnormal ALT levels in response to infliximab is presented in Table 4 for RA, UC and CD patients.

Table 4 – Proportion of patients with elevated ALT in subcutaneous infliximab clinical trials

8.5. Post-Market Adverse Reactions

Subcutaneous Infliximab

The following adverse reactions have been identified during post-approval use of REMSIMA SC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to REMSIMA SC exposure.

• Infections and infestations: cellulitis, disseminated tuberculosis, lower respiratory tract infection, pneumonia, sepsis
• Neoplasms benign, malignant and unspecified: breast cancer, gastric cancer, lung cancer
• Nervous system disorders: multiple sclerosis
• General disorders and administration site conditions: fatigue, malaise

Intravenous Infliximab

Additional adverse events, some with fatal outcome, reported from worldwide post-marketing experience with intravenous infliximab are included in Table 5 (see ADVERSE REACTIONS, Infections and Infusion-related Reactions). Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to intravenous infliximab exposure.

Table 5 – Post-marketing Reports

*including bovine tuberculosis (disseminated BCG infection), see 7 Warnings and Precautions, Immune, Live Vaccines/Therapeutic Infectious Agents)

9. Drug Interactions

9.2. Drug Interactions Overview

Specific drug interaction studies have not been conducted. All RA patients that received REMSIMA SC were on concomitant methotrexate therapy.

9.4. Drug-Drug Interactions

Concurrent Use of REMSIMA SC with other Biological Therapeutics

The combination of REMSIMA SC with other biological therapeutics used to treat the same conditions as REMSIMA SC, including anakinra or abatacept, is not recommended (see 7 Warnings and Precautions, Infections).

Live Vaccines/Therapeutic Infectious Agents

It is recommended that live vaccines not be given concurrently with REMSIMA SC. It is also recommended that live vaccines not be given to infants after in utero exposure to infliximab for at least 12 months following birth, unless infliximab exposure was limited to the first trimester or if infant infliximab serum levels are undetectable. Administration of a live vaccine prior to 12 months of age might be considered if the benefit of the vaccination clearly outweighs the theoretical risk of administration of live vaccines to the infants (see 7 Warnings and Precautions).

Administration of a live vaccine to a breastfed infant while the mother is receiving infliximab is not recommended unless infant infliximab serum levels are undetectable (see 7 Warnings and Precautions).

It is recommended that therapeutic infectious agents not be given concurrently with REMSIMA SC (see 7 Warnings and Precautions).

Cytochrome P450 Substrates

The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-1, IL-6, IL-10, IFN) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as infliximab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of REMSIMA SC in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.

Interactions with other drugs have not been established.

9.5. Drug-Food Interactions

Interactions with food have not been established.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

Infliximab is a chimeric IgG1κ monoclonal antibody that binds specifically to human TNFα. Infliximab binds to the soluble and transmembrane forms of TNFα with high affinity, thereby neutralizing the biological activity of TNFα. Infliximab was also shown to bind to Fcγ receptors [FcγRI, FcγRIIa, FcγRIIb, FcγRIIIa (V and F) and FcγRIIIb], FcRn, and C1q. Following binding, cells expressing transmembrane TNFα can be lysed in vitro by complement or effector cell-mediated mechanisms. Infliximab was shown to inhibit the functional activity of TNFα in a wide variety of in vitro bioassays, which demonstrated the following: induction of complement dependent cytotoxicity (CDC), induction of antibody-dependent cell-mediated cytotoxicity (ADCC), inhibition of transmembrane TNFα-dependent apoptosis, suppression of pro-inflammatory cytokine secretion [interleukin 6 (IL-6) and IL-8], and induction of regulatory macrophages.

10.2. Pharmacodynamics

There are no relevant data on the pharmacodynamic effects of subcutaneously administered infliximab.

10.3. Pharmacokinetics

Table 6 – Summary of Infliximab Pharmacokinetic Parameters in RA, UC and CD Populations at Steady State

Absorption

Single subcutaneous injections of 120, 180 and 240 mg of infliximab yielded approximately dose proportional increases in the maximum serum concentration (C_max) and area under the concentration-time curve (AUC).

After single doses of 120, 180 and 240 mg of subcutaneous infliximab administered to healthy subjects, the mean C_max values were 10.0, 15.1 and 23.1 mcg/mL, respectively, and for all doses infliximab could be detected in the serum for at least 12 weeks thereafter.

After administration of infliximab 120 mg subcutaneously every 2 weeks (from Week 6 after 2 doses of intravenous infliximab at Weeks 0 and 2 for RA; and from Week 10 after 3 doses of intravenous infliximab at Weeks 0, 2 and 6 for IBD), the median (CV%) C_trough level at Week 22 was 12.8 mcg/mL (80.1%), 17.5 mcg/mL (45.9%) and 20.4 mcg/mL (46.5%) at steady state for RA, UC and CD, respectively.

Estimated by a population PK model, the bioavailability of subcutaneous infliximab was 64.5% (95% CI: 62.5% - 66.4%).

There are no clinical trials with REMSIMA SC 120 mg without intravenous loading doses of infliximab in patients with rheumatoid arthritis. However, population pharmacokinetic and pharmacokinetics/pharmacodynamics modelling and simulation predicted comparable infliximab exposure (AUC over 8 weeks) and efficacy (DAS28 and ACR20 response) in rheumatoid arthritis patients treated with REMSIMA SC 120 mg given at Weeks 0, 1, 2, 3 and 4 when compared with REMSIMA 3 mg/kg given intravenously for the induction phase only or for both the induction and maintenance phases (REMSIMA 3 mg/kg given intravenously at Weeks 0, 2 and 6, and then every 8 weeks thereafter.

Distribution

The apparent volume of distribution during the terminal phase (mean of 7.3 to 8.8 litres) was not dependent on the administered dose of subcutaneous infliximab.

Metabolism

It is believed that infliximab is metabolized in a similar manner to other proteins in the body. It is probably hydrolysed into its component amino acids and recycled or catabolized.

Elimination

The elimination pathways for infliximab have not been characterised. Unchanged infliximab was not detected in urine.

In studies in healthy subjects, the mean (± SD) apparent clearance of infliximab 120 mg administered subcutaneously was 19.3 ± 6.9 mL/hr.

In the rheumatoid arthritis patients, the mean (± SD) clearance of infliximab 120 mg subcutaneous at Week 22 was 18.8 ± 8.3 mL/hr at steady state.

In the ulcerative colitis and Crohn’s disease patients, the mean (± SD) clearance of infliximab 120 mg subcutaneous at Week 22 was 20.3 ± 8.3 mL/hr and 17.2 ± 7.1 mL/hr at steady state, respectively.

The mean terminal half-life ranged from 11.3 days to 13.7 days for 120, 180 and 240 mg of subcutaneous infliximab administered to healthy subjects.

Special populations and conditions

It is not known if age differences, gender differences, genetic polymorphism, renal insufficiency or hepatic insufficiency have effects on clearance or volume of distribution of subcutaneous infliximab.

10.4. Immunogenicity

Rheumatoid Arthritis

In Study CT-P13 3.5 Part 2, samples that were positive for ADA were tested for neutralizing capacity. The proportion of patients who had ADA positive results at Week 30 was lower for subcutaneous infliximab-treated RA patients compared to intravenous infliximab-treated RA patients: 29.2% vs 61.1%. Among the patients who had ADA positive results at Week 30, 69.4% of subcutaneous infliximab-treated RA patients showed neutralizing antibody (NAb) positive response vs 60.7% of intravenous infliximab-treated RA patients.

The proportion of patients who had ADA positive results at Week 54 was lower for subcutaneous infliximab-treated RA patients compared to intravenous infliximab-treated RA patients: 28.6% vs 36.6%. Among the patients who had ADA positive results at Week 54, 75.0% of subcutaneous infliximab-treated RA patients showed NAb positive response vs 67.2% of intravenous infliximab-treated RA patients.

Ulcerative Colitis and Crohn’s Disease

Approximately 62.7% of subjects with ulcerative colitis and 65.1% of subjects with Crohn’s disease, treated with REMSIMA SC developed ADA to infliximab following induction treatment with intravenous infliximab and maintenance treatment with REMSIMA SC by Week 54. ADA to subcutaneous infliximab were associated with reduced or undetectable serum infliximab concentrations. The steady-state serum infliximab concentration was 11.7 mcg/mL and 17.0 mcg/mL in ADA-positive and ADA-negative patients in the UC study, respectively, and 10.9 mcg/mL and 18.0 mcg/mL in ADA-positive and ADA-negative patients in the CD study, respectively. Among ADA positive patients, 92.2% had neutralizing antibodies [160/180 (88.9%) subjects with UC and 149/151 (98.7%) subjects with CD].

1. 11. Storage, Stability, and Disposal

Store in a refrigerator (2 to 8°C).

Do not freeze. Keep the medicinal product in its outer carton in order to protect from light.

The medicinal product may be stored at temperatures up to a maximum of 25°C for a period of up to 28 days. The medicinal product must be discarded if not used within the 28-day period.

12. Special Handling Instructions

REMSIMA SC is a solution that is clear to opalescent, colourless to pale brown. Do not use if the solution is cloudy, discoloured or contains visible particulate matter.

After use, place the pre-filled syringe/ pre-filled syringe with automatic needle guard/ pre-filled pen into a puncture resistant container and discard as required by local regulations. Do not recycle the injecting device. Always keep the medicinal product out of the sight and reach of children.

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

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance: Infliximab

Chemical name: Infliximab

Molecular mass: 145,878 daltons

Molecular formula: The infliximab molecule consists of 2 identical heavy chains and 2 identical light chains. Each heavy chain consists of 450 amino acids with 11 cysteine residues, and each light chain consists of 214 amino acids with 5 cysteine residues. All cysteine residues in the heavy and light chains are involved in either intra- or inter-disulfide bonding. C-terminal lysine variation is a feature of infliximab drug substance. The oligosaccharide is bound exclusively to Asn₃₀₀ in the CH₂ domain of each heavy chain.

Physicochemical properties: Inflixmab drug substance is a clear to opalescent, colorless to pale brown solution for subcutaneous injection.

Product Characteristics

Infliximab drug substance is a purified, recombinant DNA-derived, chimeric human-mouse IgG monoclonal antibody (MAb) which binds to and neutralizes human tumor necrosis factor α (TNFα) with high affinity. Infliximab contains murine heavy (H) and light (L) chain variable regions (VH and VL, respectively) derived from the murine anti-TNFα MAb, A2, and genomic DNA-derived human H and L chain constant regions (C_H and C_L, respectively).

14. Clinical Trials

14.1. Clinical Trials by Indication

Rheumatoid Arthritis

Table 7 – Summary of Patient Demographics for Clinical Trials in RA

The efficacy and safety of subcutaneous infliximab in rheumatoid arthritis patients was assessed in a randomized, parallel-group pivotal Phase I/III study consisting of two parts: Part 1 to determine the optimal dose of subcutaneous infliximab and Part 2 to demonstrate non-inferiority in terms of efficacy of subcutaneous infliximab compared to intravenous infliximab maintenance treatment.

All patients in Parts 1 and 2 of the study received dose-loading with intravenous infliximab at a dose of 3 mg/kg at Week 0 and Week 2. In Part 2 of this study, 167 patients were randomized to receive subcutaneous infliximab 120 mg at Week 6 and every 2 weeks up to Week 54, while 176 patients were randomized to receive intravenous infliximab 3 mg/kg at Weeks 6, 14 and 22 and then switched to subcutaneous infliximab at Week 30 once-every 2 weeks up to Week 54. Methotrexate was given concomitantly.

The primary endpoint of the study was the treatment difference of the change from baseline of DAS28 (CRP) at Week 22. The estimate of treatment difference was 0.27 with corresponding lower limit of the two-sided 95% confidence interval [CI] of 0.02 (95% CI: 0.02, 0.52), which was greater than the pre-specified non-inferiority margin of -0.6 indicating non-inferiority of subcutaneous infliximab to intravenous infliximab.

Table 8 – Mean (SD) Actual Values of DAS28 (CRP and ESR)

The analysis of other efficacy endpoints showed that the efficacy profile of subcutaneous infliximab compared to intravenous infliximab in RA patients was generally comparable in terms of disease activity measured by DAS28 (CRP and ESR) and ACR response up to Week 54.

Table 9 – Proportions of Patients Achieving Clinical Response According to the ACR Criteria

Ulcerative Colitis

Table 10 – Summary of Patient Demographics for Clinical Trials in UC

Maintenance Phase Study: CP-P13 3.7

The efficacy and safety of REMSIMA SC were assessed in a randomized, double-blind, placebo-controlled clinical study in subjects with moderately to severely active UC (defined as a modified Mayo score [mMs] of 5 to 9, including an endoscopy subscore [ES] of 2 or 3). Subjects had previously demonstrated an inadequate response, loss or response, or intolerance to conventional therapy (i.e., corticosteroids alone or in combination with 6-mercaptopurine or azathioprine). Concomitant treatment with stable doses of aminosalicylates, corticosteroids, UC-related antibiotics, and/or immunomodulatory agents were permitted. Corticosteroid taper was permitted after Week 10.

A total of 548 subjects received open-label infliximab 5 mg/kg administered intravenously as induction dosing at Weeks 0, 2, and 6. A total of 438 subjects achieved clinical response at Week 10 and were randomized (2:1) in a double-blind fashion to receive REMSIMA SC 120 mg or placebo SC administered subcutaneously every 2 weeks (Q2W) via pre-filled syringe (PFS) from Week 10 through Week 54. Randomization was stratified by previous exposure to UC-related biologic agent and/or JAK inhibitors (used or not used), use of UC-related oral corticosteroids at Week 0 (used or not used), and clinical remission at Week 10 (remitter or non-remitter). Clinical response was defined as a decrease from baseline in the mMs of at least 2 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1 point.

At the time of randomization into the double-blind phase (Week 10), 92% of subjects were receiving concomitant aminosalicylates, 41% were receiving UC-related oral corticosteroids, and 22% were receiving UC-related immunomodulators. A total of 10% of randomized subjects had prior exposure to a UC-related biological or JAK inhibitor.

Subjects had a median mMs of 7.0 and 55.3% had severely active disease (mMs ≥7).

The primary endpoint was the proportion of subjects in clinical remission at Week 54. The key secondary endpoints were the proportion of subjects achieving clinical response, endoscopic-histologic mucosal improvement, and corticosteroid-free remission at Week 54.

Study Results

The results of primary and key secondary endpoints are provided in Table 11.

Table 11 – Results of Key Efficacy Endpoints at Week 54 in Subjects with Ulcerative Colitis in Study CT-P13 3.7

Crohn’s Disease

Table 12 – Summary of Patient Demographics for Clinical Trials in CD

Maintenance Phase Study: CT-P13 3.8

The efficacy and safety of REMSIMA SC were assessed in a randomized, double-blind, placebo-controlled clinical study in subjects with moderately to severely active Crohn’s Disease (CD). Enrolled subjects had a Crohn’s Disease Activity Index (CDAI) of 220 to 450 points, an average daily stool frequency (SF) ≥4 points and/or average worst daily abdominal pain (AP) score ≥2 points, and a Simplified Endoscopic Activity Score for CD (SES-CD) of ≥6 for ileal-colonic CD (or ≥4 points for isolated ileal/colonic CD). Subjects had previously demonstrated an inadequate response or intolerance to conventional therapies (corticosteroids and/or immunosuppressants). Concomitant treatment with stable doses of aminosalicylates, corticosteroids, CD-related antibiotics and/or immunomodulatory agents were permitted. Corticosteroid dose was tapered after Week 10.

A total of 396 subjects received open-label infliximab 5 mg/kg administered intravenously as induction dosing at Weeks 0, 2, and 6. A total of 343 subjects achieved clinical response at Week 10 and were randomized (2:1) in a double-blind fashion to receive REMSIMA SC 120 mg or placebo SC administered subcutaneously every 2 weeks (Q2W) via pre-filled syringe (PFS) from Week 10 through Week 54. Randomization was stratified by previous exposure to a biologic agent and/or JAK inhibitor (used or not used), use of treatment with oral corticosteroids at Week 0 (used or not used), and clinical remission at Week 10 (remitter or non-remitter). Clinical response was defined as a decrease from baseline in CDAI of at least 100 points (i.e., CDAI-100 responders).

At baseline, 63.0% subjects, 30.7% subjects and 40.8% subjects received aminosalicylates, immunomodulators and oral corticosteroids, respectively, in the REMSIMA SC group, and 57.1% subjects, 35.2% subjects and 37.1% subjects received aminosalicylates, immunomodulators and oral corticosteroids, respectively, in the Placebo SC group.

At baseline, 11.3% subjects were exposed to biologic agent and/or JAK inhibitors in REMSIMA SC group, and 8.0% subjects were exposed to biological agent and/or JAK inhibitors in Placebo SC group.

The co-primary endpoints were the proportion of subjects in clinical remission (based on CDAI) and the proportion of subjects achieving endoscopic response at Week 54. The key secondary endpoints were the proportion of subjects achieving CDAI-100 response, clinical remission (based on abdominal pain [AP] and stool frequency [SF]), endoscopic remission and corticosteroid-free remission at Week 54.

Study Results

The results of primary and key secondary endpoints are provided in Table 13.

Table 13 – Results of Key Efficacy Endpoints at Week 54 in Subjects with Crohn’s Disease in Study CT-P13 3.8

16. Non-Clinical Toxicology

General Toxicology

Two repeat-dose toxicity studies were performed in rats where intravenous infliximab were administered on Days 1 and 8 to assess for off-target toxicities. In the first study, the doses administered were 0, 10, or 40 mg/kg/dose, and in the second study, the doses administered were 0, 10, or 50 mg/kg/dose. In the first study, slight increases in absolute reticulocyte counts in males and platelet counts in males and females were observed at 40 mg/kg/dose. Minimal Kupffer cell hyperplasia was also observed in the livers of both males and females at 10 and 40 mg/kg/dose. All findings were considered non-adverse due to minimal severity. In the second study, transient subdued behavior following dosing, slight increases in reticulocyte counts and total protein levels, slight decreases in creatine kinase levels and the albumin/globulin ratio, and increased liver weights (females only) were observed in males and females at 50 mg/kg/dose; however, there were no test article-related histopathological correlates and the findings were considered non-adverse.

Carcinogenicity

Studies have not been conducted to evaluate the carcinogenic potential of subcutaneous infliximab.

Genotoxicity

Studies have not been conducted to evaluate the genotoxic potential of subcutaneous infliximab.

Reproductive and Developmental Toxicity

Studies have not been conducted to evaluate the potential reproductive or developmental toxicity of subcutaneous infliximab.

Local Tolerance

A single-dose study was conducted in rabbits in which animals were administered a single dose of 80.4 mg of infliximab by a single SC injection. The concentration of the formulation administered was 120 mg/mL, which corresponds to the clinical subcutaneous dosing concentration. No notable abnormal signs were observed during clinical inspection of the injection site. In addition, no adverse macroscopic or histopathological findings were observed at the injection site. It was concluded that subcutaneous administration of infliximab was locally well-tolerated in rabbits at a concentration of 120 mg/mL.