REMSIMA

Remsima treatment is to be initiated and supervised by qualified physicians experienced in the diagnosis and treatment of conditions for which Remsima is indicated. Patients treated with Remsima should be given the package leaflet and the patient reminder card.

Instruction for use is provided in the package leaflet. For subsequent injections and after proper training in subcutaneous injection technique, patients may self-inject with Remsima if their physician determines that it is appropriate and with medical follow-up 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. 4).

, corticosteroids and immunosuppressants should be optimised. It is important to check the product labels to ensure that the correct formulation (intravenous or subcutaneous) is being administered to the patient, as prescribed. Remsima subcutaneous formulation is not intended for intravenous administration and should be administered via a subcutaneous injection only.

Posology Adults (≥18 years) Rheumatoid arthritis Treatment with Remsima subcutaneous formulation should be initiated with loading doses of infliximab which may be intravenous or subcutaneous. When subcutaneous loading is used, Remsima 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 administered subcutaneously should be initiated as maintenance therapy 4 weeks after the second intravenous administration.

The recommended maintenance dose for Remsima subcutaneous formulation is 120 mg once every 2 weeks. Remsima must be given concomitantly with methotrexate. Available data suggest that the clinical response is usually achieved within 12 weeks of treatment.

1). Moderately to severely active Crohn’s disease The first treatment with Remsima administered subcutaneously should be initiated as maintenance therapy 4 weeks after the last administration of intravenous infusions. Before initiating treatment with Remsima subcutaneous formulation, 2 intravenous infusions of infliximab 5 mg/kg should be given at 2 weeks apart, and an additional intravenous infusion of infliximab 5 mg/kg may be given 4 weeks after the second infusion.

The recommended maintenance dose for Remsima subcutaneous formulation is 120 mg once every 2 weeks. If a patient does not respond after loading doses of intravenous infliximab, 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. 1). Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.

Fistulising, active Crohn’s disease The first treatment with Remsima administered subcutaneously should be initiated as maintenance therapy 4 weeks after the last administration of intravenous infusions. Before initiating treatment with Remsima subcutaneous formulation, 2 intravenous infusions of infliximab 5 mg/kg should be given at 2 weeks apart, and an additional intravenous infusion of infliximab 5 mg/kg may be given 4 weeks after the second infusion.

The recommended maintenance dose for Remsima subcutaneous formulation is 120 mg once every 2 weeks. If a patient does not respond after loading doses of intravenous infliximab, no additional treatment with infliximab should be given.

Available data do not support further infliximab treatment, in patients not responding within 14 weeks of the initial infusion. 1). Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.

In Crohn’s disease, experience with re-administration if signs and symptoms of disease recur is limited and comparative data on the benefit/risk of the alternative strategies for continued treatment are lacking. Ulcerative colitis The first treatment with Remsima administered subcutaneously should be initiated as maintenance therapy 4 weeks after the last administration of intravenous infusions.

Before initiating treatment with Remsima subcutaneous formulation, 2 intravenous infusions of infliximab 5 mg/kg should be given at 2 weeks apart, and an additional intravenous infusion of infliximab 5 mg/kg may be given 4 weeks after the second infusion.

The recommended maintenance dose for Remsima subcutaneous formulation is 120 mg once every 2 weeks. 1). Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.

Ankylosing spondylitis Treatment with Remsima administered subcutaneously should be initiated as maintenance therapy 4 weeks after the last administration of two intravenous infusions of infliximab 5 mg/kg given 2 weeks […]

5% of control patients. 4). The safety profile of Remsima subcutaneous formulation from active rheumatoid arthritis (evaluated in 168 and 175 patients for the subcutaneous infliximab group and the intravenous infliximab group, respectively), active Crohn’s disease (evaluated in 297, 38 and 105 patients for the subcutaneous infliximab group, the intravenous infliximab group and the placebo group, respectively) and active ulcerative colitis patients (evaluated in 334, 40 and 140 patients for the subcutaneous infliximab group, the intravenous infliximab group and the placebo group, respectively) was overall similar to the safety profile of the intravenous formulation.

Tabulated list of adverse reactions Table 1 lists the ADRs based on experience from clinical studies as well as adverse reactions, some with fatal outcome, reported from post-marketing experience. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. g. influenza, herpes virus infection, COVID-19*). g. sepsis, cellulitis, abscess). g. candidiasis, onychomycosis).

Rare:

Meningitis, opportunistic infections (such as invasive fungal infections [pneumocystosis, histoplasmosis, aspergillosis, coccidioidomycosis, cryptococcosis, blastomycosis], bacterial infections [atypical mycobacterial, listeriosis, salmonellosis], and viral infections [cytomegalovirus]), parasitic infections, hepatitis B reactivation.

Not known:

Vaccine breakthrough infection (after in utero exposure to infliximab)**.

Neoplasms benign, malignant and unspecified (including cysts and polyps) Rare:

Lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s disease, leukaemia, melanoma, cervical cancer.

Not known:

Hepatosplenic T-cell lymphoma (primarily in adolescents and young adult males with Crohn’s disease and ulcerative colitis), Merkel cell carcinoma, Kaposi’s sarcoma.

Blood and lymphatic system disorders Common:

Neutropenia, leukopenia, anaemia, lymphadenopathy.

Uncommon:

Thrombocytopenia, lymphopenia, lymphocytosis.

Rare:

Agranulocytosis (including infants exposed in utero to infliximab), thrombotic thrombocytopenic purpura, pancytopenia, haemolytic anaemia, idiopathic thrombocytopenic purpura.

Immune system disorders Common:

Allergic respiratory symptom.

Uncommon:

Anaphylactic reaction, lupus-like syndrome, serum sickness or serum sickness-like reaction. Rare Anaphylactic shock, vasculitis, sarcoid-like reaction Metabolism and nutrition disorders Uncommon: Dyslipidaemia Psychiatric disorders Common: Depression, insomnia.

Uncommon:

Amnesia, agitation, confusion, somnolence, nervousness.

Rare:

Apathy.

Nervous system disorders Very common:

Headache.

Common:

Vertigo, dizziness, hypoaesthesia, paraesthesia.

Uncommon:

Seizure, neuropathy.

Rare:

Transverse myelitis, central nervous system demyelinating disorders (multiple sclerosis-like disease and optic neuritis), peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy).

Not known:

Cerebrovascular accidents in close temporal association with infusion. g. bronchitis, pneumonia), dyspnoea, epistaxis Uncommon Pulmonary oedema, bronchospasm, pleurisy, pleural effusion Rare Interstitial lung disease (including rapidly progressive disease, lung fibrosis and pneumonitis) Gastrointestinal disorders Very common: Abdominal pain, nausea Common: Gastrointestinal haemorrhage, diarrhoea, dyspepsia, gastroesophageal reflux, constipation Uncommon Intestinal perforation, intestinal stenosis, diverticulitis, pancreatitis, cheilitis Hepatobiliary disorders Common: Hepatic function abnormal, transaminases increased.

Uncommon:

Hepatitis, hepatocellular damage, cholecystitis.

Rare:

Autoimmune hepatitis, jaundice.

Not known:

Liver failure.

Skin and subcutaneous tissue disorders Common:

New onset or worsening psoriasis including […]

Traceability In order to improve the traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded. 8). Acute reactions including anaphylactic reactions may develop during (within seconds) or within a few hours following administration of infliximab.

If acute reactions occur, medical treatment should be sought immediately. For this reason, the initial intravenous administrations should take place where emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway is immediately available.

, an antihistamine, hydrocortisone and/or paracetamol to prevent mild and transient effects. Localised injection site reactions predominantly of mild to moderate in nature included the following reactions limited to injection site: erythema, pain, pruritus, swelling, induration, bruising, haematoma, oedema, coldness, paraesthesia, haemorrhage, irritation, rash, ulcer, urticaria, application site vesicles and scab were reported to be associated with infliximab subcutaneous treatment.

Most of these reactions may occur immediately or within 24 hours after subcutaneous injection. Most of these reactions resolved spontaneously without any treatment. Antibodies to infliximab may develop and have been associated with an increased frequency of infusion reactions when administered by intravenous infusion.

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 with intravenously administered infliximab.

Concomitant administration of immunomodulators has been associated with lower incidence of antibodies to infliximab and in the case of intravenously administered infliximab, 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 infliximab treatment are at greater risk of developing these antibodies. Antibodies to infliximab cannot always be detected in serum samples. 8). In clinical studies, delayed hypersensitivity reactions have been reported.

Available data suggest an increased risk for delayed hypersensitivity with increasing infliximab free interval. 8). If patients are re-treated after a prolonged period, they must be closely monitored for signs and symptoms of delayed hypersensitivity.

Infections Patients must be monitored closely for infections including tuberculosis before, during and after treatment with infliximab. Because the elimination of infliximab may take up to six months, monitoring should be continued throughout this period.

Further treatment with infliximab must not be given if a patient develops a serious infection or sepsis. Caution should be exercised when considering the use of infliximab 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 (TNFα) mediates inflammation and modulates cellular immune responses. Experimental data show that TNFα 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 TNFα may mask symptoms of infection such as fever. Early recognition of atypical clinical presentations of serious infections and of typical clinical presentation of rare and unusual infections is critical in order to minimise delays in diagnosis and treatment.

Patients taking TNF-blockers are more susceptible to serious infections. Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral, and other opportunistic infections have been observed in patients treated with infliximab.

Some of these infections have been fatal; the most frequently reported opportunistic infections with a mortality rate of >5% include pneumocystosis, candidiasis, listeriosis and aspergillosis. Patients who develop a new infection while undergoing treatment with infliximab, should be monitored closely and undergo a complete diagnostic evaluation.

Administration of infliximab 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. Tuberculosis There have been reports of active tuberculosis in patients receiving infliximab.

It should be noted that in the majority of these reports tuberculosis was extrapulmonary, presenting as either local or disseminated disease. Before starting treatment with infliximab, 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. g. tuberculin skin test, chest X-ray, and/or Interferon Gamma Release Assay), 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 reminder card. […]

1. 4). 8).