INFLECTRA Powder for solution for infusion Ref.[50510] Active ingredients: Infliximab

Inflectra treatment is to be initiated and supervised by qualified physicians experienced in the diagnosis and treatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosing spondylitis, psoriatic arthritis or psoriasis. Inflectra should be administered intravenously. Inflectra infusions should be administered by qualified healthcare professionals trained to detect any infusion-related issues. Patients treated with Inflectra should be given the package leaflet and the patient reminder card.

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

Posology

Adults (≥18 years)

Rheumatoid arthritis

3 mg/kg given as an intravenous infusion followed by additional 3 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.

Inflectra must be given concomitantly with methotrexate.

Available data suggest that the clinical response is usually achieved within 12 weeks of treatment. If a patient has an inadequate response or loses response after this period, consideration may be given to increase the dose step-wise by approximately 1.5 mg/kg, up to a maximum of 7.5 mg/kg every 8 weeks. Alternatively, administration of 3 mg/kg as often as every 4 weeks may be considered. If adequate response is achieved, patients should be continued on the selected dose or dose frequency. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within the first 12 weeks of treatment or after dose adjustment.

Moderately to severely active Crohn’s disease

5 mg/kg given as an intravenous infusion followed by an additional 5 mg/kg infusion 2 weeks after the first infusion. If a patient does not respond after 2 doses, no additional treatment with infliximab should be given. Available data do not support further infliximab treatment, in patients not responding within 6 weeks of the initial infusion.

In responding patients, the alternative strategies for continued treatment are:

• Maintenance: Additional infusion of 5 mg/kg at 6 weeks after the initial dose, followed by infusions every 8 weeks or
• Re-administration: Infusion of 5 mg/kg if signs and symptoms of the disease recur (see ‘Re-administration’ below and section 4.4).

Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg but who lost response indicate that some patients may regain response with dose escalation (see section 5.1). Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.

Fistulising, active Crohn’s disease

5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusions at 2 and 6 weeks after the first infusion. If a patient does not respond after 3 doses, no additional treatment with infliximab should be given.

In responding patients, the alternative strategies for continued treatment are:

• Maintenance: Additional infusions of 5 mg/kg every 8 weeks or
• Re-administration: Infusion of 5 mg/kg if signs and symptoms of the disease recur followed by infusions of 5 mg/kg every 8 weeks (see ‘Re-administration’ below and section 4.4).

Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg but who lost response indicate that some patients may regain response with dose escalation (see section 5.1). Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.

In Crohn’s disease, experience with re-administration if signs and symptoms of disease recur is limited and comparative data on the benefit/risk of the alternative strategies for continued treatment are lacking.

Ulcerative colitis

5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.

Available data suggest that the clinical response is usually achieved within 14 weeks of treatment, i.e. three doses. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.

Ankylosing spondylitis

5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 6 to 8 weeks. If a patient does not respond by 6 weeks (i.e. after 2 doses), no additional treatment with infliximab should be given.

Psoriatic arthritis

5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Psoriasis 5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. If a patient shows no response after 14 weeks (i.e. after 4 doses), no additional treatment with infliximab should be given.

Re-administration for Crohn’s disease and rheumatoid arthritis

If the signs and symptoms of disease recur, infliximab can be re-administered within 16 weeks following the last infusion. In clinical studies, delayed hypersensitivity reactions have been uncommon and have occurred after infliximab-free intervals of less than 1 year (see sections 4.4 and 4.8). The safety and efficacy of re-administration after an infliximab-free interval of more than 16 weeks has not been established. This applies to both Crohn’s disease patients and rheumatoid arthritis patients.

Re-administration for ulcerative colitis

The safety and efficacy of re-administration, other than every 8 weeks, has not been established (see sections 4.4 and 4.8).

Re-administration for ankylosing spondylitis

The safety and efficacy of re-administration, other than every 6 to 8 weeks, has not been established (see sections 4.4 and 4.8).

Re-administration for psoriatic arthritis

The safety and efficacy of re-administration, other than every 8 weeks, has not been established (see sections 4.4 and 4.8).

Re-administration for psoriasis

Limited experience from re-treatment with one single infliximab dose in psoriasis after an interval of 20 weeks suggests reduced efficacy and a higher incidence of mild to moderate infusion reactions when compared to the initial induction regimen (see section 5.1). Limited experience from re-treatment following disease flare by a re-induction regimen suggests a higher incidence of infusion reactions, including serious ones, when compared to 8-weekly maintenance treatment (see section 4.8).

Re-administration across indications

In case maintenance therapy is interrupted, and there is a need to restart treatment, use of a re-induction regimen is not recommended (see section 4.8). In this situation, infliximab should be re-initiated as a single dose followed by the maintenance dose recommendations described above.

Special populations

Elderly

Specific studies of infliximab in elderly patients have not been conducted. No major age-related differences in clearance or volume of distribution were observed in clinical studies. No dose adjustment is required (see section 5.2). For more information about the safety of infliximab in elderly patients (see sections 4.4 and 4.8).

Renal and/or hepatic impairment

Infliximab has not been studied in these patient populations. No dose recommendations can be made (see section 5.2).

Paediatric population

Crohn’s disease (6 to 17 years):

5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Available data do not support further infliximab treatment in children and adolescents not responding within the first 10 weeks of treatment (see section 5.1).

Some patients may require a shorter dosing interval to maintain clinical benefit, while for others a longer dosing interval may be sufficient. Patients who have had their dose interval shortened to less than 8 weeks may be at greater risk for adverse reactions. Continued therapy with a shortened interval should be carefully considered in those patients who show no evidence of additional therapeutic benefit after a change in dosing interval.

The safety and efficacy of infliximab have not been studied in children with Crohn’s disease below the age of 6 years. Currently available pharmacokinetic data are described in section 5.2 but no recommendation on a posology can be made in children younger than 6 years.

Ulcerative colitis (6 to 17 years):

5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Available data do not support further infliximab treatment in paediatric patients not responding within the first 8 weeks of treatment (see section 5.1).

The safety and efficacy of infliximab have not been studied in children with ulcerative colitis below the age of 6 years. Currently available pharmacokinetic data are described in section 5.2 but no recommendation on a posology can be made in children younger than 6 years.

Psoriasis:

The safety and efficacy of infliximab in children and adolescents younger than 18 years for the indication of psoriasis have not been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.

Juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis:

The safety and efficacy of infliximab in children and adolescents younger than 18 years for the indications of juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis have not been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.

Juvenile rheumatoid arthritis:

The safety and efficacy of infliximab in children and adolescents younger than 18 years for the indication of juvenile rheumatoid arthritis have not been established. Currently available data are described in sections 4.8 and 5.2 but no recommendation on a posology can be made.

Method of administration

Infliximab should be administered intravenously over a 2 hour period. All patients administered infliximab are to be observed for at least 1-2 hours post-infusion for acute infusion-related reactions. Emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway must be available. Patients may be pre-treated with e.g. an antihistamine, hydrocortisone and/or paracetamol and infusion rate may be slowed in order to decrease the risk of infusion-related reactions especially if infusion-related reactions have occurred previously (see section 4.4).

Shortened infusions across adult indications

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

For preparation and administration instructions, see section 6.6.

No case of overdose has been reported. Single doses up to 20 mg/kg have been administered without toxic effects.

Before reconstitution:

5 years at 2°C–8°C.

Inflectra may be stored at temperatures up to a maximum of 25°C for a single period of up to 6 months, but not exceeding the original expiry date. The new expiry date must be written on the carton. Upon removal from refrigerated storage, Inflectra must not be returned to refrigerated storage.

After reconstitution and dilution:

Chemical and physical in use stability of the diluted solution has been demonstrated for up to 60 days at 2°C-8°C and for an additional 24 hours at 25°C after removal from refrigeration. From a microbiological point of view, the infusion solution should be administered immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C–8°C, unless reconstitution/dilution has been taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C–8°C).

For storage conditions up to 25°C before reconstitution of the medicinal product, see section 6.3.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Type 1 glass vial with a (butyl) rubber stopper and an aluminium seal with a flip-off button.

Pack sizes of 1, 2, 3, 4, 5 vials.

Not all pack sizes may be marketed.

1. The dose and the number of Inflectra vials have to be calculated. Each Inflectra vial contains 100 mg infliximab. The required total volume of reconstituted Inflectra solution has to be calculated.

2. Under aseptic conditions, each Inflectra vial should be reconstituted with 10 mL of water for injections, using a syringe equipped with a 21-gauge (0.8 mm) or smaller needle. The flip-top from the vial has to be removed and the top has to be wiped with a 70% alcohol swab. The syringe needle should be inserted into the vial through the centre of the rubber stopper and the stream of water for injections directed to the glass wall of the vial. The solution has to be gently swirled by rotating the vial to dissolve the powder. Prolonged or vigorous agitation must be avoided. THE VIAL MUST NOT BE SHAKEN. Foaming of the solution on reconstitution may occur. The reconstituted solution should stand for 5 minutes. The solution should be colourless to light yellow and opalescent. The solution may develop a few fine translucent particles, as infliximab is a protein. The solution must not be used if opaque particles, discolouration, or other foreign particles are present.

3. The required volume of the reconstituted Inflectra solution should be diluted to 250 mL with sodium chloride 9 mg/mL (0.9%) solution for infusion. Do not dilute the reconstituted Inflectra solution with any other diluent. The dilution can be accomplished by withdrawing a volume of the sodium chloride 9 mg/mL (0.9%) solution for infusion from the 250-mL glass bottle or infusion bag equal to the volume of reconstituted Inflectra. The required volume of reconstituted Inflectra solution should slowly be added to the 250-mL infusion bottle or bag and gently be mixed. For volumes greater than 250 mL, either use a larger infusion bag (e.g. 500 mL, 1000 mL) or use multiple 250 mL infusion bags to ensure that the concentration of the infusion solution does not exceed 4 mg/mL. If stored refrigerated after reconstitution and dilution, the infusion solution must be allowed to equilibrate at room temperature to 25 °C for 3 hours prior to Step 4 (infusion). Storage beyond 24 hours at 2°C-8°C applies to preparation of Inflectra in the infusion bag only.

4. The infusion solution has to be administered over a period of not less than the infusion time recommended (see section 4.2). Only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 1.2 micrometre or less) should be used. Since no preservative is present, it is recommended that the administration of the solution for infusion is to be started as soon as possible and within 3 hours of reconstitution and dilution. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution/dilution has been taken place in controlled and validated aseptic conditions (see section 6.3 above). Any unused portion of the infusion solution should not be stored for reuse.

5. Inflectra should be visually inspected for particulate matter or discolouration prior to administration. If visibly opaque particles, discolouration or foreign particles are observed it should not be used.

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