ZESSLY Powder for concentrate for solution for infusion Ref.[7418] Active ingredients: Infliximab

Zessly 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. Zessly should be administered intravenously. Zessly infusions should be administered by qualified healthcare professionals trained to detect any infusion-related issues. Patients treated with Zessly should be given the package leaflet and the patient reminder card.

During Zessly 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.

Zessly 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, Zessly 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, Zessly 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

Zessly should be administered intravenously over a 2 hour period. All patients administered Zessly 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 Zessly (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

4 years at 2°C–8°C.

Zessly may be stored at temperatures up to a maximum of 30°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, Zessly must not be returned to refrigerated storage.

After reconstitution

Chemical and physical in use stability of the reconstituted solution has been demonstrated for 24 hours at 2°C–30°C. From a microbiological point of view, the product should be used as soon as possible but 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 should not be longer than 24 hours at 2°C–8°C.

Store in a refrigerator (2°C–8°C).

For storage conditions up to 30°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 rubber stopper and aluminium crimp protected by a plastic cap.

Zessly is available in packs containing 1, 2, 3, 4 or 5 vials.

Not all pack sizes may be marketed.

1. Calculate the dose and the number of Zessly vials needed. Each Zessly vial contains 100 mg infliximab. Calculate the total volume of reconstituted Zessly solution required.
2. Under aseptic conditions, reconstitute each Zessly vial with 10 ml of water for injections, using a syringe equipped with a 21-gauge (0.8 mm) or smaller needle. Remove flip-top from the vial and wipe the top with a 70% alcohol swab. Insert the syringe needle into the vial through the centre of the rubber stopper and direct the stream of water for injections to the glass wall of the vial. Gently swirl the solution by rotating the vial to dissolve the lyophilised powder. Avoid prolonged or vigorous agitation. DO NOT SHAKE. Foaming of the solution on reconstitution is not unusual. Allow the reconstituted solution to stand for 5 minutes. Check that the solution is colourless to light brown and opalescent. The solution may develop a few fine translucent particles, as infliximab is a protein. Do not use if opaque particles, discolouration, or other foreign particles are present.
3. Dilute the total volume of the reconstituted Zessly solution dose to 250 ml with sodium chloride 9 mg/ml (0.9%) solution for infusion. Do not dilute the reconstituted Zessly 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 Zessly. Slowly add the total volume of reconstituted Zessly solution to the 250-ml infusion bottle or bag. Gently mix.
4. Administer the infusion solution over a period of not less than the infusion time recommended (see section 4.2). Use only an infusion set with an in-line, sterile, non- pyrogenic, low protein-binding filter (pore size 1.2 micrometre or less). 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. When reconstitution and dilution are performed under aseptic conditions, Zessly infusion solution can be used within 24 hours if stored at 2°C–8°C. Do not store any unused portion of the infusion solution for reuse.
5. No physical biochemical compatibility studies have been conducted to evaluate the co-administration of Zessly with other agents. Do not infuse Zessly concomitantly in the same intravenous line with other agents.
6. Visually inspect Zessly for particulate matter or discolouration prior to administration. Do not use if visibly opaque particles, discolouration or foreign particles are observed.
7. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.