TEIZEILD Concentrate for solution for infusion Ref.[116513] Active ingredients: Teplizumab

Teizeild should be administered by a healthcare professional with access to appropriate medical support to manage potential severe adverse reactions.

Laboratory evaluation and vaccination prior to initiation

• Prior to initiating Teizeild, a complete blood count and liver enzyme tests should be obtained.
• Use of Teizeild is not recommended in patients with (see section 4.4):
  • Lymphocyte count less than 1.0 x 10⁹ lymphocytes/L
  • Haemoglobin less than 100 g/L
  • Platelet count less than 100 x 10⁹ platelets/L
  • Absolute neutrophil count less than 1.5 x 10⁹ neutrophils/L
  • Elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 2 times the upper limit of normal (ULN) or bilirubin greater than 1.5 times ULN
  • Laboratory or clinical evidence of acute infection with Epstein-Barr virus (EBV) or cytomegalovirus (CMV)
  • Active serious infection or chronic active infection other than localised skin infections
• All age-appropriate vaccinations should be administered prior to initiating Teizeild (see section 4.4 for detailed guidance).

Premedication

Premedication should be used prior to Teizeild infusion for the first 5 days of dosing with: (1) a nonsteroidal anti-inflammatory drug (NSAID) or paracetamol, (2) an antihistamine, and (3) use of an antiemetic could be considered (see section 4.4). Additional doses of premedication should be administered if needed.

Posology

Teizeild should be administered by intravenous infusion (over a minimum of 30 minutes), using a body surface area (BSA)-based dosing, once daily for 14 consecutive days as follows:

• Day 1: 65 micrograms/m²
• Day 2: 125 micrograms/m²
• Day 3: 250 micrograms/m²
• Day 4: 500 micrograms/m²
• Days 5 through 14: 1 030 micrograms/m²

Missed dose(s)

If a planned Teizeild infusion is missed, dosing should be resumed by administering all remaining doses on consecutive days to complete the 14-day treatment course.

Treatment discontinuation

Temporary treatment discontinuation may be required according to the severity of laboratory abnormalities. Based on clinical judgment, treatment should be paused if platelet count, neutrophil count, or haemoglobin level decreases significantly.

Dose interruption should not exceed 3 days. Dosing may be resumed by administering all remaining doses on consecutive days to complete the 14-day treatment course (e.g. if dosing is missed on Days 4 and 5, dosing may restart at Day 6 with the dosing level specified for Day 4).

Treatment should be permanently discontinued if:

• Elevated liver enzymes (ALT or AST greater than 5 times ULN) or bilirubin greater than 3 times ULN
• Prolonged severe lymphopenia (<0.5 x 10⁹ lymphocytes/L lasting 1 week or longer)
• Clinically relevant (physician´s decision based on the individual patient´s data) decrease of platelet count, neutrophil count, or haemoglobin level for 3 consecutive days
• A serious infection develops

For additional information, see sections 4.4 and 4.8.

Special populations

Elderly

Clinical studies did not include elderly patients (65 years of age and older).

Renal impairment

No studies have been performed in patients with renal impairment (see section 5.2).

Hepatic impairment

No studies have been performed in patients with hepatic impairment (see section 5.2).

Body weight

BSA-based dosing is required to normalise the exposure of Teizeild across body weight (see Posology and section 5.2).

Paediatric population

The safety and efficacy of Teizeild in children younger than 8 years of age have not been established.

Method of administration

Teizeild should be administered by intravenous infusion over a minimum of 30 minutes.

Two doses should not be administered on the same day.

For instructions on preparation of the medicinal product before administration, see section 6.6 and at the end of the package leaflet.

There is no clinical experience with overdose with teplizumab.

There is no known specific antidote for Teizeild overdose. In the event of overdose the patient should be monitored for any signs or symptoms of adverse reactions and all appropriate measures should be taken immediately. Clinical judgement should be applied.

Unopened vial:

3 years.

After dilution:

IV infusion bags

Chemical, physical and microbial in-use stability has been demonstrated for 6 hours at ambient temperature (15°C to 25°C).

From a microbiological point of view, it is recommended that the product should be used immediately. 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 6 hours at ambient temperature (15°C to 25°C).

Syringe-based infusions

Chemical, physical and microbial in-use stability has been demonstrated for 12 hours under refrigerated conditions (2°C to 8°C), followed by no more than 6 hours at ambient temperature (15°C to 25°C).

From a microbiological point of view, it is recommended that the product should be used immediately. 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 12 hours under refrigerated conditions (2°C to 8°C), followed by no more than 6 hours at ambient temperature (15°C to 25°C).

Store in a refrigerator (2°C to 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

Store upright.

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

Teizeild is supplied in a 2 mL Type 1 borosilicate glass vial with a butyl rubber stopper and an aluminium seal with a coloured polypropylene flip-off cap.

Pack sizes of 1, 10 or 14 vials.

Not all pack sizes may be marketed.

Preparation for intravenous administration

• Must dilute Teizeild prior to use. This requires a two-step dilution process.
• In preparation for dilution, inspect the vial visually before use (the solution should be clear and colourless). Do not use if particulate matter or colouration is seen.
• Prepare using aseptic technique. Each vial is intended for single dose only.
• Start the infusion immediately after dilution. If not used immediately, store the diluted solution for infusion (see section 6.3).

Step 1: Initial dilution (1:10)

Prepare 18 mL of sodium chloride 9 mg/mL (0.9%) solution for injection in a:

• Sterile glass vial
  or
• Sterile polyvinylchloride (PVC) with di-(2-ethylhexyl)phthalate (DEHP) infusion bag
  or
• Sterile syringe (polypropylene (PP), polycarbonate (PC) or glass)

Remove the cap from the vial – this is the preparation start time (see section 6.3).

Based on BSA dosing requirements (e.g. >1.94 m²), two (2) Teizeild vials may be needed for days 5 through 14.

In this case, to make sure the complete dose for each day is contained in one (1) infusion bag or syringe:

• Prepare two (2) dilution solutions
• Add the cumulative volume for the calculated dose to a single infusion bag or syringe

Remove 2 mL of Teizeild from the vial and slowly add to the 18 mL of sodium chloride 9 mg/mL (0.9%) solution for injection. Mix gently by slowly swirling the vial or rocking the infusion bag or syringe. The resulting 20 mL diluted solution contains 100 micrograms (mcg)/mL of teplizumab.

Calculate patient's BSA (e.g. using the Mosteller formula) before treatment.

Using the patient's BSA, calculate the dose based on treatment day (see section 4.2).

Dose (x mcg)=Daily dosage level (x mcg / m²) x BSA (m²)

Calculate the volume of 100 mcg/mL Teizeild solution (prepared in Step 1) to be further diluted in Step 2.

Volume of initial dilution, 1:10 (mL) = Dose (x mcg) / 100

Step 2: Final dilution

There are two different methods for intravenous administration of final dilution: infusion bag or syringe pump infusion. Use the appropriate calculation depending on the selected method.

Infusion bag for intravenous administration:

• Using an appropriately sized syringe (e.g. 5 mL), withdraw the volume of diluted solution required for that day's calculated dose from the 100 mcg/mL solution (see Step 1: Initial dilution (1:10)).
• Slowly add contents of the syringe containing the dose to a PVC with DEHP infusion bag containing 25 mL sodium chloride 9 mg/mL (0.9%) solution for injection. Gently rock the infusion bag to ensure that the solution mixes sufficiently. Do not shake.
• Infusion administration has a minimum duration of 30 minutes. Rate may be slowed for patient's tolerability.

Syringe (PP, PC or glass) for intravenous infusion via syringe pump [Concentration range 15 mcg/mL to 60 mcg/mL]:

• Calculate the maximum volume that can be administrated for the calculated dose (based on treatment day, dose and patient BSA) using a minimum infusion concentration of 15 mcg/mL.

Volume_Infusion (mL) = Dose (x mcg) / Minimum infusion concentration 15 mcg/mL

• Calculate the volume of saline to be added to the infusion syringe:

a) If the calculated maximum volume to be administered is ≤60 mL:

Volume_Saline (mL) = Volume_Infusion (mL) - Volume_{initialdilution,1:10} (mL)

b) If the calculated maximum volume to be administered exceeds 60 mL – the maximum infusion volume is capped at 60 mL.

Volume_Saline (mL) = 60 mL - Volume_{initialdilution,1:10} (mL)

• Measure the appropriate volume of saline and transfer it to the infusion syringe.
• Using an appropriately sized syringe (e.g. 5 mL), withdraw the volume of diluted Teizeild solution calculated above (see volume of initial dilution, 1:10) and add it to the infusion syringe.
• Gently rock the infusion syringe to ensure that the solution mixes sufficiently. Do not shake.
• Attach infusion syringe to a syringe pump. The syringe pump should support rates as low as 1 mL/hour.
• Run infusion with syringe pump – do not manually push the syringe. Calculate the infusion rate (to ensure a minimum of 30 minutes). The maximum infusion rate should be 2 mL/min (maximum 120 mL/hour). The actual rate will vary based on the volume of infusion, as shown below.

Infusion rate (mL/minute) = Volume_Infusion (mL) / 30 minutes

• Infusion administration has a minimum duration of 30 minutes. Rate may be slowed for patient's tolerability.

These steps may be followed if using a sterile glass vial for dilution preparation instead of a syringe (for intravenous infusion via syringe pump). An overfill should be considered as part of the calculations.

Disposal

The unused portion of remaining diluted Teizeild solution in the PVC with DEHP infusion bag, syringe or sterile glass vial should be discarded.

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