KIMMTRAK Concentrate for solution for infusion Ref.[49841] Active ingredients: Tebentafusp

KIMMTRAK should be administered under the direction and supervision of a physician experienced in the use of anti-cancer agents and who is prepared to manage cytokine release syndrome in an environment where full resuscitation facilities are immediately available. Hospitalisation is recommended for at least the first three infusions of KIMMTRAK (see section 4.4).

Patients treated with KIMMTRAK must have HLA-A*02:01 genotype determined by any validated HLA genotyping assay.

Posology

The recommended dose of KIMMTRAK is 20 micrograms on Day 1, 30 micrograms on Day 8, 68 micrograms on Day 15, and 68 micrograms once every week thereafter (see section 6.6). Treatment with KIMMTRAK should be continued while patient is deriving clinical benefit and in the absence of unacceptable toxicities (see section 5.1).

Premedication

To minimize the risk of hypotension associated with cytokine release syndrome (CRS), intravenous fluids should be administered prior to starting KIMMTRAK infusion based on clinical evaluation and the volume status of the patient.

For patients with preexisting adrenal insufficiency on maintenance systemic corticosteroids, adjusting the corticosteroid dose should be considered to manage the risk of hypotension.

Dose adjustments

No dose reductions of KIMMTRAK are recommended. KIMMTRAK should be withheld or discontinued to manage adverse reactions as described in Table 1 and Table 2.

If CRS is suspected, the symptoms should be identified and promptly managed according to recommendations in Table 1. See Table 2 for management guidelines for acute skin reactions.

Table 1. CRS grading and management guidance:

^* Based on American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading of CRS criteria (Lee et. al 2019).

Table 2. Recommended management and dose modifications for acute skin reactions:

^a Based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (NCI CTCAEv4.03).

Special populations

Paediatric population

The safety and efficacy of KIMMTRAK in children under the age of 18 years have not been established. No data are available.

Elderly

No dose adjustment is required for elderly patients (≥65 years of age).

Renal impairment

Based on safety and efficacy analyses, dose adjustment is not necessary in patients with mild to moderate renal dysfunction. No dose recommendations can be made for patients with severe renal impairment because of the lack of pharmacokinetic data; therefore, dosing in patients with severe renal impairment should be done with caution and careful monitoring (see section 5.2).

Patients with history of cardiac disease

KIMMTRAK has not been studied in patients with history of significant cardiac disease. Patients with cardiac disease, QT prolongation and risk factors for cardiac failure should be monitored carefully (see section 4.4).

Method of administration

KIMMTRAK is for intravenous use. The recommended infusion period is 15 to 20 minutes.

KIMMTRAK requires dilution with sodium chloride 9 mg/mL (0.9%) solution for injection containing human albumin for intravenous infusion. Each vial of KIMMTRAK is intended for use as single-dose only. Do not shake the KIMMTRAK vial.

For instructions on dilution and administration of the medicinal product, see section 6.6.

First three treatment doses

First three doses of KIMMTRAK should be administered in a hospital setting with overnight monitoring for signs and symptoms of CRS for at least 16 hours. Vital signs should be monitored pre dose and at a minimum of every 4 hours until resolution of symptoms. If clinically indicated, more frequent monitoring or prolongation of hospitalization should be performed.

If patients experience Grade 3 or 4 hypotension during any of the first three KIMMTRAK infusions, patients should be monitored every hour for at least 4 hours in an outpatient setting for the next three infusions.

Subsequent treatment doses

After 68 mcg dose level is tolerated (i.e., absence of Grade ≥2 hypotension requiring medical intervention), subsequent doses can be administered in appropriate outpatient ambulatory care setting. Patients should be observed for a minimum of 60 minutes following each infusion. For patients who have received outpatient treatment with KIMMTRAK for at least 3 months and have not experienced any interruptions greater than 2 weeks, outpatient monitoring following infusion may be decreased to a minimum of 30 minutes for subsequent doses.

There is no information on overdose with tebentafusp. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment should be instituted immediately.

Unopened vial:

3 years.

After opening:

From a microbiological point of view, once opened, the medicinal product should be diluted and infused immediately.

After preparation of solution for infusion:

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Store and transport refrigerated (2°C–8°C).

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

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

Type I glass vial with a bromobutyl rubber stopper and an aluminium/plastic flip-off seal, containing 0.5 mL concentrate.

Pack size of 1 vial.

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

General precautions:

The solution for infusion should be prepared by a healthcare professional using proper aseptic technique throughout the handling of this medicinal product.

Use aseptic technique for dilution and preparation of dosing solutions.

Closed system transfer devices (CSTDs) must not be used for dose preparation of KIMMTRAK solution for infusion.

Parenteral medicinal products and infusion bags should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.

Preparation:

KIMMTRAK must be diluted prior to intravenous administration.

Ensure the following supplies are available prior to preparing KIMMTRAK for administration:

• 1 mL sterile syringes with graduations of 2 decimal places.
• Sterile needles.
• Human albumin; use concentration as per local availability. Local concentrations include but not restricted to 4% (40 g/L), 5% (50 g/L), 20% (200 g/L), 25% (250 g/L).
• A 100 mL infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection:
  • The infusion bag should be constructed of polyolefins (PO) [such as polyethylene (PE) and polypropylene (PP)] or polyvinyl chloride (PVC).
• A sterile, nonpyrogenic, low protein binding 0.2 micron in-line filter infusion set for administration of the final infusion bag.

Dilution and Administration:

A 2-step process is required for preparation of the final KIMMTRAK dose:

Step 1: Prepare the infusion bag

Using aseptic technique, prepare the infusion bag as follows:

a. Using a 1 mL syringe and a sterile needle, withdraw the calculated volume of human albumin into the syringe (see Table 6 below) and add to the 100 mL infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection to make a final human albumin concentration between 225 mcg/mL and 275 mcg/mL.

Table 6. Examples of human albumin concentration and acceptable withdrawal volumes:

b. Gently homogenize the diluted solution by completing the following steps:

i. Invert the infusion bag so that the entry port is positioned at the top of the bag and tap the side of port tubing to ensure that any residual solution is released into the bulk solution.

ii. Mix by gently rotating the bag lengthwise 360 degrees from the inverted position at least 5 times. Do NOT shake the infusion bag. iii. Repeat (i) and (ii) an additional three times.

Step 2: Preparation of KIMMTRAK solution for infusion

c. Using a 1 mL syringe and a sterile needle, withdraw the required volume of KIMMTRAK 100 micrograms/0.5 mL as per the dose required (shown in Table 6 below) and add to the prepared 100 mL infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection, plus human albumin.

d. Do NOT flush the needle and syringe on transfer. Discard the vial containing the unused portion of KIMMTRAK in accordance with local requirements. Do not prepare more than one dose from the vial.

Table 7. KIMMTRAK volumes required for addition to infusion bag:

e. Mix the infusion bag by following the same procedure outlined in Step 1b.

Administration:

• Administer KIMMTRAK as intravenous infusion only.
• Immediately administer the infusion over 15 to 20 minutes through a dedicated intravenous line. A sterile, nonpyrogenic, low protein binding 0.2 micron in line filter infusion set should be used. Administer the entire contents of the KIMMTRAK infusion bag to the patient.
• Upon completion of KIMMTRAK infusion, flush the infusion line with adequate volume of sterile sodium chloride 9 mg/mL (0.9%) solution for injection, to ensure that the entire contents of the infusion bag are administered. Do not administer KIMMTRAK as an intravenous push or bolus. Do not mix KIMMTRAK with other drugs or administer other drugs through the same intravenous line.

Storage of prepared infusion bag:

• KIMMTRAK does not contain a preservative. The prepared infusion bag should be administered within 4 hours from the time of preparation including the duration of infusion. During the 4 hour window, the KIMMTRAK infusion bag should remain below 30°C.
• If not used immediately, store the KIMMTRAK infusion bag in a refrigerator at 2°C to 8°C for up to 24 hours from the time of preparation which includes the time allowed for equilibration of the infusion bag to room temperature and the duration of the infusion.
• Once removed from the refrigerator, KIMMTRAK infusion bag must not be refrigerated again. Discard unused KIMMTRAK solution beyond the recommended storage time.