TIVDAK Powder for concentrate for solution for infusion Ref.[115066] Active ingredients: Tisotumab vedotin

Treatment with Tivdak should be initiated and supervised by a physician experienced in the use of anti-cancer therapies. Prior to the first infusion and as clinically indicated, an eye care professional should conduct an ophthalmic exam, including visual acuity and slit lamp exam (see “Eye care” at the end of this section and section 4.4).

Posology

The recommended dose of Tivdak is 2 mg/kg (up to a maximum of 200 mg for patients ≥100 kg) every 3 weeks until disease progression or unacceptable toxicity.

Dose modifications

The recommended Tivdak dose reduction schedule is provided in Table 1. Tivdak should be permanently discontinued in patients who cannot tolerate 0.9 mg/kg.

Table 1. Dose reduction schedule:

The recommended dose modifications for adverse reactions are provided in Table 2. Patients should be referred to an eye care professional as soon as possible for an assessment of new or worsening ocular symptoms (see section 4.4).

Table 2. Dose modifications:

^* Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) where Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, and Grade 4 is life-threatening

Missed doses

If a planned dose of Tivdak is missed, it should be administered as soon as possible. The scheduling of administration should be adjusted to maintain the appropriate interval between doses.

Eye care

Patients should adhere to the following recommendations to reduce the risk of ocular adverse reactions (see section 4.4).

Ocular evaluation by treating healthcare provider

Prior to each infusion, the treating healthcare provider should inspect the patient’s eyes, including control of normal eye movement, and ask about any ocular signs or symptoms. The patient should be referred to an eye care professional for any ocular signs or symptoms (see section 4.4).

Topical preservative-free corticosteroid eye drops (e.g., dexamethasone 0.1% 3 times a day or the equivalent as prescribed)

Patients should be instructed to administer 1 drop in each eye 3 times daily starting 1 day prior to each infusion and to continue to administer as prescribed for 3 days after each infusion.

Topical preservative-free ocular vasoconstrictor drops (e.g., brimonidine tartrate 0.2% 3 drops per eye or the equivalent as prescribed)

Drops should be administered in each eye immediately prior to each infusion.

Cold packs

Following administration of eye drops, cooling eye pads should be applied prior to the start of the infusion and used during and for 30 minutes after the infusion.

Topical preservative-free lubricating eye drops

Patients should be instructed to administer lubricating eye drops multiple times every day throughout treatment and for 30 days after the last dose of Tivdak.

Contact lenses

Patients should be advised to avoid wearing contact lenses for the entire duration of therapy unless advised by their eye care professional.

Special populations

Elderly

No dose adjustment is required in patients aged ≥ 65 years (see section 5.2).

Renal impairment

No dose adjustment is required in patients with mild renal impairment [creatinine clearance (CrCL) >60-90 mL/min], moderate (CrCL 30-60 mL/min). Tisotumab vedotin has not been studied in patients with severe renal impairment (CrCL 15 - <30 mL/min) or end-stage renal disease (CrCL <15 mL/min) (see section 5.2).

Hepatic impairment

No dose adjustment is required in patients with mild hepatic impairment (total bilirubin of >1 to 1.5 × upper limit of normal (ULN) and any aspartate aminotransferase (AST), or total bilirubin ≤ ULN and AST > ULN, as defined using the National Cancer Institute criteria for hepatic impairment). However, as the exposure is expected to increase in patients with mild hepatic impairment, caution is advised when treating patients with mild hepatic impairment. Tisotumab vedotin has not been studied in patients with moderate or severe hepatic impairment (see section 5.2).

Paediatric population

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

Method of administration

Tivdak is for intravenous use. The recommended dose must be administered by intravenous infusion over 30 minutes. Tisotumab vedotin must not be administered as an intravenous push or bolus injection.

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

There is no known antidote for overdose with tisotumab vedotin. In case of overdose, the patient should be closely monitored for adverse reactions and supportive treatment should be administered.

Unopened vial:

5 years.

Reconstituted solution in the vial:

Chemical and physical in-use stability of the reconstituted solution has been demonstrated for up to 24 hours at 2°C to 8°C or for up to 8 hours at 9°C to 25°C.

From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the reconstituted solution should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Diluted solution in the infusion bag:

Chemical and physical in-use stability of the diluted solution has been demonstrated for the durations listed in Table 5.

From a microbiological point of view, unless the method of dilution precludes the risk of microbial contamination, the diluted solution should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Table 5. Diluted Tivdak solution refrigeration storage conditions:

Store in a refrigerator (2°C–8°C).

Do not freeze.

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

10 mL Type I glass vial with grey butyl rubber stopper, plug and top, 20 mm seal with silver coloured aluminium cap and garnet disc. Each carton contains 1 vial.

Reconstitution in single-dose vial:

1. Follow procedures for proper handling and disposal of cytotoxic medicinal products.

2. Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.

3. Calculate the recommended dose based on the patient’s actual body weight to determine the number of vials needed.

4. Reconstitute each 40 mg vial with 4 mL of sterile water for injection, resulting in 10 mg/mL Tivdak.

5. Slowly swirl each vial until the contents are completely dissolved. Allow the reconstituted vial(s) to settle. Do not shake the vial. Do not expose to direct sunlight.

6. Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. The reconstituted solution should be clear to slightly opalescent, colourless to brownish-yellow and free of visible particles. Discard any vial with visible particles or discolouration.

7. Based upon the calculated dose amount, the reconstituted solution from the vial(s) should be added to the infusion bag immediately. This product does not contain a preservative. If not used immediately, reconstituted vials may be stored for up to 24 hours refrigerated at 2°C to 8°C or at room temperature (9°C to 25°C) up to a maximum of 8 hours prior to dilution. Do not freeze. Discard unused vials with reconstituted solution beyond the recommended storage time.

Dilution in infusion bag:

8. Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag.

9. Dilute Tivdak with one of the following: dextrose 50 mg/mL (5%), sodium chloride 9 mg/mL (0.9%), or Lactated Ringer’s solution for injection. The infusion bag size should allow enough diluent to achieve a final concentration of 0.7 mg/mL to 2.4 mg/mL Tivdak.

10. Mix diluted solution by gentle inversion. Do not shake the bag. Do not expose to direct sunlight.

11. Visually inspect the infusion bag for any particulate matter or discolouration prior to use. The reconstituted solution should be clear to slightly opalescent, colourless to brownish-yellow and free of visible particles. Do not use the infusion bag if particulate matter or discolouration is observed.

12. Discard any unused portion left in the single-dose vials.

Administration:

13. Confirm administration of steroid and vasoconstrictor eye drops (see section 4.2).

14. Apply cold packs fully over the eyes following administration of the vasoconstrictor eye drops, leave on during infusion and until 30 minutes after infusion. Change cold packs as needed throughout infusion to ensure eye area remains cold (see section 4.2).

15. Immediately administer the infusion over 30 minutes through an intravenous line containing a 0.2 μm in-line filter.

16. If the infusion is not administered immediately, store the diluted Tivdak solution in refrigeration as specified in Table 5 (see section 6.3). Discard if storage time exceeds these limits. Do not freeze. Once removed from refrigeration, complete administration of the diluted infusion solution of Tivdak within 4 hours (including infusion time).

Disposal:

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