Tivdak

Recommended Dosage

The recommended dose of TIVDAK is 2 mg/kg (up to a maximum of 200 mg for patients ≥100 kg) administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

Premedication and Required Eye Care

Adhere to the following recommendations to reduce the risk of ocular adverse reactions [see Warnings and Precautions ].

• Ophthalmic exam by eye care provider: Conduct an ophthalmic exam prior to initiation of TIVDAK, prior to every cycle for the first nine cycles, and as clinically indicated. The ophthalmic exam should include visual acuity, slit lamp exam of the anterior segment of the eye, and an assessment of normal eye movement.
  
• Topical corticosteroid eye drops: Instruct patients to administer one drop in each eye prior to each infusion and to continue to administer eye drops in each eye three times daily for 72 hours after each infusion. The initial prescription and all renewals of any corticosteroid medication should be made only after examination with a slit lamp.
• Topical ocular vasoconstrictor drops: Administer in each eye immediately prior to each infusion of TIVDAK.
  
• Cold packs: Use cooling eye pads during each infusion of TIVDAK.
  
• Topical lubricating eye drops: Instruct patients to administer for the duration of therapy and for 30 days after the last dose of TIVDAK.
  
• Contact lenses: Advise patients to avoid wearing contact lenses for the entire duration of therapy unless advised by their eye care provider.
  

Dosage Modifications for Adverse Reactions

The recommended TIVDAK dose reduction schedule is provided in Table 1.

The recommended dose modifications for adverse reactions are provided in Table 2. 

Instructions for Preparation and Administration

• Administer TIVDAK as an intravenous infusion only.
• TIVDAK is a hazardous drug. Follow applicable special handling and disposal procedures1.
  
• DO NOT administer TIVDAK as an intravenous push or bolus.
  
• DO NOT mix TIVDAK with, or administer as an infusion with, other medicinal products.
  

Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.  Prior to administration, the TIVDAK vial is reconstituted with Sterile Water for Injection, USP. The reconstituted solution is subsequently diluted in an intravenous infusion bag containing one of the following: 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer’s Injection, USP.

Reconstitution in Single-dose Vial

1. Calculate the recommended dose based on the patient’s weight to determine the number of vials needed.
   
2. Reconstitute each 40 mg vial with 4 mL of Sterile Water for Injection, USP, resulting in 10 mg/mL TIVDAK.
   
3. 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.
   
4. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be clear to slightly opalescent, colorless to brownish-yellow and free of visible particles. Discard any vial with visible particles or discoloration.
   
5. 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 in refrigeration at 2°C to 8°C (36 °F to 46 °F) or at room temperature up to 25°C (77°F) for up to a maximum of 8 hours prior to dilution. DO NOT FREEZE. Do not expose to direct sunlight.  Discard unused vials with reconstituted solution beyond the recommended storage time.
   

Dilution in Infusion Bag

1. Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag.
2. Dilute TIVDAK with one of the following: 5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP or Lactated Ringer's Injection, USP. The infusion bag size should allow enough diluent to achieve a final concentration of 0.7 mg/mL to 2.4 mg/mL TIVDAK.
3. Mix diluted solution by gentle inversion. DO NOT SHAKE THE BAG.  Do not expose to direct sunlight.
   
4. Visually inspect the infusion bag for any particulate matter or discoloration prior to use. The reconstituted solution should be clear to slightly opalescent, colorless to brownish-yellow and free of visible particles. Discard the infusion bag if particulate matter or discoloration is observed.
   
5. Discard any unused portion left in the single-dose vials.
   

Administration

1. Confirm administration of steroid and vasoconstrictor eye drops [see Dosage and Administration ].
2. Apply cold packs fully over the eyes following administration of the vasoconstrictor eye drops. Change cold packs as needed throughout infusion to ensure eye area remains cold during the entire infusion [see Dosage and Administration ].
3. Immediately administer the infusion over 30 minutes through an intravenous line containing a 0.2 µm in-line filter.
   
4. If the infusion is not administered immediately, store the diluted TIVDAK solution in refrigeration as specified in Table 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).
   

Pregnancy

Risk Summary

Based on the mechanism of action and findings in animals, TIVDAK can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ]. There are no available human data on TIVDAK use in pregnant women to inform a drug-associated risk.  In an animal reproduction study, administration of the small molecule component of TIVDAK, MMAE, to pregnant rats during organogenesis caused embryo-fetal mortality and structural abnormalities at exposures below the clinical exposure at the recommended dose (see Data). Advise patients of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Data
Animal Data

No embryo-fetal development studies in animals have been performed with tisotumab vedotin-tftv. In an embryo-fetal development study in pregnant rats, administration of two intravenous doses of MMAE, the small molecule component of TIVDAK, on gestational days 6 and 13 caused embryo-fetal mortality and structural abnormalities, including protruding tongue, malrotated limbs, gastroschisis, and agnathia compared to controls at a dose of 0.2 mg/kg (approximately 0.5-fold the human area under the curve [AUC] at the recommended dose).

Lactation

Risk Summary

There are no data on the presence of tisotumab vedotin-tftv in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with TIVDAK and for 3 weeks after the last dose.

Females and Males of Reproductive Potential

TIVDAK can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ].

Pregnancy testing

Verify pregnancy status in females of reproductive potential prior to initiating TIVDAK treatment.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with TIVDAK and for 2 months after the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TIVDAK and for 4 months after the last dose.

Infertility

Females

Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), TIVDAK may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology ].

Males

Based on findings from animal studies, TIVDAK may impair male fertility [see Nonclinical Toxicology ].

Pediatric Use

Safety and effectiveness of TIVDAK in pediatric patients have not been established.

Geriatric Use

Of the 425 patients with cervical cancer treated with TIVDAK across clinical trials, 14% were ≥65 years of age and 2.4% were ≥75 years of age. Grade ≥3 adverse reactions occurred in 60% of patients ≥65 years and in 55% of patients <65 years. Drug was discontinued due to an adverse reaction in 25% of patients ≥65 years and in 13% of patients <65 years. Clinical studies of TIVDAK did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients.

Hepatic Impairment

Avoid use of TIVDAK in patients with moderate or severe hepatic impairment [aspartate aminotransferase (AST) > 3 x upper limit of normal (ULN) or total bilirubin > 1.5 × ULN] [see Clinical Pharmacology ].

In patients with mild hepatic impairment (total bilirubin ≤ ULN and AST >ULN or total bilirubin > 1 to 1.5 × ULN and any AST), closely monitor patients for adverse reactions of TIVDAK, but no dosage adjustment in the starting dose of TIVDAK is recommended.