2.1 Recommended Dose for Extravasation

Reconstitute and further dilute Totect before use [see Dosage and Administration (2.4)].

For extravasation, administer Totect via intravenous infusion over 1 to 2 hours once daily for 3 consecutive days. Initiate the first infusion as soon as possible and within the first six hours after extravasation [see Dosage and Administration (2.5)].

The individual dosage is based on calculation of the Body Surface Area (BSA) up to a maximum dose of 2000 mg (each on Day 1 and 2) and 1000 mg (Day 3), corresponding to a BSA of 2 m2.

The recommended dose is: Maximum daily dose:
Day one: 1000 mg/m2 2000 mg
Day two: 1000 mg/m2 2000 mg
Day three: 500 mg/m2 1000 mg

2.2 Recommended Dose for Cardiomyopathy

Reconstitute and further dilute Totect before use [see Dosage and Administration (2.4)].

For cardiomyopathy, administer Totect via intravenous infusion over 15 minutes prior to doxorubicin administration until discontinuation of doxorubicin. Do not administer via an intravenous push [see Dosage and Administration (2.5)]​.

​The recommended dosage ratio of Totect to doxorubicin is 10:1 (e.g., 500 mg/m2 Totect to 50 mg/m2 doxorubicin). Administer doxorubicin within 30 minutes after the completion of Totect infusion.

2.3 Dose Modifications

​Dosing in Patients with Renal Impairment

Reduce the Totect dose by 50% in patients with creatinine clearance values < 40 mL/min [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

​Dosing in Patients with Hepatic Impairment

​In patients with anthracycline extravasation, treatment with Totect is not recommended. In patients receiving dexrazoxane for cardiomyopathy, reduce the Totect dosage proportionately (maintaining the 10:1 ratio) in patients with hepatic impairment, since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Preparation

Read this entire section carefully before mixing and diluting.

Use caution when handling and preparing the reconstituted solution. The use of gloves is recommended. If Totect powder or solutions contact the skin or mucosae, wash exposed area immediately and thoroughly with soap and water. Follow special handling and disposal procedures.1

Totect should not be mixed or administered with any other drug during the infusion. The prepared solution of Totect is slightly yellow.

Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Solutions containing a precipitate should be discarded. Vials are for single use only. Unused solution should be discarded.

Preparation for the Treatment of Extravasation

Step 1. Reconstitute each Totect vial with 50 mL of Sterile Water for Injection, USP. Once reconstituted, the reconstituted Totect solution contains 10 mg/mL of Totect.

Step 2. Calculate the volume of the 10 mg/mL reconstituted Totect solution needed for the recommended dose. In order to obtain the required dose, more than one vial may be needed. The reconstituted solution should be further diluted within 30 minutes after initial reconstitution. It contains no antibacterial preservative.

Step 3. Withdraw the calculated volume from the reconstituted Totect solution and further dilute into an infusion bag containing 1000 mL of Lactated Ringer’s Injection. Do not mix Totect with any other drugs.

Use the Totect infusion bag immediately after preparation. If not used immediately, the product is stable for 4 hours from the time of preparation when stored at room temperature or for up to 12 hours when stored refrigerated between 2ºC to 8ºC (36°F to 46°F).

​Preparation for Reducing the Incidence and Severity of Cardiomyopathy

Step 1.​ Reconstitute each Totect vial with 50 mL of Sterile Water for Injection, USP. Once reconstituted, the reconstituted Totect solution contains 10 mg/mL of Totect.

Step 2.​ Calculate the volume of the 10 mg/mL reconstituted Totect solution needed for the recommended dose. In order to obtain the required dose, more than one vial may be needed. The reconstituted solution should be further diluted within 30 minutes after initial reconstitution. It contains no antibacterial preservative.

​Step 3. Withdraw the calculated volume from the reconstituted Totect solution and further dilute to a concentration of 1.3 to 3 mg/mL in Lactated Ringer’s Injection. Do not mix Totect with any other drugs.

​Use the Totect infusion solution immediately after preparation. If not used immediately, the product is stable for 4 hours from the time of preparation when stored at room temperature or for up to 12 hours when stored refrigerated between 2ºC to 8ºC (36°F to 46°F).

The infusion solutions have a pH of 3.5 to 5.5.

Administration

Do not administer or mix Totect with any other drugs during the infusion.

Administration for Treatment of Extravasation

Remove cooling procedures such as ice packs, if used, from the extravasation area at least 15 minutes before Totect administration in order to allow sufficient blood flow to the area of extravasation.

Administer the final diluted solution of Totect as an intravenous infusion over 1 to 2 hours at room temperature and normal light conditions in a large caliber vein in an extremity/area other than the one affected by the extravasation.

Treatment on Day 2 and Day 3 should start at the same hour (+/- 3 hours) as on the first day.

Perform local examination for extravasation on a regular basis after treatment and until resolution.

If vesicant compounds other than anthracyclines are being used through the same intravenous access, (e.g. vincristine, mitomycin, and vinorelbine), consider treatments for these other vesicant compounds. Totect is not effective against the effects of vesicants other than anthracyclines [see Clinical Studies (14.1)].

​Administration for Reducing the Incidence and Severity of Cardiomyopathy

​Administer the final diluted solution of Totect by intravenous infusion over 15 minutes before the administration of doxorubicin.

Do not​ administer via an intravenous push.

​Administer doxorubicin within 30 minutes after the completion of Totect infusion.

​Do not use Totect with non-anthracycline chemotherapy regimens.