Data from FDA - Curated by EPG Health - Last updated 04 March 2018

Indication(s)

1 INDICATIONS AND USAGE Totect® is indicated for the treatment of extravasation resulting from intravenous anthracycline chemotherapy. Totect is a cytoprotective agent indicated for the treatment of extravasation resulting from intravenous anthracycline chemotherapy. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
6 ADVERSE REACTIONS The most common adverse reactions (≥15%) are nausea, pyrexia, injection site pain, vomiting, and postoperative infection. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Cumberland Pharmaceuticals Inc. at 1-877-484-2700 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. In the clinical studies, Totect was administered to patients also receiving chemotherapeutic agents for cancer, and the adverse reaction profile and laboratory abnormalities presented in Tables 1 and 2 reflect the combination of Totect, underlying disease, and already administered chemotherapy. The adverse reaction data reflect exposure to Totect from two clinical studies in 80 patients who received the first dose, 72 patients who received two doses, and 69 patients who received all three doses. Table 1 summarizes adverse reactions occurring with ≥ 5% frequency. Table 1 Adverse Reactions Occurring at ≥ 5% Frequency System Organ Class (SOC) and Adverse Reaction Study 1 and 2 Combined (All causalities) % (N=80) Total number of patients with at least one event 85 General disorders and administration site conditions 58 Pyrexia 21 Injection site pain/injection site discomfort 16 Fatigue 13 Edema peripheral 10 Injection site phlebitis 6 Gastrointestinal disorders 55 Nausea 43 Vomiting 19 Diarrhea 11 Abdominal pain 6 Constipation 6 Infections and infestations 30 Postoperative infection 16 Nervous system disorders 24 Dizziness 11 Headache 6 Skin and subcutaneous disorders 18 Alopecia 14 Respiratory, thoracic and mediastinal disorders 16 Dyspnea 8 Pneumonia Cough 6 5 Vascular disorders 15 Blood and lymphatic system disorders 14 Anemia 6 Psychiatric disorders 14 Depression Insomnia 8 5 Musculoskeletal and connective tissue disorders 13 Metabolism and nutrition disorders Anorexia 10 5 Cardiac disorders 5 Table 2 summarizes laboratory abnormalities from studies 1 and 2. Table 2: Laboratory Abnormalities Laboratory Abnormality Grade 3 Grade 4 Grade 2 to 4 % % % Hematologic: Decreased hemoglobin 3 0 43 Decreased WBC 25 20 73 Decreased neutrophils 22 24 61 Decreased platelets 21 0 26 Hepatic: Increased bilirubin 2 0 11 Increased AST 1 1 28 Increased ALT 1 5 22 Increased alkaline phosphatase 0 0 4 Increased LDH 0 0 5 Metabolic: Increased creatinine 2 2 14 Decreased sodium 5 1 6 Increased calcium total 2 2 7

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Totect must be mixed and diluted with 50 mL of 0.167 M sodium lactate injection solution before use. (2.3) Administer Totectby intravenous infusion over 1 to 2 hours once daily for 3 consecutive days. (2.1, 2.4) Initiate the first infusion as soon as possible and within the first six hours after extravasation. (2.1) Recommended dose Maximum daily dose Day one: 1000 mg/m2 2000 mg Day two: 1000 mg/m2 2000 mg Day three: 500 mg/m2 1000 mg Reduce dose by 50% for patients with creatinine clearance < 40 mL/min. (2.2) 2.1 Recommended Dose Vial contents and diluted with 50 mL of 0.167 M sodium lactate injection solution before use [see Dosage and Administration (2.3)]. Administer Totect 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 (2.4)]. 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 Dose Modifications Reduce the Totect dose by 50% in patients with creatinine clearance values < 40 mL/min. 2.3 Directions for Mixing and Final Dilution Read this entire section carefully before mixing and diluting. Aseptic technique should be used during preparation. 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. Preparation of Totect Step 1. Each vial of Totect (dexrazoxane for injection) (500 mg) must first be mixed with 50 mL of 0.167M sodium lactate injection solution. Dilution of sodium lactate injection to 0.167M is required before using it to reconstitute Totect. Add 1.67 mL of 5 mEq/mL sodium lactate injection to 50 mL sterile water for injection to make 50 mL of 0.167M sodium lactate injection solution. After reconstitution of Totect with 50 mL of 0.167M sodium lactate injection solution, the resultant Totect solution contains 10 mg/mL. This resultant solution should be further diluted within 2 hours. It contains no antibacterial preservative. Step 2. Withdraw the recommended dose from the Totect solution containing 10 mg/mL as prepared in Step 1 and further dilute into an infusion bag containing 1000 mL 0.9% Sodium Chloride. In order to obtain the required dose, more than one vial may be needed. Totect must not be mixed with any other drugs. The infusion bag should be used immediately after preparation. The product is stable for 4 hours from the time of preparation when stored below 25ºC (77ºF). The 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. 2.4 Administration Do not administer or mix Totect with any other drug during the infusion. 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 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 IV 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)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. (8.2) Renal impairment: Monitor patient for signs of hematological toxicity. Reduce the Totect dose by 50% in patients with creatinine clearance values < 40 mL/min. (8.6) Hepatic impairment: Use in patients with hepatic impairment is not recommended. (8.7) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, Totect can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Limited available data with Totect use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, intravenous administration of dexrazoxane to pregnant rats and rabbits during organogenesis resulted in teratogenicity at maternal doses that were approximately 0.1 and 0.2 times, respectively, the human dose of 1000 mg/m² . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 In an embryo-fetal development study in rats, pregnant females received intravenous doses of up to 8 mg/kg dexrazoxane during the period of organogenesis. A dose of 8 mg/kg (approximately 0.1 times the human dose of 1000 mg/m²) was teratogenic, resulting in imperforate anus, microphthalmia, and anophthalmia. Doses ≥ 2 mg/kg (approximately 0.01 times the human dose of 1000 mg/m²) caused maternal toxicity. In an embryo-fetal development study in rabbits, pregnant females received intravenous doses of up to 20 mg/kg (approximately 0.2 times the human dose of 1000 mg/m²) were teratogenic, resulting in several skeletal malformations such as short tail, rib and thoracic malformations, and soft tissue variations including subcutaneous, eye and cardiac hemorrhagic areas, as well as agenesis of the gallbladder and of the intermediate lobe of the lung. Doses ≥ 5 mg/kg (approximately 0.1 times the human dose of 1000 mg/m²) caused maternal toxicity. In a pre and postnatal development study in rats, intravenous administration of 8 mg/kg dexrazoxane to pregnant rats during organogenesis resulted in impairment of fertility in the male and female offspring. A dose of 8 mg/kg in rats is approximately 0.1 times the human dose of 1000 mg/m². 8.2 Lactation Risk Summary There are no data on the presence of dexrazoxane in human milk, the effects on the breastfed child, or the effect on milk production. Because of the potential for serious adverse reactions, such as myelosuppression, in a breastfed child from Totect, advise women not to breastfeed during treatment and for 2 weeks following the final dose of Totect. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing should be performed prior to initiation of chemotherapy. Therefore, repeat pregnancy testing prior to administration of Totect is not recommended, because treatment of extravasation of anthracycline chemotherapy should not be delayed. Contraception Females Totect can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)]. Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment and for 6 months following the final dose of Totect. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months following the final dose of Totect [see Nonclinical Toxicology (13.1)]. Infertility Males Based on findings in animal studies, Totect may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of Totect in pediatric patients have not been established. 8.5 Geriatric Use In total, 21% of the patients treated with Totect were age 65 years or older and 9% were 75 and older. No differences in safety or efficacy were observed between older and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal and hepatic function, care should be taken in dose selection, and it may be useful to monitor renal and hepatic function [see Dosage and Administration (2.2)]. 8.6 Renal Impairment Greater exposure to dexrazoxane may occur in patients with compromised renal function. Monitor patients with impaired renal function for signs of hematological toxicity. The Totect dose should be reduced by 50% in patients with creatinine clearance values < 40 mL/min. [see Dosage and Administration (2.2)] 8.7 Hepatic Impairment Totect has not been studied in patients with hepatic impairment. Since liver dysfunction (increases in transaminases and bilirubin) may occur (especially after doses of above 1000 mg/m² dexrazoxane), it is recommended that routine liver function tests be performed before each administration of dexrazoxane in patients with known liver function disorders. Use in patients with hepatic impairment is not recommended.

Interactions

7 DRUG INTERACTIONS Dimethyl sulfoxide: Totect is not recommended for use with topical dimethyl sulfoxide (DMSO). (7.1) 7.1 Dimethyl sulfoxide Totect is not recommended for use with topical dimethyl sulfoxide (DMSO). Based on anecdotal reports concurrent use of topical DMSO at the site of tissue injury may reduce the benefit of Totect. Additionally, nonclinical studies using a mouse model that simulates extravasation of anthracyclines has shown that concomitant treatment with topical DMSO decreases the efficacy of systemic dexrazoxane.

More information

Category Value
Authorisation number NDA022025
Agency product number 5346058Q7S
Orphan designation No
Product NDC 66220-110
Date Last Revised 08-02-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1736590
Marketing authorisation holder Cumberland Pharmaceuticals Inc.