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Totect® (dexrazoxane for injection) is a sterile, pyrogen-free lyophilized powder intended for intravenous (IV) administration. Each Totect® carton contains 1 single dose vial of Totect® (dexrazoxane for injection) 500 mg.
Chemically, dexrazoxane, a cytoprotective agent, is 2,6-piperazinedione,4,4’-(1- methyl-1,2-ethanediyl)bis-,(S)- or (S)-(+)-1,2-bis(3,5-dioxopiperazin-1- yl)propane. The following diagram shows the chemical structure:
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The molecular formula is C11H16N4O4; the molecular weight is 268.3. Dexrazoxane is a white to off-white powder, with a melting point of 194 ± 3 °C. It is soluble in dioxane and 0.1 N HCl, sparingly soluble in water, tetrahydrofuran, citrate buffer at pH 4.0, phosphate buffer at pH 7.0, and borate-potassium chloride sodium hydroxide buffer at pH 9.0. The acid dissociation constants, pKa, are 2.5 (for the tertiary piperazine nitrogen) and 9.7 (for the nitrogen imide). Log P is - 2.135.
The finished product is supplied in a sterile form for intravenous infusion only following mixing and diluting.
Each carton contains one 50 mL Type I glass vial. Each vial contains dexrazoxane hydrochloride equivalent to 500 mg dexrazoxane (free base). Each vial of dexrazoxane for injection is closed with an aluminum flip-off cap covered with a dark red overcap.
When reconstituted as directed with 50 mL of sodium lactate injection solution (0.167 M), the admixture contains dexrazoxane (10 mg/mL) and the following excipients: hydrochloric acid, sodium lactate, water for injection, sodium hydroxide and lactic acid [see DOSAGE AND ADMINISTRATION]. The admixture should be further diluted in 0.9 % NaCl prior to administration to patients.
Totect® is indicated for the treatment of extravasation resulting from intravenous anthracycline chemotherapy.
Totect is indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m² and who will continue to receive doxorubicin therapy to maintain tumor control. Do not use with the initiation of doxorubicin therapy [see WARNINGS AND PRECAUTIONS].
Reconstitute and further dilute Totect before use [see Preparation].
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 Administration].
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 |
Reconstitute and further dilute Totect before use [see Preparation ].
For cardiomyopathy, administer Totect via intravenous infusion over 15 minutes prior to to doxorubicin administration until discontinuation of doxorubicin. Do not administer via an intravenous push [see Administration].
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.
Reduce the Totect dose by 50% in patients with creatinine clearance values < 40 mL/min [see Use In Specific Populations and CLINICAL PHARMACOLOGY].
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 and CLINICAL PHARMACOLOGY].
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.
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 2 °C to 8°C (36°F to 46°F).
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 2 °C to 8°C (36°F to 46°F).
The infusion solutions have a pH of 3.5 to 5.5.
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].
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.
For Injection: 500 mg as a sterile, pyrogen-free lyophilized powder in a single dose vial for reconstitution.
Each Totect carton contains 1 single dose vial of Totect (dexrazoxane for injection) 500 mg as a sterile, pyrogen-free lyophilized powder.
NDC 76310-110-01: Carton of 1 vial of Totect
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Keep vial in carton until ready for use.
Follow special handling and disposal procedures [see DOSAGE AND ADMINISTRATION].1
REFERENCES
1.“OSHA Hazardous Drugs.” OSHA. https://www.osha.gov/SLTC/hazardousdrugs/index.html
Manufactured for: Clinigen, Inc. Yardley, PA 19067. Revised: Nov 2020
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 | 6 |
| Cough | 5 |
| Vascular disorders | 15 |
| Blood and lymphatic system disorders | 14 |
| Anemia | 6 |
| Psychiatric disorders | 14 |
| Depression | 8 |
| Insomnia | 5 |
| Musculoskeletal and connective tissue disorders | 13 |
| Metabolism and nutrition disorders | 10 |
| Anorexia | 5 |
| Cardiac disorders | 5 |
Table 2 summarizes laboratory abnormalities from studies 1 and 2.
Table 2: Laboratory Abnormalities
| Laboratory Abnormality | Grade 3 % | Grade 40 % | 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 |
The adverse reaction profile described in this section was identified from randomized, placebo-controlled, double-blind studies in patients with metastatic breast cancer who received the combination of the fluorouracil, doxorubicin, and cyclophosphamide (FAC) chemotherapy regimen with or without dexrazoxane. The dose of doxorubicin was 50 mg/m² in each of these trials. Treatment was administered every three weeks until disease progression or cardiac toxicity.
Patients in clinical trials who received FAC with dexrazoxane experienced more severe leukopenia, granulocytopenia, and thrombocytopenia than patients receiving FAC without dexrazoxane [see WARNINGS AND PRECAUTIONS].
Table 3 below lists the incidence of adverse reactions for patients receiving FAC with either dexrazoxane or placebo in the breast cancer studies. Adverse experiences occurring during courses 1 through 6 are displayed for patients receiving dexrazoxane or placebo with FAC beginning with their first course of therapy (columns 1 and 3, respectively). Adverse experiences occurring at course 7 and beyond for patients who received placebo with FAC during the first six courses and who then received either dexrazoxane or placebo with FAC are also displayed (columns 2 and 4, respectively).
The adverse reactions listed below in Table 3 demonstrate that the frequency of adverse reaction “Pain on Injection” has been greater for dexrazoxane arm, as compared to placebo.
Table 3: Adverse Reactions for Patients Receiving FAC with either Dexrazoxane or Placebo
| Adverse Reaction | Percentage (%) of Breast Cancer Patients With Adverse Reaction | |||
| FAC + Dexrazoxane | FAC +Placebo | |||
| Courses 1 -6 N = 413 |
Courses ≥ 7 N = 102 |
Courses 1-6 N = 458 |
Courses ≥ 7 N = 99 |
|
| Alopecia | 94 | 100 | 97 | 98 |
| Nausea | 77 | 51 | 84 | 60 |
| Vomiting | 59 | 42 | 72 | 49 |
| Fatigue/Malaise | 61 | 48 | 58 | 55 |
| Anorexia | 42 | 27 | 47 | 38 |
| Stomatitis | 34 | 26 | 41 | 28 |
| Fever | 34 | 22 | 29 | 18 |
| Infection | 23 | 19 | 18 | 21 |
| Diarrhea | 21 | 14 | 24 | 7 |
| Pain on injection | 12 | 13 | 3 | 0 |
| Sepsis | 17 | 12 | 14 | 9 |
| Neurotoxicity | 17 | 10 | 13 | 5 |
| Streaking/Erythema | 5 | 4 | 4 | 2 |
| Phlebitis | 6 | 3 | 3 | 5 |
| Esophagitis | 6 | 3 | 7 | 4 |
| Dysphagia | 8 | 0 | 10 | 5 |
| Hemorrhage | 2 | 3 | 2 | 1 |
| Extravasation | 1 | 3 | 1 | 2 |
| Urticaria | 2 | 2 | 2 | 0 |
| Recall Skin Reaction | 1 | 1 | 2 | 0 |
When used to treat extravasation, 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 in this indication. 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.
The potential for a delayed hypersensitivity reaction to fluorouracil exists. Patch testing to prove hypersensitivity may be inconclusive.
Patients should discontinue therapy with Carac if symptoms of DPD enzyme deficiency develop.
Rarely, unexpected systemic toxicity (e.g., stomatitis, diarrhea, neutropenia, neurotoxicity) associated with parenteral administration of fluorouracil has been attributed to deficiency of dihydropyrimidine dehydrogenase "DPD" activity. One case of life-threatening systemic toxicity has been reported with the topical use of 5% fluorouracil in a patient with a complete absence of DPD enzyme activity. Symptoms included severe abdominal pain, bloody diarrhea, vomiting, fever, and chills. Physical examination revealed stomatitis, erythematous skin rash, neutropenia, thrombocytopenia, inflammation of the esophagus, stomach, and small bowel. Although this case was observed with 5% fluorouracil cream, it is unknown whether patients with profound DPD enzyme deficiency would develop systemic toxicity with lower concentrations of topically applied fluorouracil.
Applications to mucous membranes should be avoided due to the possibility of local inflammation and ulceration.
There is a possibility of increased absorption through ulcerated or inflamed skin.
Patients using Carac should receive the following information and instructions:
To rule out the presence of a frank neoplasm, a biopsy may be considered for those areas failing to respond to treatment or recurring after treatment.
Adequate long-term studies in animals to evaluate carcinogenic potential have not been conducted with fluorouracil. Studies with the active ingredient of Carac, fluorouracil, have shown positive effects in in vitro and in vivo tests for mutagenicity and on impairment of fertility in in vivo animal studies.
Fluorouracil produced morphological transformation of cells in in vitro cell transformation assays. Morphological transformation was also produced in an in vitro assay by a metabolite of fluorouracil, and the transformed cells produced malignant tumors when injected into immunosuppressed syngeneic mice. Fluorouracil has been shown to exert mutagenic activity in yeast cells, Bacillus subtilis, and Drosophila assays. In addition, fluorouracil has produced chromosome damage at concentrations of 1.0 and 2.0 mcg/mL in an in vitro hamster fibroblast assay, was positive in a microwell mouse lymphoma assay, and was positive in in vivo micronucleus assays in rats and mice following intraperitoneal administration. Some patients receiving cumulative doses of 0.24 to 1.0 g of fluorouracil parenterally have shown an increase in numerical and structural chromosome aberrations in peripheral blood lymphocytes.
Fluorouracil has been shown to impair fertility after parenteral administration in rats. Fluorouracil administered at intraperitoneal doses of 125 and 250 mg/kg has been shown to induce chromosomal aberrations and changes in chromosome organization of spermatogonia in rats. In mice, single-dose intravenous and intraperitoneal injections of fluorouracil have been reported to kill differentiated spermatogonia and spermatocytes at a dose of 500 mg/kg and produce abnormalities in spermatids at 50 mg/kg.
Actinic keratosis is not a condition seen within the pediatric population, except in association with rare genetic diseases. Carac should not be used in children. The safety and effectiveness of Carac have not been established in patients less than 18 years old.
No significant differences in safety and efficacy measures were demonstrated in patients age 65 and older compared to all other patients.
See CONTRAINDICATIONS.
It is not known whether fluorouracil is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from fluorouracil, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Disposition studies with dexrazoxane have not been conducted in cancer patients undergoing dialysis, but retention of a significant dose fraction (>0.4) of the unchanged drug in the plasma pool, minimal tissue partitioning or binding, and availability of greater than 90% of the systemic drug levels in the unbound form suggest that it could be removed using conventional peritoneal or hemodialysis.
Overdose with dexrazoxane can lead to signs of bone marrow failure. There is no known antidote for dexrazoxane. Instances of suspected overdose should be managed with supportive care until resolution of myelosuppression and related conditions is complete. Management of overdose should include treatment of infections, fluid regulation, and maintenance of nutritional requirements.
None.
The mechanism by which dexrazoxane reduces tissue damage caused by anthracycline-related cardiomyopathy or following anthracycline extravasation is not fully understood. Dexrazoxane is a cyclic derivative of EDTA that penetrates cell membranes. Results of laboratory studies suggest that dexrazoxane is converted intracellularly to a ring-opened chelating agent that interferes with iron-mediated free radical generation. Some evidence suggests that dexrazoxane inhibits topoisomerase II reversibly.
The pharmacokinetics of dexrazoxane have been studied in advanced cancer patients with normal renal and hepatic function. Generally, the pharmacokinetics of dexrazoxane can be adequately described by a two-compartment open model with first-order elimination. Dexrazoxane has been administered as a 15 minute infusion over a dose-range of 60 to 900 mg/m² with 60 mg/m² of doxorubicin, and at a fixed dose of 500 mg/m² with 50 mg/m² doxorubicin. The disposition kinetics of dexrazoxane are dose-independent, as shown by linear relationship between the area under plasma concentration-time curves and administered doses ranging from 60 to 900 mg/m². The mean peak plasma concentration of dexrazoxane was 36.5 μg/mL at the end of the 15 minute infusion of a 500 mg/m² dose of dexrazoxane administered 15 to 30 minutes prior to the 50 mg/m² doxorubicin dose. The important pharmacokinetic parameters of dexrazoxane are summarized in the following table.
Table 4: Summary of Mean (%CVa) Dexrazoxane Pharmacokinetic Parameters at a Dosage Ratio of 10:1 of Dexrazoxane: Doxorubicin
| Dose Doxorubicin (mg/m²) | Dose Dexrazoxane (mg/m²) | Number of Subjects | Elimination Half-Life (h) | Plasma Clearance (L/h/m²) | Renal Clearance (L/h/m²) | bVolume of Distribution (L/m²) |
| 50 | 500 | 10 | 2.5 (16) | 7.88 (18) | 3.35 (36) | 22.4 (22) |
| 60 | 600 | 5 | 2.1 (29) | 6.25 (31) | — | 22.0 (55) |
| a Coefficient of variation b Steady-state volume of distribution |
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Following a rapid distributive phase (~0.2 to 0.3 hours), dexrazoxane reaches post-distributive equilibrium with dexrazoxane have confirmed the presence of unchanged drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products in the urine of animals and man. The metabolite levels were not measured in the pharmacokinetic studies.
Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of the 500 mg/m² dose of dexrazoxane was excreted in the urine.
Protein Binding: In vitro studies have shown that dexrazoxane is not bound to plasma proteins.
There are no clinically relevant differences in the pharmacokinetics of dexrazoxane between males and females.
The pharmacokinetics of dexrazoxane were assessed following a single 15 minute IV infusion of 150 mg/m² of dexrazoxane in male and female subjects with varying degrees of renal dysfunction as determined by creatinine clearance (CLCR) based on a 24-hour urinary creatinine collection. Dexrazoxane clearance was reduced in subjects with renal dysfunction. Compared with controls, the mean AUC0-inf value was twofold greater in subjects with moderate (CLCR 30-50 mL/min) to severe (CLCR < 30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC0-inf) could be achieved if dosing were reduced by 50% in subjects with creatinine clearance values < 40 mL/min compared with control subjects (CLCR > 80 mL/min) [see DOSAGE AND ADMINISTRATION]. Monitor patients with renal insufficiency for signs of hematological toxicity [see Use In Specific Populations].
The pharmacokinetics of dexrazoxane have not been evaluated in patients with hepatic impairment.
In vitro studies indicated that dexrazoxane is not an inhibitor for CYP1A, CYP2C9, CYP2C19, CYP2D6 or CYP3A.
In studies of dexrazoxane co-administrated with doxorubicin (50 to 60 mg/m²) or epirubicin (60 to 100 mg/m²), there were no indications of significant pharmacokinetic interactions.
Totect was studied in two open-label, single arm, multi-center studies testing whether Totect administration could reduce tissue injury following anthracycline extravasation and thereby reduce or avoid surgical intervention. Totect is not effective against the effects of vesicants other than anthracyclines.
In the studies, eligible patients were receiving single-agent anthracycline intravenously (usually as part of combination chemotherapy) and developed extravasation symptoms of pain, burning, swelling, and/or redness near the infusion site. Skin biopsy samples from the suspected skin area were examined for the presence of anthracycline as determined by the presence of tissue fluorescence; however, therapy was not delayed for this test result.
In both studies, treatment with Totect was to begin as soon as possible and no later than 6 hours after extravasation with retreatment 24 and 48 hours later (a total of 3 doses). Totect was administered as 1-2 hour IV infusions through a different venous access location. The first and second doses were 1000 mg/m² and the third dose was 500 mg/m². No dose modifications were planned except for patients whose body surface area exceeded 2.0 m², in which case the total daily dose limit on the first and second day was 2000 mg/day and 1000 mg on the third day.
In total, 80 patients were enrolled and 57 were evaluable. Demographics in the two studies were similar. The median age was 57 years, and sixty-five percent of patients were women. The anthracyclines most commonly associated with extravasation were epirubicin (56%) and doxorubicin (41%). Peripheral IV sites of extravasation included the forearm in 63%, the hand in 21%, and the antecubital area in 11%; four patients (5%) received the anthracycline via a central venous access device (CVAD). Most patients presented with swelling (83%), redness (78%), and pain (43%). The median baseline lesion area was 25 cm² (range 1-253 cm²).
Evaluable patients had to be receiving IV anthracycline (single agent or in combination) at the time of extravasation, to have skin biopsies showing fluorescence, and to receive the first Totect dose within 6 hours of the extravasation.
In study 1, none of the 19 evaluable patients required surgical intervention and none had serious late sequelae. In study 2, one of the 38 evaluable patients required surgery. One additional non-evaluable patient required surgery for tissue necrosis. Thirteen patients had late sequelae at the event site such as site pain, fibrosis, atrophy, and local sensory disturbance; all were judged as mild except in the one patient who required surgery. None of the 4 patients with CVADs required surgical intervention.
The ability of dexrazoxane to reduce the incidence and severity of doxorubicin-induced cardiomyopathy was evaluated in three prospectively randomized placebo-controlled studies. In these studies, patients were treated with a doxorubicin-containing regimen and either dexrazoxane or placebo starting with the first course of chemotherapy. There was no restriction on the cumulative dose of doxorubicin. Cardiac function was assessed by measurement of the left ventricular ejection fraction (LVEF), utilizing resting multigated nuclear medicine (MUGA) scans, and by clinical evaluations. Patients receiving dexrazoxane had significantly smaller mean decreases from baseline in LVEF and lower incidences of congestive heart failure than the control group; however, in the largest study, patients with advanced breast cancer receiving FAC with dexrazoxane had a lower response rate (48% vs. 63%) and a shorter time to progression than patients who received FAC versus placebo.
In the clinical trials, patients who were initially randomized to receive placebo were allowed to receive dexrazoxane after a cumulative dose of doxorubicin above 300 mg/m². Retrospective historical analyses showed that the risk of experiencing a cardiac event (see Table 5 for definition) at a cumulative dose of doxorubicin above 300 mg/m² was greater in the patients who did not receive dexrazoxane beginning with their seventh course of FAC than in the patients who did receive dexrazoxane (HR=13.08; 95% CI: 3.72, 46.03; p<0.001). Overall, 3% of patients treated with dexrazoxane developed CHF compared with 22% of patients not receiving dexrazoxane.
Table 5: Definition of Cardiac Events
Figure 1 shows the number of patients still on treatment at increasing cumulative doses.
Figure 1 : Cumulative Number of Patients On Treatment FAC vs. FAC/Dexrazoxane Patients Patients Receiving at Least Seven Courses of Treatment
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Totect®
(TOE-TECT)
(dexrazoxane) injection
What is Totect?
Totect is a prescription medicine used:
It is not known if Totect is safe and effective in children.
Before you receive Totect, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal or dietary supplements.
Especially tell your healthcare provider if you:
How will I receive Totect?
What are the possible side effects of Totect?
Totect can cause serious side effects, including:
The most common side effects of Totect in people treated for anthracycline chemotherapy leaks include:
The most common side effect of Totect in women with metastatic breast cancer to reduce the occurrence and severity of heart muscle problems is pain at the intravenous (IV) site.
Totect may cause fertility problems in males, which may affect the ability to father children. Talk to your healthcare provider if you have concerns about fertility.
These are not all the possible side effects of Totect. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of Totect.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about Totect that is written for health professionals.
What are the ingredients in Totect?
Active ingredient: dexrazoxane (as a hydrochloride salt).
Inactive ingredients: none
This Patient Information has been approved by the U.S. Food and Drug Administration.
