Totect

Generic Name: dexrazoxane
Date of Approval: September 6, 2007
Company: TopoTarget A/S

Treatment for: Anthracycline Extravasation

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FDA Approves Totect

The United States Food and Drug Administration (FDA) has approved Totect for the treatment of extravasation resulting from intravenous anthracycline chemotherapy.

Totect is used as a therapy when anthracycline, intravenously administered, accidentally leaks into the surrounding healthy tissue. Anthracyclines are chemotherapeutic agents used to treat a large number of cancers and constitute one of the cornerstones in the treatment of breast cancer and leukemia.

About Totect

Totect is a catalytic inhibitor of Topoisomerase II, an enzyme found in the cell nucleus. Topoisomerase enzymes are essential for cell growth and proliferation and the target for a group of anti-cancer chemotherapeutics called anthracyclines. Totect blocks the activity of the topoisomerase enzyme and prevents the effect of anthracyclines.

Totect is used as a detoxifying agent, administered intravenously as an antidote following an extravasation. An extravasation is a serious clinical accident in which anthracyclines accidentally leak into surrounding tissue. The high concentration of drug causes severe and cumulative damage to the skin, subcutaneous tissue, muscle and nerves. Current treatment often involves surgical removal of the tissue followed by plastic surgery and rehabilitation.

Totect: Indication and Usage

Totect is indicated for the treatment of extravasation resulting from IV anthracycline chemotherapy:

• daunorubicin
• doxorubicin
• epirubicin
• idarubicin

Totect is packaged as an emergency treatment carton for single patient use. Each carton contains 10 vials of Totect (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent, which provides a complete three day treatment.

Totect: Dosage and Administration

The patient’s Totect dose is based on the patient’s body surface area.

Day one: 1000 mg/m² Day two: 1000 mg/m² Day three: 500 mg/m²

A maximum single dose of Totect should not exceed 2000 mg.

Dosage adjustment is required for patients with impaired renal function. The Totect dose should be reduced 50% in patients with creatinine clearance values <40 mL/min.

Totect (dexrazoxane for injection) must be reconstituted with supplied diluent to provide a concentration of 10 mg/mL. The reconstituted solution has a slight yellow color. The patient’s dose of Totect (based on body surface area) is injected into a 1000 ml infusion bag of 0.9% sodium chloride (NaCl) for infusion. Totect must be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.

The first infusion of Totect should be administered as soon as possible and within the first 6 hours following the extravasation.

Topical cooling, such as ice packs, should be removed for at least 15 minutes prior to and during Totect administration.

Concurrent extravasation treatment, such as topical dimethyl sulfoxide (DMSO) application, should not be used in conjunction with Totect, and if administered, may worsen extravasation-induced tissue injury.

Totect administration on days two and three should begin as close to 24 and 48 hours after the time of the day one infusion (e.g. if the day one infusion was initiated at noon, then the day two infusion should begin at noon on the following day, and the day three infusion should begin at noon on the third day).

Totect: Handling, Storage and Disposal

Caution when handling and preparing Totect must be exercised. Procedures normally used for proper handling and disposal of anticancer drugs should be adopted for use with Totect. If Totect (dexrazoxane for injection) or the mixed solution comes in contact with the skin or mucous membranes, wash immediately and thoroughly with water.

Totect (dexrazoxane for injection) and Totect diluent vials should be kept in the treatment carton box to protect them from light and reduce the risk of breakage.

The Totect treatment carton should be stored at room temperature and protected from heat.

The reconstituted product is preservative-free and should be used immediately after mixing and diluting (within 2 hours). The mixed and diluted product is stable for 4 hours when stored below 25°C (77°F).

Dispose of any unused product or waste material in accordance with institutional procedures.

Totect: Warnings and Precautions

Warnings: Pregnancy Category D. Dexrazoxane was toxic to pregnant rats at doses of 2 mg/kg (1/80 the human dose on a mg/m² basis) and embryotoxic and teratogenic at 8 mg/kg when given daily during the period of organogenesis. Teratogenic effects in the rat included imperforate anus, microphthalmia, and anophthalmia. In offspring allowed to develop to maturity, fertility was impaired in the male and female rats treated in utero during organogenesis at 8 mg/kg. In rabbits, doses of 5 mg/kg daily during the period of organogenesis caused maternal toxicity and doses of 20 mg/kg were embryotoxic and teratogenic. Teratogenic effects in the rabbit included 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. There is no adequate information about the use of Totect in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Precautions: Totect is a cytotoxic drug. When administered to patients receiving anthracycline-containing cytotoxic therapy, additive cytotoxicity may occur. Treatment with Totect is associated with leukopenia, neutropenia, and thrombocytopenia. Reversible elevations of liver enzymes may occur. Blood counts and liver enzymes should be monitored. Greater exposure to dexrazoxane may occur in patients with compromised renal function. The Totect dose should be reduced by 50% in patients with creatinine clearance values <40 mL/min. Dimethyl sulfoxide (DMSO) should not be used in patients who are receiving dexrazoxane to treat anthracycline-induced extravasation. Women of who have the potential to become pregnant should be advised that Totect might cause fetal harm. There are no known drug interactions. No carcinogenicity studies have been done with Totect in animals. The carcinogenic potential of dexrazoxane has not been investigated. Long term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice. Dexrazoxane was not mutagenic to bacteria in vitro (Ames assay), but caused significant chromosomal aberrations in mammalian cells in vitro. It also increased the formation of micronucleated polychromatic erythrocytes in mice. Dexrazoxane is mutagenic and clastogenic. The possible adverse effects of Totect on the fertility of humans and experimental animals, male or female, have not been adequately studied. Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (about 1/5 the human dose on a mg/m² basis) and as low as 20 mg/kg weekly for 13 weeks in dogs. The effect of dexrazoxane on labor and delivery in humans has not been studied. It is not known whether dexrazoxane or its metabolites are 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 dexrazoxane, 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. The safety and effectiveness of Totect in pediatric patients have not been established. 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 patients has been observed. 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 function, care should be taken in dose selection, and it may be useful to monitor renal function.

Totect: Adverse Reactions

Possible side effects are nausea and vomiting, diarrhea, sore mouth, decreased white blood cell count, decreased platelet count, increased liver enzyme levels, and infusion site burning.

Totect: Use in Special Populations

Pediatric: The pharmacokinetics of dexrazoxane have not been evaluated in pediatric patients.

Gender: There are no clinically relevant differences in the pharmacokinetics of dexrazoxane between males and females.

Renal insufficiency: 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)

Hepatic insufficiency: The pharmacokinetics of dexrazoxane have not been evaluated in patients with hepatic impairment.

Totect: Mechanism of Action

Totect has a unique dual mechanism of action. It inhibits DNA topoisomerase II, the target of anthracycline chemotherapy, and binds to DNA topoisomerase II at a different step in the catalytic cycle.^1,2,3 This locks the enzyme in a form that is no longer affected by the anthracycline.

Totect also acts as an iron chelator and minimizes oxidative damage caused by formation of anthracycline-iron complexes.^4,5 Totect is rapidly metabolized within the cell to chelate iron and limits anthracycline-mediated oxidative injury.

Totect: Preclinical and Clinical Studies

Preclinical studies support the efficacy of Totect. In studies of mice with anthracycline extravasations,^6,7,8 Totect was effective in protecting the tissue from injury. DMSO and hydrocortisone were ineffective, and data suggest that concurrent topical application of DMSO may reduce the efficacy of Totect.

In preclinical studies, Totect was found to be most effective when administered promptly after an anthracycline extravasation occurred. To fully protect tissue from anthracycline damage, Totect should be administered as soon as possible and within 6 hours of the extravasation.

The efficacy of Totect was confirmed in two clinical trials conducted in Europe.¹⁰ In the first clinical trial, none of the 18 patients treated with Totect (European trade name Savene) required surgical debridement of their anthracycline extravasations. In the second clinical trial, only one of the 36 patients treated with Totect required surgery. Overall efficacy was 98%.

The majority of adverse events in the two clinical trials were those expected from anthracycline chemotherapy treatment. The most common side effects potentially related to Totect were nausea and hematological toxicities (neutropenia and thrombocytopenia). Adverse events related to Totect were reversible and manageable.¹⁰

Totect is uniquely formulated to minimize infusion site reactions (pain, phlebitis, induration, and swelling). In the first clinical trial, Totect was mixed with standard saline solution. In the second clinical trial, Totect was mixed with a specially formulated diluent, which significantly reduced the number of injection site reactions.¹⁰

References

1. Sehested M, Jensen PB. Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle. Biochem Pharmacol. 1996;51:879-886.
2. Jensen PB, Sehested M. DNA topoisomerase II rescue by catalytic inhibitors. Biochem Pharmacol. 1997;54:755-759.
3. Hasinoff BB. Chemistry of dexrazoxane and analogues. Semin Oncol. 1998;25(4) (Suppl 10):3-9.
4. Andoh T, Ishida R. Catalytic inhibitors of DNA topoisomerase II. Biochem Biophys Acta. 1998;1400:155-71.
5. Hasinoff BB, Schroeder PE, Patel D. The metabolites of the cardioprotective drug dexrazoxane do not protect myocytes from doxorubicin-induced cytotoxicity. Mol Pharmacol. 2003;64(3):670-678.
6. Langer SW, et al. Treatment of anthracycline extravasation in mice with dexrazoxane with or without DMSO and hydrocortisone. Cancer Chemother Pharmacol. 2006;57:125-128.
7. Langer SW, Sehested M, Jensen PB. Dexrazoxane is a potent and specific inhibitor of anthracycline induced subcutaneous lesions in mice. Annals of Oncology. 2001;12:405-410.
8. Langer SW, Sehested M, Jensen PB. Treatment of anthracycline extravasation with dexrazoxane. Clin Cancer Res 2000;6:3980-3686.
9. Langer SW et al., ICRF-187 (dexrazoxane) Inhibits Doxorubicin-Induced S.C. Necrosis in Mice: A New Strategy in Treating Accidental Anthracycline Extravasation. Proceedings 1999 ASCO meeting, Abstract no. 695.
10. Mouridsen HT et al. Treatment of anthracycline extravasation with Savene (dexrazoxane): Results from two prospective clinical multicenter studies. Ann Oncology 2007;18:546-550.

Totect Patient Information

What Totect is and what it is used for:

Totect is a treatment for anthracycline chemotherapy extravasation.

Many chemotherapy drugs are given I.V. (into a vein). They sometimes leak from the vein or go into the tissue instead of the vein. When an anthracycline (a type of chemotherapy drug) goes into the tissue, damage to the tissue can occur. This is called an anthracycline extravasation.

Do NOT use Totect if:

• you are allergic to dexrazoxane or any of the other ingredients in Totect
• you have an extravasation of a chemotherapy drug that is not an anthracycline.

Before using Totect:

Tell your healthcare provider if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant or could be pregnant, are planning to become pregnant, or are breastfeeding
• if you have any kidney or liver problems
• if you are taking any prescription or nonprescription medicine, herbal preparations, or dietary supplements

How to use Totect:

• Use Totect as directed by your healthcare provider.
• Totect is usually administered at a doctor’s office, clinic, or hospital.
• Totect is given I.V. into a vein over 1-2 hours each day for a total of three days.
• The first dose of Totect needs to be given within 6 hours of an anthracycline extravasation. The second dose is given 24 hours later on the second day and the last dose is given at about the same time on the third day.

Important safety information about Totect:

• Blood tests may be needed to monitor your progress or check for side effects. Be sure to keep all lab and doctor’s appointments.
• Totect should not be given to children. Safety and effectiveness in children have not been confirmed.

Possible side effects of Totect:

The most common side effect of Totect is nausea. Other possible side effects are pain at the injection site, decreased white blood cell count, diarrhea, dry mouth, hair loss, and tiredness. Contact your healthcare provider if any of these side effects persist or become bothersome.

If you have questions or need medical advice about side effects, contact your healthcare provider. You may report side effects to the FDA at 1-800-FDA-1088 (1-800-332-1088) or at www.fda.gov/medwatch.

General Information:

• If you have any questions about Totect, talk to your doctor, nurse, pharmacist, or other healthcare provider.
• This information is a summary only and does not contain all information about Totect. If you would like more information, contact your healthcare provider.

For more information, please visit www.totect.com.

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