Generic Name: dexrazoxane
Date of Approval: September 6, 2007
Company: TopoTarget A/S
Discussion for: Anthracycline Eructation
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FDA Approves Totect
The Joined States Intellectual nourishment and Drug Administration (FDA) has sanctioned Totect for the discussion 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 ane of the cornerstones in the discussion 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 crucial for cell growth and proliferation and the quarry 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 counterpoison following an extravasation. An extravasation is a dangerous clinical accident in which anthracyclines incidentally leak into surrounding tissue. The highschool concentration of drug causes severe and cumulative terms to the skin, hypodermic 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 trinity day discourse.
Totect: Dose and Organization
The patient’s Totect dose is based on the patient’s body surface surface area.
Day one: 1000 mg/m2 Clarence Shepard Day Jr. two: G mg/m2 Day trine: 500 mg/m2
A maximum unmarried dose of Totect should not outstrip 2000 mg.
Dosage adjustment is required for patients with afflicted renal routine. The Totect dose should be decreased 50% in patients with creatinine clearance values <40 mL/min.
Totect (dexrazoxane for injection) must be reconstituted with supplied dilutant to allow for a assiduousness of 10 mg/mL. The reconstituted solution has a slight chickenhearted color. The patient’s dose of Totect (based on body surface area) is injected into a 1000 ml infusion bag of 0.9% na chloride (NaCl) for infusion. Totect must be administered under the supervision of a medico experienced in the habit of cancer the Crab chemotherapeutic agents.
The number one infusion of Totect should be administered as soon as possible and within the first 6 hours following the extravasation.
Topical cooling, such as water ice packs, should be removed for at least 15 minutes prior to and during Totect administration.
Cooccurring extravasation treatment, such as topical dimethyl sulfoxide (DMSO) application, should not be used in conjunction with Totect, and if administered, may exasperate extravasation-induced tissue injury.
Totect administration on days iI and trio should begin as close to 24 and 48 hours after the time of the day one infusion (e.g. if the daytime one infusion was initiated at noontide, then the day 2 infusion should begin at noon on the next day, and the day three infusion should start at twelve noon on the third clarence Day).
Totect: Handling, Storage and Disposal
Caveat when treatment and preparing Totect must be exercised. Procedures commonly used for proper handling and garbage disposal of anticancer drugs should be adoptive for usance with Totect. If Totect (dexrazoxane for injection) or the motley solution comes in physical contact with the skin or mucous membranes, wash immediately and exhaustively with water.
Totect (dexrazoxane for shot) 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 secondhand immediately afterward mixing and diluting (within 2 hours). The interracial and dilute product is stable for 4 hours when stored below 25°C (77°F).
Discard of whatsoever unused product or devastate material in accordance with institutional procedures.
Totect: Warnings and Precautions
Warnings: Gestation Category D. Dexrazoxane was toxic to pregnant rats at doses of 2 mg/kg (1/80 the human dose on a mg/m2 foundation) 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 young allowed to develop to maturity, fertility rate 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 pectoral malformations, and soft tissue variations including subcutaneous, eye and cardiac hemorrhagic areas, as well as agenesia of the gallbladder and of the intermediate lobe of the lung. Thither 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 patch taking this drug, the patient should be apprised of the potential chance to the fetus.
Precautions: Totect is a cytotoxic drug. When administered to patients receiving anthracycline-containing cytotoxic therapy, additive cytotoxicity whitethorn 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 office. The Totect dose should be decreased by 50% in patients with creatinine clearance values <40 mL/min. Dimethyl sulfoxide (DMSO) should non be used in patients who are receiving dexrazoxane to treat anthracycline-induced eructation. Women of who ingest the potential to turn pregnant should be well-advised that Totect might movement fetal impairment. There ar no known drug interactions. No carcinogenicity studies take been through 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 non mutagenic to bacteria in vitro (Ames assay), but caused significant chromosomal aberrations in mammal 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 humankind and experimental animals, male or distaff, have non been adequately studied. Testicular atrophy was seen with dexrazoxane governance at doses as broken as 30 mg/kg weekly for 6 weeks in rats (about 1/5 the human dosage on a mg/m foundation) and as low as 20 mg/kg weekly for 13 weeks in dogs. The upshot of dexrazoxane on labor and manner of speaking in mankind has non 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 untoward reactions in nursing infants from dexrazoxane, a decision should be made whether to give up nursing or to discontinue the drug, taking into account the importance of the do drugs to the mother. The safety and effectiveness of Totect in pediatric patients have not been naturalized. No differences in refuge or efficaciousness 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 ascertained. This dose is known to be substantially excreted by the kidney, and the hazard of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have reduced renal role, care should be taken in dose selection, and it may be useful to monitor renal function.
Totect: Adverse Reactions
Possible side personal effects are nausea and vomit, diarrhea, painful mouth, reduced white origin cell reckon, decreased blood platelet count, increased liver enzyme levels, and infusion web site burning.
Totect: Use in Special Populations
Paediatric: The pharmacokinetics of dexrazoxane hold 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 disfunction 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. Clay sculpture demonstrated that equivalent exposure (AUC0-inf) could be achieved if dosing were rock-bottom 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 at law
Totect has a unequaled dual mechanism of action. It inhibits DNA topoisomerase II, the target of anthracycline chemotherapy, and binds to Deoxyribonucleic acid topoisomerase II at a different step in the catalytic cycle.1,2,3 This locks the enzyme in a variant that is no yearner affected by the anthracycline.
Totect also acts as an branding iron chelator and minimizes oxidative damage caused by formation of anthracycline-iron complexes.4,5 Totect is quickly metabolized within the cell to chelate iron and limits anthracycline-mediated oxidative injury.
Totect: Preclinical and Clinical Studies
Presymptomatic studies reenforcement 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 unable, and information suggest that concurrent topical application of DMSO may reduce the efficacy of Totect.
In preclinical studies, Totect was found to be to the highest degree effective when administered quick after an anthracycline extravasation occurred. To fully protect tissue from anthracycline harm, Totect should be administered as soon as possible and inside 6 hours of the extravasation.
The efficacy of Totect was confirmed in two clinical trials conducted in Europe.10 In the first clinical run, none of the 18 patients treated with Totect (European trade wind name Savene) required surgical debridement of their anthracycline extravasations. In the second clinical trial, only one of the 36 patients treated with Totect needed surgery. Boilers suit 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). Untoward events related to to Totect were reversible and doable.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 solution. In the second clinical trial, Totect was mixed with a especially formulated diluent, which significantly reduced the number of injection situation reactions.10
References
- Sehested M, Jensen PB. Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and catalytic inhibitors (aclarubicin, ICRF-187) to four decided steps in the topoisomerase II catalytic cycle. Biochem Pharmacol. 1996;51:879-886.
- Jensen PB, Sehested M. DNA topoisomerase II rescue by catalytic inhibitors. Biochem Pharmacol. 1997;54:755-759.
- Hasinoff BB. Chemistry of dexrazoxane and analogues. Semin Oncol. 1998;25(4) (Suppl 10):3-9.
- Andoh T, Ishida R. Catalytic inhibitors of DNA topoisomerase II. Biochem Biophys Acta. 1998;1400:155-71.
- Hasinoff BB, Schroeder PE, Patel D. The metabolites of the cardioprotective drug dexrazoxane do non protect myocytes from doxorubicin-induced cytotoxicity. Mole Pharmacol. 2003;64(3):670-678.
- Langer SW, et al. Treatment of anthracycline extravasation in mice with dexrazoxane with or without DMSO and hydrocortisone. Cancer the Crab Chemother Pharmacol. 2006;57:125-128.
- Langer SW, Sehested M, Jensen PB. Dexrazoxane is a potent and specific inhibitor of anthracycline induced hypodermic lesions in mice. Annals of Oncology. 2001;12:405-410.
- Langer SW, Sehested M, Jensen PB. Treatment of anthracycline extravasation with dexrazoxane. Clin Cancer Reticuloendothelial system 2000;6:3980-3686.
- Langer SW et al., ICRF-187 (dexrazoxane) Inhibits Doxorubicin-Induced S.C. Gangrene in Mice: A New Strategy in Treating Accidental Anthracycline Extravasation. Proceedings 1999 ASCO group meeting, Abstract no. 695.
- Mouridsen HT et al. Handling 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 granted I.V. (into a vein). They sometimes passing water 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 eruption.
Do Non use Totect if:
- you ar 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 whatever medical weather, 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 whatsoever kidney or liver problems
- if you are pickings any prescription medicine or nonprescription medicine, herbal tea preparations, or dietary supplements
How to use Totect:
- Use Totect as directed by your healthcare supplier.
- Totect is usually administered at a doctor’s office, clinic, or infirmary.
- Totect is given I.V. into a mineral vein over 12 hours each day for a total of three days.
- The first dosage of Totect needs to be granted within 6 hours of an thracycline extravasation. The sec dose is given 24 hours later on the second twenty-four hour period and the last venereal disease is given at almost the same time on the third gear 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 science laboratory and doctor’s appointments.
- Totect should not be given to children. Safety and effectiveness in children have non been confirmed.
Possible side personal effects of Totect:
The most common side effect of Totect is nausea. Other possible side effects ar pain at the injection site, reduced white blood cell count, diarrhea, dry mouth, hair loss, and tiredness. Contact your healthcare provider if any of these slope effects remain 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 web.fda.gov/medwatch.
Cosmopolitan Information:
- If you have whatsoever questions nigh Totect, babble to your doctor, entertain, pharmacist, or other healthcare provider.
- This information is a compact only and does non contain all information about Totect. If you would like more than information, contact your healthcare provider.
For more than information, please visit world Wide Web.totect.com.
