DRUGS & SUPPLEMENTS
1 INDICATIONS AND USAGE
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 .
Totect is a cytoprotective agent 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 Totect with doxorubicin initiation. (1)
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
Administer Totect Injection via intravenous infusion over 15 minutes. DO NOT ADMINISTER VIA AN INTRAVENOUS PUSH.
The recommended dosage ratio of Totect to doxorubicin is 10:1 (e.g., 500 mg/m2 Totect to 50 mg/m2 doxorubicin). Do not administer doxorubicin before Totect. Administer doxorubicin within 30 minutes after the completion of Totect infusion.
2.2 Dose Modifications
Dosing in Patients with Renal Impairment
Reduce Totect dosage in patients with moderate to severe renal impairment by 50% (ZINECARD to doxorubicin ratio reduced to 5:1; such as 250 mg/m2 Totect to 50 mg/m2 doxorubicin) .
Dosing in Patients with Hepatic Impairment
Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, reduce the Totect dosage proportionately (maintaining the 10:1 ratio) in patients with hepatic impairment.
2.3 Preparation and Administration
Preparation and Handling of Infusion Solution
Reconstitute Totect with Sterile Water for Injection, USP. Reconstitute with 25 mL for a Totect 250 mg vial and 50 mL for a Totect 500 mg vial to give a concentration of 10 mg/mL. Dilute the reconstituted solution further with Lactated Ringer's Injection, USP to a concentration of 1.3 to 3.0 mg/mL in intravenous infusion bags for intravenous infusion.
Following reconstitution with Sterile Water for Injection, USP, Totect is stable for 30 minutes at room temperature or if storage is necessary, up to 3 hours from the time of reconstitution when stored under refrigeration, 2° to 8°C (36° to 46°F). The pH of the resultant solution is 1.0 to 3.0. DISCARD UNUSED SOLUTIONS. The diluted infusion solutions are stable for one hour at room temperature or if storage is necessary, up to 4 hours when stored under refrigeration, 2° to 8°C (36° to 46°F). The infusion solutions have a pH of 3.5 to 5.5. DISCARD UNUSED SOLUTIONS.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Solutions containing a precipitate should be discarded.
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
Do not mix Totect with other drugs.
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.
3 DOSAGE FORMS AND STRENGTHS
Totect (dexrazoxane for injection) is available in 250 mg or 500 mg single dose vials as sterile, pyrogen-free lyophilizates.
250 mg or 500 mg single dose vials as sterile, pyrogen-free lyophilizates. (3)
Do not use Totect with non-anthracycline chemotherapy regimens.
Totect should not be used with non-anthracycline chemotherapy regimens. (4)
5 WARNINGS AND PRECAUTIONS
Totect may add to the myelosuppression caused by chemotherapeutic agents. Obtain a complete blood count prior to and during each course of therapy, and administer Totect and chemotherapy only when adequate hematologic parameters are met.
5.2 Concomitant Chemotherapy
Only use Totect in those patients who have received a cumulative doxorubicin dose of 300 mg/m2 and are continuing with doxorubicin therapy. Do not use with chemotherapy initiation as Totect may interfere with the antitumor activity of the chemotherapy regimen. In a trial conducted in patients with metastatic breast cancer who were treated with fluorouracil, doxorubicin, and cyclophosphamide with or without Totect starting with their first cycle of FAC therapy, patients who were randomized to receive Totect had a lower response rate (48% vs. 63%) and shorter time to progression than patients who were randomized to receive placebo.
5.3 Cardiac Toxicity
Treatment with Totect does not completely eliminate the risk of anthracycline-induced cardiac toxicity. Monitor cardiac function before and periodically during therapy to assess left ventricular ejection fraction (LVEF). In general, if test results indicate deterioration in cardiac function associated with doxorubicin, the benefit of continued therapy should be carefully evaluated against the risk of producing irreversible cardiac damage.
5.4 Secondary Malignancies
Secondary malignancies such as acute myeloid leukemia and myelodysplastic syndrome (MDS) have been reported in studies of pediatric patients who have received Totect in combination with chemotherapy. Totect is not indicated for use in pediatric patients. Some adult patients who received Totect in combination with anti-cancer agents known to be carcinogenic have also developed secondary malignancies, including AML and MDS.
Razoxane is the racemic mixture, of which Totect is the S(+)-enantiomer. Secondary malignancies (primarily acute myeloid leukemia) have been reported in patients treated chronically with oral razoxane. In these patients, the total cumulative dose of razoxane ranged from 26 to 480 grams and the duration of treatment was from 42 to 319 weeks. One case of T-cell lymphoma, one case of B-cell lymphoma, and six to eight cases of cutaneous basal cell or squamous cell carcinoma have also been reported in patients treated with razoxane. Long-term administration of razoxane to rodents was associated with the development of malignancies .
5.5 Embryo-Fetal Toxicity
Totect can cause fetal harm when administered to pregnant women. Totect administration during the period of organogenesis resulted in maternal toxicity, embryotoxicity and teratogenicity in rats and rabbits at doses significantly lower than the clinically recommended dose . 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 a fetus.
Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment .
6 ADVERSE REACTIONS
In clinical studies, Totect was administered to patients also receiving chemotherapeutic agents for cancer. Pain on injection was observed more frequently in patients receiving Totect versus placebo.
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 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.
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 FAC chemotherapy regimen with or without Totect. 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 Totect experienced more severe leukopenia, granulocytopenia, and thrombocytopenia than patients receiving FAC without Totect .
Table 1 below lists the incidence of adverse reactions for patients receiving FAC with either Totect or placebo in the breast cancer studies. Adverse experiences occurring during courses 1 through 6 are displayed for patients receiving Totect 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 Totect or placebo with FAC are also displayed (columns 2 and 4, respectively).
The adverse reactions listed below in Table 1 demonstrate that the frequency of adverse reaction "Pain on Injection" has been greater for Totect arm, as compared to placebo.
7 DRUG INTERACTIONS
No drug interactions have been identified .
8 USE IN SPECIFIC POPULATIONS
Totect can cause fetal harm when administered to pregnant women. Totect administration resulted in maternal toxicity, embryotoxicity and teratogenicity in rats and rabbits at doses significantly lower than the clinically recommended dose. 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 a fetus .
Totect resulted in maternal toxicity in rats at doses of ≥2 mg/kg (1/40 the human dose on a mg/m2 basis) and embryotoxicity and teratogenicity at 8 mg/kg (approximately 1/10 the human dose on a mg/m2 basis) when given daily to pregnant rats 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 (approximately 1/10 the human dose on a mg/m2 basis) daily during the period of organogenesis caused maternal toxicity and doses of 20 mg/kg (1/2 the human dose on a mg/m2 basis) 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.
8.3 Nursing Mothers
It is not known whether Totect 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 Totect, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
The safety and effectiveness of Totect in pediatric patients have not been established .
8.5 Geriatric Use
Clinical studies of Totect did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
8.6 Females of Reproductive Potential
Totect can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment .
8.7 Renal Impairment
Greater exposure to Totect may occur in patients with compromised renal function. Reduce the Totect dose by 50% in patients with creatinine clearance values <40 mL/min .
There are no data on overdosage in the cardioprotective trials; the maximum dose administered during the cardioprotective trials was 1000 mg/m2 every three weeks.
Disposition studies with Totect 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.
There is no known antidote for Totect. Instances of suspected overdose should be managed with good 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.
Totect (dexrazoxane for injection), a cardioprotective agent for use in conjunction with doxorubicin, is a sterile, pyrogen-free lyophilizate intended for intravenous administration.
Chemically, Totect is (S)-4,4'-(1-methyl-1,2-ethanediyl)bis-2,6-piperazinedione. The structural formula is as follows:
Totect, an intracellular chelating agent, is a derivative of EDTA. Totect is a whitish crystalline powder that melts at 191° to 197°C. It is sparingly soluble in water and 0.1 N HCl, slightly soluble in ethanol and methanol, and practically insoluble in nonpolar organic solvents. The pKa is 2.1. Totect has an octanol/water partition coefficient of 0.025 and degrades rapidly above a pH of 7.0.
Each 250 mg vial contains Totect hydrochloride equivalent to 250 mg Totect. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with 25 mL of Sterile Water for Injection, USP, each mL contains: 10 mg Totect. The pH of the resultant solution is 1.0 to 3.0.
Each 500 mg vial contains Totect hydrochloride equivalent to 500 mg Totect. Hydrochloric Acid, NF is added for pH adjustment. When reconstituted as directed with 50 mL of Sterile Water for Injection, USP, each mL contains: 10 mg Totect. The pH of the resultant solution is 1.0 to 3.0.
The reconstituted Totect solutions prepared from Sterile Water for Injection, USP, are intended for further dilution with Lactated Ringer's Injection, USP, for rapid intravenous drip infusion. DO NOT ADMINISTER VIA AN INTRAVENOUS PUSH .
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism by which Totect exerts its cytoprotective activity is not fully understood. Totect is a cyclic derivative of EDTA that penetrates cell membranes. Results of laboratory studies suggest that Totect is converted intracellularly to a ring-opened chelating agent that interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracycline-induced cardiomyopathy.
The pharmacokinetics of Totect have been studied in advanced cancer patients with normal renal and hepatic function. The pharmacokinetics of Totect can be adequately described by a two-compartment open model with first-order elimination. Totect 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 Totect 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 Totect was 36.5 µg/mL at 15- minute after intravenous administration of 500 mg/m2 dose of Totect over 15 to 30 minutes prior to the 50 mg/m2 doxorubicin dose.
The important pharmacokinetic parameters of Totect are summarized in Table 2:
Following a rapid distributive phase (0.2 to 0.3 hours), Totect reaches post-distributive equilibrium within two to four hours. The estimated mean steady-state volume of distribution of Totect is 22.4 L/m2 after 500 mg/m2 of Totect dose followed by 50 mg/m2 of doxorubicin, suggesting distribution throughout total body water (25 L/m2).
In vitro studies have shown that Totect is not bound to plasma proteins.
Qualitative metabolism studies with Totect 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 Totect. Forty-two percent of a 500 mg/m2 dose of Totect was excreted in the urine. Renal clearance averages 3.35 L/h/m2 after the 500 mg/m2 Totect dose followed by 50 mg/m2 of doxorubicin.
Pharmacokinetics following Totect administration have not been evaluated in pediatric patients.
Effect of Renal Impairment
The pharmacokinetics of Totect were assessed following a single 15-minute IV infusion of 150 mg/m2 of Totect. Totect clearance was reduced in subjects with renal dysfunction. Compared with controls, the mean AUC0–inf value was two-fold greater in subjects with moderate (CLCR 30–50 mL/min) to severe (CLCR <30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC-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) .
Effect of Hepatic Impairment
Pharmacokinetics following Totect administration have not been evaluated in patients with hepatic impairment. The Totect dose is dependent upon the dose of doxorubicin .
There was no significant change in the pharmacokinetics of doxorubicin (50 mg/m2) and its predominant metabolite, doxorubicinol, in the presence of Totect (500 mg/m2) in a crossover study in cancer patients.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term carcinogenicity studies have been carried out with Totect in animals. Nevertheless, a study by the National Cancer Institute has reported that long-term dosing with razoxane (the racemic mixture of Totect, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice .
Totect was not mutagenic in the bacterial reverse mutation (Ames) test, but was found to be clastogenic to human lymphocytes in vitro and to mouse bone marrow erythrocytes in vivo (micronucleus test).
Totect has the potential to impair fertility in male patients based on effects in repeat-dose toxicology studies. Testicular atrophy was seen with Totect administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (1/3 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (approximately equal to the human dose on a mg/m2 basis).
14 CLINICAL STUDIES
The ability of Totect to prevent/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 Totect 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 LVEF, utilizing resting multigated nuclear medicine (MUGA) scans, and by clinical evaluations. Patients receiving Totect 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 Totect 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 Totect after a cumulative dose of doxorubicin above 300 mg/m2. Retrospective historical analyses showed that the risk of experiencing a cardiac event at a cumulative dose of doxorubicin above 300 mg/m2 was greater in the patients who did not receive Totect beginning with their seventh course of FAC than in the patients who did receive Totect (HR=13.08; 95% CI: 3.72, 46.03; p<0.001). Overall, 3% of patients treated with Totect developed CHF compared with 22% of patients not receiving Totect.
Figure 1 shows the number of patients still on treatment at increasing cumulative doses.
16 HOW SUPPLIED/STORAGE AND HANDLING
Totect (dexrazoxane for injection) is available in the following strengths as sterile, pyrogen-free lyophilizates.
250 mg single dose vial with a red flip-top seal, packaged in single vial packs.
500 mg single dose vial with a blue flip-top seal, packaged in single vial packs.
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
Follow special handling and disposal procedures.1
17 PATIENT COUNSELING INFORMATION
Treatment with Totect is associated with leukopenia, neutropenia, and thrombocytopenia. Perform hematological monitoring .
17.2 Embryo-Fetal Toxicity
Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential that Totect can cause fetal harm and to use highly effective contraception during treatment .
This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.
For Intravenous Use Only
Totect pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Totect available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Totect destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Totect Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Totect pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Totect?
Depending on the reaction of the Totect after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Totect not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Totect addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
Reviewsdrugs.com conducted a study on Totect, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Totect consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
Visitor reported usefulNo survey data has been collected yet
Visitor reported side effectsNo survey data has been collected yet
Visitor reported price estimatesNo survey data has been collected yet
Visitor reported frequency of useNo survey data has been collected yet
Visitor reported dosesNo survey data has been collected yet
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The information was verified by Dr. Arunabha Ray, MD Pharmacology