Totect

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 reflects the combination of Totect®, underlying disease, and already administered chemotherapy. The adverse reaction data reflect exposure to Totect® 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

Neutropenia and febrile neutropenia each occurred in 2.5% of patients.

Table 2 summarizes laboratory adverse events from studies 1 and 2.

Table 2: Laboratory Adverse Reactions

Read the entire FDA prescribing information for Totect (Dexrazoxane for Injection, Intravenous Infusion Only )

Dexrazoxane is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting.

Totect is usually started within 6 hours after extravasation, and continued once daily for 3 days.

Zinecard is usually started 30 minutes before you receive your doxorubicin injection.

Dexrazoxane can add to the bone marrow lowering effects of chemotherapy. This can weaken your immune system, making it easier for you to get sick from being around others who are ill.

To be sure this medication is not causing harmful effects, your blood cells and kidney function will need to be tested often. Do not miss any follow up visits to your doctor for blood or urine tests.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

In the U.S.

• Totect
• Zinecard

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Cardioprotective Agent

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Upset stomach or throwing up.
• Irritation where the shot is given.
• Pain where the shot was given.
• Feeling tired or weak.
• Loose stools (diarrhea).
• Stomach pain.
• Hard stools (constipation).
• Dizziness.
• Headache.
• Not hungry.
• Hair loss.
• Not able to sleep.
• Mouth irritation or mouth sores.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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:

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 (2.4)]. The admixture should be further diluted in 0.9 % NaCl prior to administration to patients.

Mechanism of Action

The mechanism by which Totect® diminishes tissue damage resulting from the extravasation of anthracycline drugs is unknown. Some evidence suggests that dexrazoxane inhibits topoisomerase II reversibly.

Pharmacokinetics

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.

Following a rapid distributive phase (~0.2 to 0.3 hours), dexrazoxane reaches post-distributive equilibrium within 2 to 4 hours. The estimated steady-state volume of distribution of dexrazoxane suggests its distribution primarily in the total body water (25 L/m2).

In a study of the pharmacokinetics of dexrazoxane following the recommended dosing for patients with anthracycline extravasation, the mean systemic clearance and steady-state volume of distribution of dexrazoxane in six female patients undergoing treatment for anthracycline extravasations at a dose of 1000 mg/m2 Totect® on Days 1 and 2 and 500 mg/m2 on Day 3 were similar to that observed when administered with doxorubicin. The systemic clearances (mean ± SD) were similar among Day 1 (5.9 ± 2.0 L/h/m2), Day 2 (6.4 ± 2.1 L/h/m2), and Day 3 (7.9 ± 3.0 L/h/m2). The terminal elimination half life did not change over 3 days (2.1-2.2 h). The volume of distribution was 17.9 ~ 22.6 L/m2.

Qualitative metabolism studies 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.

Effects of 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) [see Dosage and Administration (2.2)].

Hepatic insufficiency

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

Drug interactions

There were no significant changes in the pharmacokinetics of doxorubicin (50 mg/m2) and its predominant metabolite, doxorubicinol, in the presence of dexrazoxane (500 mg/m2) in a crossover study in cancer patients.

1. "OSHA Hazardous Drugs." OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

See FDA-approved patient labeling (Patient Information)

Myelosuppression

Treatment with Totect® is associated with leukopenia, neutropenia, and thrombocytopenia. Perform hematological monitoring. [see Warnings and Precautions (5.1)]

Pregnancy

Women who have potential to become pregnant should be advised that Totect® might cause fetal harm. [see Warnings and Precautions (5.2)]

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.