TOTECT- dexrazoxane hydrochloride injection, powder, lyophilized, for solution

United States - English - NLM (National Library of Medicine)

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Active ingredient:
DEXRAZOXANE HYDROCHLORIDE (UNII: 5346058Q7S) (DEXRAZOXANE - UNII:048L81261F)
Available from:
Cumberland Pharmaceuticals Inc.
INN (International Name):
DEXRAZOXANE HYDROCHLORIDE
Composition:
DEXRAZOXANE 500 mg
Administration route:
INTRAVENOUS
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Totect® is indicated for the treatment of extravasation resulting from intravenous anthracycline chemotherapy. None. Risk Summary Based on findings from animal studies and its mechanism of action, Totect can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . Limited available data with Totect use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, intravenous administration of dexrazoxane to pregnant rats and rabbits during organogenesis resulted in teratogenicity at maternal doses that were approximately 0.1 and 0.2 times, respectively, the human dose of 1000 mg/m². Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of ma
Product summary:
Each Totect carton contains 1 single dose vial of Totect (dexrazoxane for injection) 500 mg as a sterile, pyrogen-free lyophilized powder. NDC 66220-110-01: Carton of 1 vial of Totect Store at 25ºC (77ºF); excursions permitted between 15-30ºC (59-86ºF) [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 (2.3)] .1
Authorization status:
New Drug Application
Authorization number:
66220-110-01

TOTECT- dexrazoxane hydrochloride injection, powder, lyophilized, for solution

Cumberland Pharmaceuticals Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Totect safely and effectively. See full

prescribing information for Totect.

T o te c t

(dexrazoxane) for injection, for intravenous use

Initial U.S. Approval: 2007

RECENT MAJOR CHANGES

Dosage and Administration (2.3) 11/2018

Warnings and Precautions (5.1) 02/2018

Warnings and Precautions (5.2) 02/2018

Warnings and Precautions (5.3) 02/2018

INDICATIONS AND USAGE

Totect is a cytoprotective agent indicated for the treatment of extravasation resulting from intravenous anthracycline

chemotherapy. (1)

DOSAGE AND ADMINISTRATION

Reconstitute and further dilute Totect before use. (2.3)

Administer Totect by intravenous infusion over 1 to 2 hours once daily for 3 consecutive days. (2.1, 2.4)

Initiate the first infusion as soon as possible and within the first six hours after extravasation. (2.1)

Recommended doseMaximum daily dose

Day one: 1000 mg/m 2000 mg

Day two: 1000 mg/m 2000 mg

Day three: 500 mg/m 1000 mg

Reduce dose by 50% for patients with creatinine clearance < 40 mL/min. (2.2)

DOSAGE FORMS AND STRENGTHS

For Injection: 500 mg as a sterile, pyrogen-free lyophilized powder in a single dose vial for reconstitution. (3)

CONTRAINDICATIONS

None. (4)

WARNINGS AND PRECAUTIONS

Myelosuppression: Dexrazoxane is associated with leukopenia, neutropenia, and thrombocytopenia. Perform

hematological monitoring. (5.1)

Anaphylactic/Hypersensitivity Reactions: Monitor for signs and symptoms. Permanent treatment discontinuation

should be considered for severe hypersensitivity reactions. (5.2)

Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the risk to a fetus and to use

effective contraception (5.3, 8.1, 8.3)

ADVERSE REACTIONS

The most common adverse reactions (≥15%) are nausea, pyrexia, injection site pain, vomiting, and postoperative infection.

(6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Cumberland Pharmaceuticals Inc. at 1-877-484-2700

or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

Dimethyl sulfoxide: Totect is not recommended for use with topical dimethyl sulfoxide (DMSO). (7.1)

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed. (8.2)

Renal impairment: Monitor patient for signs of hematological toxicity. Reduce the Totect dose by 50% in patients with

creatinine clearance values < 40 mL/min. (8.6)

Hepatic impairment: Use in patients with hepatic impairment is not recommended. (8.7)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 12/2019

®

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

2.2 Dose Modifications

2.3 Directions for Mixing and Final Dilution

2.4 Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

5.2 Anaphylactic/Hypersensitivity Reactions

5.3 Embryo-Fetal Toxicity

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

7 DRUG INTERACTIONS

7.1 Dimethyl sulfoxide

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Totect

is indicated for the treatment of extravasation resulting from intravenous anthracycline

chemotherapy.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

Reconstitute and further dilute Totect before use [see Dosage and Administration (2.3)].

Administer Totect once daily for 3 consecutive days. Initiate the first infusion as soon as possible and

Sections or subsections omitted from the full prescribing information are not listed.

within the first six hours after extravasation [see Dosage and Administration (2.4)].

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 m .

The recommended dose is: Maximum daily dose:

Day one: 1000 mg/m 2000 mg

Day two: 1000 mg/m 2000 mg

Day three: 500 mg/m 1000 mg

2.2 Dose Modifications

Reduce the Totect dose by 50% in patients with creatinine clearance values < 40 mL/min.

2.3 Directions for Mixing and Final Dilution

Read this entire section carefully before mixing and diluting.

Aseptic technique should be used during preparation.

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.

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.

Totect solution can be prepared with EITHER Sterile Water for Injection, USP and Lactated Ringer’s

Injection OR 0.167M sodium lactate injection and 0.9% Sodium Chloride Injection– refer carefully to

the instructions below.

Preparation of Totect Solution using Sterile Water for Injection, USP and Lactated Ringer’s

Injection, USP

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 2-8ºC (36-46°F).

Preparation of Totect Solution using 0.167M Sodium Lactate Injection and 0.9% Sodium

Chloride Injection

Step 1. Reconstitute each Totect vial with 50 mL of 0.167M sodium lactate injection solution.

Preparation of 0.167M sodium lactate injection solution

Dilution of sodium lactate injection to 0.167M is required before using it to reconstitute Totect. Add

1.67 mL of 5 mEq/mL sodium lactate injection to 50 mL Sterile Water for Injection, USP to make 50 mL

of 0.167M sodium lactate injection solution.

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 0.9% Sodium Chloride 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 2-8ºC (36-46°F).

2.4 Administration

Do not administer or mix Totect with any other drug during the infusion.

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 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 IV 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 (14)].

3 DOSAGE FORMS AND STRENGTHS

For Injection: 500 mg as a sterile, pyrogen-free lyophilized powder in a single dose vial for

reconstitution.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

Treatment with Totect is associated with leukopenia, neutropenia, and thrombocytopenia. Grade 2-4

decreased white blood cells (73%), decreased neutrophils (61%), and decreased platelets (26%)

occurred in patients treated with Totect and cytotoxic chemotherapy in clinical trials. Febrile

neutropenia occurred in 2.5% of patients [see Adverse Reactions (6.1)].

Monitor complete blood counts during treatment with Totect and cytotoxic chemotherapy. The

myelosuppression and cytotoxic potential of Totect and cytotoxic chemotherapy (with a nadir occurring

on days 10-12) may be additive to that of the chemotherapy administered alone.

5.2 Anaphylactic/Hypersensitivity Reactions

Hypersensitivity reactions including anaphylactic reaction, angioedema, skin reactions, bronchospasm,

respiratory distress, hypotension and loss of consciousness have occurred in patients treated with

dexrazoxane products and anthracyclines [see Adverse Reactions (6)]. Previous history of allergy to

dexrazoxane products should be carefully considered prior to administration. Consider permanent

discontinuation in patients with severe hypersensitivity reactions.

5.3 Embryo-Fetal Toxicity

Totect can cause fetal harm when administered to a pregnant woman based on its mechanism of action

and findings from animal studies. In animal reproduction studies, intravenous administration of

dexrazoxane to pregnant rats and rabbits during organogenesis resulted in teratogenicity at maternal

doses approximately 0.1 and 0.2 times, respectively, the human dose of 1000 mg/m . Apprise pregnant

women of the potential risk to a fetus. Advise females of reproductive potential to use effective

contraception during treatment and for 6 months following the last dose of Totect. Advise males with

female partners of reproductive potential to use effective contraception during treatment with Totect

and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology

(12.1)].

6 ADVERSE REACTIONS

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.

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

General disorders and administration site conditions

Pyrexia

Injection site pain/injection site discomfort

Fatigue

Edema peripheral

Injection site phlebitis

Gastrointestinal disorders

Nausea

Vomiting

Diarrhea

Abdominal pain

Constipation

Infections and infestations

Postoperative infection

Nervous system disorders

Dizziness

Headache

Skin and subcutaneous disorders

Alopecia

Respiratory, thoracic and mediastinal disorders

Dyspnea

Pneumonia

Cough

Vascular disorders

Blood and lymphatic system disorders

Anemia

Psychiatric disorders

Depression

Insomnia

Musculoskeletal and connective tissue disorders

Metabolism and nutrition disorders

Anorexia

Cardiac disorders

Table 2 summarizes laboratory abnormalities from studies 1 and 2.

Table 2: Laboratory Abnormalities

Laboratory Abnormality

Grade 3

Grade 4

Grade 2 to 4

Hematologic:

Decreased hemoglobin

Decreased WBC

Decreased neutrophils

Decreased platelets

Hepatic:

Increased bilirubin

Increased AST

Increased ALT

Increased alkaline phosphatase

Increased LDH

Metabolic:

Increased creatinine

Decreased sodium

Increased calcium total

7 DRUG INTERACTIONS

7.1 Dimethyl sulfoxide

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.

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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action, Totect can cause fetal harm when

administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Limited available data with Totect

use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental

outcomes. In animal reproduction studies, intravenous administration of dexrazoxane to pregnant rats and

rabbits during organogenesis resulted in teratogenicity at maternal doses that were approximately 0.1

and 0.2 times, respectively, the human dose of 1000 mg/m². Advise pregnant women of the potential risk

to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is

unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In

the U.S. general population, the estimated background risk of major birth defects and miscarriage in

clinically recognized pregnancies is 2%–4% and 15–20%, respectively.

Data

Animal Data

In an embryo-fetal development study in rats, pregnant females received intravenous doses of up to 8

mg/kg dexrazoxane during the period of organogenesis. A dose of 8 mg/kg (approximately 0.1 times the

human dose of 1000 mg/m²) was teratogenic, resulting in imperforate anus, microphthalmia, and

anophthalmia. Doses ≥ 2 mg/kg (approximately 0.01 times the human dose of 1000 mg/m²) caused

maternal toxicity.

In an embryo-fetal development study in rabbits, pregnant females received intravenous doses of up to

20 mg/kg (approximately 0.2 times the human dose of 1000 mg/m²) were teratogenic, resulting in

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. Doses ≥ 5 mg/kg (approximately 0.1 times the

human dose of 1000 mg/m²) caused maternal toxicity.

In a pre and postnatal development study in rats, intravenous administration of 8 mg/kg dexrazoxane to

pregnant rats during organogenesis resulted in impairment of fertility in the male and female offspring.

A dose of 8 mg/kg in rats is approximately 0.1 times the human dose of 1000 mg/m².

8.2 Lactation

Risk Summary

There are no data on the presence of dexrazoxane in human milk, the effects on the breastfed child, or

the effect on milk production. Because of the potential for serious adverse reactions, such as

myelosuppression, in a breastfed child from Totect, advise women not to breastfeed during treatment

and for 2 weeks following the final dose of Totect.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Pregnancy testing should be performed prior to initiation of chemotherapy. Therefore, repeat

pregnancy testing prior to administration of Totect is not recommended, because treatment of

extravasation of anthracycline chemotherapy should not be delayed.

Contraception

Females

Totect can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.3),

Use in Specific Populations (8.1)]. Because of the potential for genotoxicity, advise females of

reproductive potential to use effective contraception during treatment and for 6 months following the

final dose of Totect.

Males

Because of the potential for genotoxicity, advise males with female partners of reproductive potential

to use effective contraception during treatment and for 3 months following the final dose of Totect [see

Nonclinical Toxicology (13.1)].

Infertility

Males

Based on findings in animal studies, Totect may impair fertility in males of reproductive potential. It is

not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of Totect in pediatric patients have not been established.

8.5 Geriatric Use

In total, 21% of the patients treated with Totect were age 65 years or older and 9% were 75 and older.

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 individuals cannot be ruled out.

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 and hepatic function, care should be taken in dose selection, and it may be useful to

monitor renal and hepatic function [see Dosage and Administration (2.2)].

8.6 Renal Impairment

Greater exposure to dexrazoxane may occur in patients with compromised renal function. Monitor

patients with impaired renal function for signs of hematological toxicity. The Totect dose should be

reduced by 50% in patients with creatinine clearance values < 40 mL/min. [see Dosage and

Administration (2.2)]

8.7 Hepatic Impairment

Totect has not been studied in patients with hepatic impairment. Since liver dysfunction (increases in

transaminases and bilirubin) may occur (especially after doses of above 1000 mg/m² dexrazoxane), it is

recommended that routine liver function tests be performed before each administration of dexrazoxane

in patients with known liver function disorders. Use in patients with hepatic impairment is not

recommended.

10 OVERDOSAGE

Overdose with dexrazoxane can lead to signs of bone marrow failure. Treatment should be

symptomatic. There is no known antidote for dexrazoxane.

11 DESCRIPTION

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 C

H N O ; 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). 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

dexrazoxane and the pH of the resultant solution is 1.0 to 3.0. When reconstituted as directed with the

50 mL of 0.167 M sodium lactate injection solution, each mL contains 10 mg dexrazoxane and the pH of

the resultant solution is 3.5 to 5.5.

The admixture should be further diluted prior to administration to patients. [see Dosage and

Administration (2.3)]

Each vial of dexrazoxane for injection is closed with an aluminum flip-off cap covered with a dark red

overcap.

12 CLINICAL PHARMACOLOGY

12.1 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.

12.3 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.

SUMMARY OF MEAN (%CV ) DEXRAZOXANE PHARMACOKINETIC PARAMETERS AT

A DOSAGE RATIO OF 10:1 OF DEXRAZOXANE: DOXORUBICIN

Coefficient of variation

Steady-state volume of distribution

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)

Volume of

Distribution

(L/m²)

2.5 (16)

7.88 (18)

3.35 (36)

22.4 (22)

2.1 (29)

6.25 (31)

22.0 (55)

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.

In vitro studies on dexrazoxane in human microsomes indicated that metabolism is unlikely via

cytochrome P450. 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

a

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 (CL

) based on a 24-hour urinary creatinine collection.

Dexrazoxane clearance was reduced in subjects with renal dysfunction. Compared with controls, the

mean AUC

value was twofold greater in subjects with moderate (CL

30-50 mL/min) to severe

< 30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC

could be achieved if dosing were reduced by 50% in subjects with creatinine clearance values < 40

mL/min compared with control subjects (CL

> 80 mL/min) [see Dosage and Administration (2.2)].

Monitor patients with renal insufficiency for signs of hematological toxicity [see Use in Specific

Populations (8.6)].

Hepatic insufficiency

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

Drug interactions

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with dexrazoxane. A study by the National Cancer

Institute has reported that 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 was clastogenic in an in vitro

chromosomal aberrations study in mammalian cells and in an in vivo bone marrow micronucleus study in

mice.

Fertility studies with dexrazoxane have not been conducted. Testicular atrophy was seen with

intravenous dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats

(approximately 0.2 times the human dose of 1000 mg/m²) and as low as 20 mg/kg weekly for 13 weeks in

dogs (approximately 0.4 times the human dose of 1000 mg/m²).

14 CLINICAL STUDIES

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

0-inf

0-inf

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.

15 REFERENCES

1. "OSHA Hazardous Drugs." OSHA.

http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Totect carton contains 1 single dose vial of Totect (dexrazoxane for injection) 500 mg as a sterile,

pyrogen-free lyophilized powder.

NDC 66220-110-01: Carton of 1 vial of Totect

Store at 25ºC (77ºF); excursions permitted between 15-30ºC (59-86ºF) [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 (2.3)].

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information)

Myelosuppression

Inform patients of the possibility of myelosuppression, immunosuppression, and infections. Explain the

need for routine blood cell counts. Instruct patients to monitor their temperature frequently and

immediately report any occurrence of fever [see Warnings and Precautions (5.1)].

Anaphylactic/Hypersensitivity Reactions

Instruct patients to contact their healthcare provider for signs of an allergic reaction, which could be

severe and sometimes fatal [see Warnings and Precautions (5.2)].

Embryo-Fetal Toxicity

Advise females of reproductive potential and males with female partners of reproductive potential of

the potential risk to a fetus. Advise females of reproductive potential to use effective contraception

during treatment and for 6 months following the final dose of Totect. Advise females to inform their

prescriber of a known or suspected pregnancy. Advise male patients with female partners of

reproductive potential to use effective contraception during treatment and for 3 months following the

final dose of Totect [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)].

Lactation

Advise women not to breastfeed during treatment and for 2 weeks following the final dose of Totect

[see Use in Specific Populations (8.2)].

PATIENT INFORMATION

Totect

(TOE-TECT)

(dexrazoxane)

injection

What is Totect?

Totect is a prescription medicine used to treat people when anthracycline chemotherapy leaks from your vein

into the tissue around the intravenous (IV) site.

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:

have kidney problems.

have liver problems.

have ever had an allergic reaction to products that contain dexrazoxane.

are pregnant or plan to become pregnant. Totect can harm your unborn baby. Tell your healthcare provider

right away if you become pregnant during treatment with Totect.

Females who can become pregnant should use effective birth control during treatment with Totect and

for 6 months after the final dose.

Males who have female partners who can become pregnant should use effective birth control during

treatment with Totect and for 3 months after the final dose.

are breastfeeding or plan to breastfeed. It is not known if Totect passes into your breast milk. Do not

breastfeed during treatment with Totect and for 2 weeks after the final dose.

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 use a medicine on the skin (topical) called dimethyl sulfoxide

(DMSO). Using a topical DMSO during treatment with Totect may affect how well Totect works.

How will I receive Totect?

Totect is given to you by your healthcare provider.

Totect is injected into your vein (intravenous or IV infusion) over 1 to 2 hours each day for three days.

What are the possible side effects of Totect?

Totect can cause serious side effects, including:

Low blood cell counts. Low blood cell counts, including a decrease in white blood cell counts

(leukopenia and neutropenia) and a decrease in the blood cells which help your blood to clot

(thrombocytopenia), have happened with Totect. Your healthcare provider will do blood tests to check your

blood cell counts during treatment with Totect and certain other chemotherapy medicines. You should

check your temperature often during treatment with Totect and tell your healthcare provider if you have a

fever.

Serious allergic reactions. Totect can cause allergic reactions that can be severe and may lead to death.

Get medical help right away if you get any of the following symptoms of an allergic reaction:

o trouble breathing

o dizziness or lightheadedness

o swelling of your face, lips, tongue or throat

o faint or pass out

o raised bumps (hives)

The most common side effects of Totect include:

nausea

fever

blood vessel problems

pain at the intravenous (IV) site

vomiting

infection after surgery

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. If you

would like more information, talk with your healthcare provider. 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

US Patent No 6,727,253 B2

Manufactured for: Cumberland Pharmaceuticals Inc. Nashville, TN USA 37203

Totect® is a registered trademark owned by the Clinigen Group.

For more information, call 1-877-484-2700.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Revised: 12/2019

PRINCIPAL DISPLAY PANEL - BOTTLE LABEL

NDC 66220-110-01

Rx Only

Totect

(dexrazoxane) for injection

500 mg/vial

For Intravenous Infusion Only.

Important: Please see Prescribing Information for instructions for reconstitution and final dilution.

Single Dose Vial; Discard Unused Portion.

®

PRINCIPAL DISPLAY PANEL - CARTON LABEL

NDC 66220-110-01

Rx Only

Totect

(dexrazoxane) for injection

500 mg/vial

For Intravenous Infusion Only.

Important: Please see Prescribing Information for instructions for reconstitution and final dilution.

Single Dose Vial; Discard Unused Portion.

Cumberland Pharmaceuticals Oncology

®

Cumberland Pharmaceuticals Inc.

TOTECT

dexrazoxane hydrochloride injection, powder, lyophilized, for solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 6 220 -110

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength Strength

DEXRAZO XANE HYDRO CHLO RIDE (UNII: 5346 0 58 Q7S) (DEXRAZOXANE - UNII:0 48 L8 126 1F)

DEXRAZOXANE

50 0 mg

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:6 6 220 -110 -

1 in 1 CARTON

0 7/25/20 17

10 /30 /20 20

1

1 in 1 VIAL, SINGLE-USE; Type 0 : No t a Co mbinatio n

Pro duc t

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 220 25

0 7/25/20 17

Labeler -

Cumberland Pharmaceuticals Inc. (069532880)

Revised: 12/2019

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