Taurolidine, heparin

Taurolidine, heparin
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, DMD, MD[2]

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Overview

Taurolidine, heparin is a combination of taurolidine, a thiadiazinane antimicrobial, and heparin, an anti-coagulant that is FDA approved for the prevention of atheter-related bloodstream infections (CRBSI) in adult patients with kidney failure receiving chronic hemodialysis (HD) through a central venous catheter (CVC). This drug is indicated for use in a limited and specific population of patients.

Limitations of Use

The safety and effectiveness of DEFENCATH have not been established for use in populations other than adult patients with kidney failure receiving chronic HD through a CVC.. Common adverse reactions include {{{adverseReactions}}}.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

There is limited information regarding Taurolidine, heparin FDA-Labeled Indications and Dosage (Adult) in the drug label.

Off-Label Use and Dosage (Adult)

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Taurolidine, heparin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Contraindications

DEFENCATH is contraindicated in patients with:

Known heparin-induced thrombocytopenia (HIT) Known hypersensitivity to taurolidine, heparin or the citrate excipient (components of DEFENCATH) or pork products

Warnings

1.Heparin-Induced Thrombocytopenia Heparin-induced thrombocytopenia (HIT) was reported at an incidence rate of 0.3% in Trial 1 in patients using heparin, a component of DEFENCATH, as a CLS. If HIT occurs, discontinue DEFENCATH and institute appropriate supportive measures

2. Drug Hypersensitivity Drug hypersensitivity reactions were reported at an incidence rate of 0.5% in Trial 1 in patients using heparin, a component of DEFENCATH, as a CLS. If a hypersensitivity reaction occurs, discontinue DEFENCATH and institute appropriate supportive measures

Adverse Reactions

Clinical Trials Experience

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Heparin-Induced Thrombocytopenia
• Drug Hypersensitivity

Postmarketing Experience

The following adverse reaction has been identified during the use of a taurolidine and heparin containing CLS outside of the United States. Because this reaction is reported from a population of uncertain size, it is not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure.

Nervous System Disorders: Paresthesia

Drug Interactions

There is limited information regarding Taurolidine, heparin Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): Risk Summary

DEFENCATH is not intended for systemic administration. It is intended for use as a CLS in patients with kidney failure requiring chronic HD; therefore, maternal use is not expected to result in fetal exposure to the drug. No animal reproduction study was conducted with DEFENCATH
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Taurolidine, heparin in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Taurolidine, heparin during labor and delivery.

Nursing Mothers

Risk Summary

DEFENCATH is not intended for systemic administration. It is intended for use as a CLS in patients with kidney failure requiring chronic HD; therefore, breastfeeding is not expected to result in exposure of the infant to DEFENCATH

Pediatric Use

The safety and effectiveness of DEFENCATH have not been established in pediatric patients. There are no available data on DEFENCATH use in pediatric patients.

Geriatic Use

There were 327 patients 65 years of age and older in Trial 1. Of the total number of patients using DEFENCATH in this study, 162 (41%) were 65 years of age and older, while 64 (16%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients.

Gender

There is no FDA guidance on the use of Taurolidine, heparin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Taurolidine, heparin with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Taurolidine, heparin in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Taurolidine, heparin in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Taurolidine, heparin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Taurolidine, heparin in patients who are immunocompromised.

Administration and Monitoring

Administration

DOSAGE AND ADMINISTRATION

DEFENCATH is for instillation into CVCs only. DEFENCATH is not intended for systemic administration. Do not use DEFENCATH as a catheter lock flush product. Withdraw a sufficient volume of DEFENCATH catheter lock solution (CLS) from the vial using a sterile needle and syringe to fill the catheter lumen. Use 3 mL or 5 mL single dose vial (depending on the volume of the catheter lumen) to instill DEFENCATH into each catheter lumen at the conclusion of each HD session. DEFENCATH must be aspirated from the catheter and discarded prior to the initiation of the next HD session. Discard any unused portion of DEFENCATH remaining in the vial.

DOSAGE FORMS AND STRENGTHS DEFENCATH is a sterile catheter lock solution available in single-dose vials in the following strengths: 3 mL containing taurolidine 40.5 mg/3 mL (13.5 mg/mL), and heparin 3,000 USP Units/3 mL (1,000 USP Units/mL) 5 mL containing taurolidine 67.5 mg/5 mL (13.5 mg/mL), and heparin 5,000 USP Units/5 mL (1,000 USP Units/mL)

Monitoring

There is limited information regarding Taurolidine, heparin Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Taurolidine, heparin and IV administrations.

Overdosage

There is limited information regarding Taurolidine, heparin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

DEFENCATH (taurolidine and heparin) CLS contains taurolidine, a thiadiazinane antimicrobial, and heparin sodium, an anti-coagulant.

Taurolidine Taurolidine is an antimicrobial agent derived from the naturally occurring amino acid taurine. The chemical name is 4,4’-methylenebis(1,2,4-thiadiazinane)-1,1,1’,1’-tetraoxide. The molecular weight is 284.36, and the molecular formula is C7H16N4O4S2.

Mechanism of Action

Heparin Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce a conformational change, which markedly enhances the serine protease activity of Antithrombin III, thereby inhibiting the activated coagulation factors involved in the clotting sequence, particularly Xa and IIa. Small amounts of heparin inhibit Factor Xa, and larger amounts inhibit thrombin (Factor IIa). Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.

Taurolidine Taurolidine is an antimicrobial drug

Structure

Heparin Sodium Heparin is an anticoagulant consisting of heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans. It is composed of polymers of alternating derivatives of α-D-glucosamido (N-sulfated, O-sulfated, or N-acetylated) and O-sulfated uronic acid (α-L-iduronic acid or β-D-glucuronic acid). Heparin is derived from porcine intestinal mucosa.

The heparin potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. The inactive ingredients are 26.1 mg/mL of citric acid, anhydrous (which is added to control pH and maintain the solubility of taurolidine),and may include hydrochloric acid and/or sodium hydroxide for pH adjustment.

Pharmacodynamics

The pharmacodynamics of DEFENCATH are unknown.

Pharmacokinetics

No pharmacokinetic studies were conducted because DEFENCATH is intended to be instilled into the catheter lumens at the conclusion of each HD session for patients with kidney failure requiring chronic HD. DEFENCATH is not intended for systemic administration

Nonclinical Toxicology

Carcinogenesis Carcinogenicity studies in animals have not been conducted with taurolidine or heparin.

Mutagenesis Taurolidine was positive in vitro in an Ames reverse mutation assay and it increased mutation frequency in L5178Y mouse lymphoma cells. However, taurolidine was negative in an in vivo combined micronucleus test and comet assay in rats at the highest dose tested, 600 mg/kg/day administered intravenously.

No studies have been conducted with heparin to determine its mutagenic potential.

Impairment of Fertility Fertility studies have not been conducted with DEFENCATH due to its negligible clinical exposure.

Clinical Studies

The efficacy and safety of DEFENCATH for reducing the incidence of CRBSI in patients with kidney failure receiving chronic HD was evaluated in LOCK-IT-100 (referred to as Trial 1, NCT02651428), a randomized, double-blind, active-controlled, multicenter trial.

A total of 806 patients were randomized in a 1:1 ratio to receive either DEFENCATH or heparin (heparin sodium USP 1,000 units/mL, benzyl alcohol 9.45 mg/mL and sodium chloride 9.0 mg/mL) as a CLS. Enrollment in Trial 1 was not limited to patients with specific types of HD catheters. DEFENCATH or heparin was instilled into central venous HD catheters at the end of all dialysis sessions and was withdrawn prior to the initiation of the next dialysis session. The median age of the study population was 63 years (range 21-94 years); 58% identified as males and 63% identified as white. The majority of patients (98%) had HD treatment three times per week, and 48% had their catheter implanted within three months prior to randomization.

A clinical adjudication committee (CAC) assessed the cases of CRBSI. The CAC definition for CRBSI included one positive blood culture (other than for coagulase-negative staphylococci, which required a confirmatory culture) from a peripheral site or either the arterial or venous catheter hub or the arterial or venous dialysis blood line and the patient had to have signs and symptoms of infection and no other apparent source of bloodstream infection.

Patients in the DEFENCATH group had a lower incidence of CRBSI events compared to patients in the control group.

In total, 5% [18/397] of subjects in the DEFENCATH arm and 5% [21/398] of subjects in the heparin arm died during the trial (difference [DEFENCATH – Heparin]: -0.7% with a 95% CI[-3.7%, 2.3%]).

Among the 9 patients in the DEFENCATH arm with a CAC-adjudicated CRBSI, 1 had a gram-negative organism isolated and 8 had a gram-positive organism isolated; among the 32 patients in the heparin arm with a CAC-adjudicated CRBSI, 14 had a gram-negative organism isolated and 18 had a gram-positive organism isolated.

How Supplied

EFENCATH cathether lock solution is available in:

3 mL of catheter lock solution in a single-dose vial containing taurolidine 40.5 mg/3 mL (13.5 mg/mL), and heparin 3,000 USP Units/3 mL (1,000 USP Units/mL) (NDC 72990-103-03) 5 mL of catheter lock solution in a single-dose vial containing taurolidine 67.5 mg/5 mL (13.5 mg/mL), and heparin 5,000 USP Units/5 mL (1,000 USP Units/mL) (NDC 72990-105-05) Each vial contains a sterile, preservative-free, clear aqueous-based solution for instillation in central venous catheters. Each carton contains 10 single-dose vials.

Storage

DEFENCATH vials must be stored at a controlled room temperature of 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not freeze. DEFENCATH vials must be stored in the commercial carton, prior to the instillation in central venous catheters.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Taurolidine, heparin Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Taurolidine, heparin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

DEFENCATH®

Look-Alike Drug Names

There is limited information regarding Taurolidine, heparin Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.