Defencath
taurolidine and heparin
Sources:FDA multi-discipline review ↗
Species
RatMouse
Longest study
2 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat (14-day IV study) and mouse (single-dose IP study)
“A single dose intraperitoneal study conducted with Defencath in mice and a 14-day repeat-dose intravenous study conducted in rats (discussed in additional detail below) did not reveal signs of toxicity.”
Why that species
No pivotal tox species needed: prior clinical experience with taurolidine and heparin in catheter lock solutions judged adequate
“However, the medical reviewers found that previous clinical experience with taurolidine (particularly as a component of CLS) was adequate to support the clinical development of Defencath and the toxicology reviewer deferred to their judgement.”
Surrogate molecule
No surrogate; the clinical product (diluted) was tested
“A diluted solution of Defencath did not cause toxicity in rats when administered intravenously daily for 14 days.”
Species: general tox
Rat (14-day IV, diluted product) and mouse (single-dose IP)
“A single dose intraperitoneal study conducted with Defencath in mice and a 14-day repeat-dose intravenous study conducted in rats (discussed in additional detail below) did not reveal signs of toxicity.”
Species: DART
Not conducted: waived, product not intended for systemic administration
“Reproductive and developmental toxicology studies were waived for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
Species: carcinogenicity
Not conducted (negligible systemic exposure)
“Carcinogenicity studies were not needed for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
Surrogate used in
No surrogate used; diluted clinical product tested in rats
“A diluted solution of Defencath did not cause toxicity in rats when administered intravenously daily for 14 days.”
Study lengthopen answer page →
Longest pivotal study
2 (14-day rat; not considered pivotal)
“Although neither of these studies were considered adequate for a pivotal nonclinical toxicology study to support human drug development (exposure to taurolidine was not sufficient to explore possible toxicity and identify potential target organs)”
Pivotal GLP studies
None required; additional acute or repeat-dose general toxicology testing was not needed
“Thus, additional acute or repeat-dose general toxicology testing in animals was not required for the components of Defencath.”
Route in tox
Intravenous (rat); intraperitoneal (mouse single dose)
“A single dose intraperitoneal study conducted with Defencath in mice and a 14-day repeat-dose intravenous study conducted in rats (discussed in additional detail below) did not reveal signs of toxicity.”
Skipped studiesopen answer page →
Genotoxicity
Taurolidine positive in vitro (mouse lymphoma and Ames) regardless of metabolic activation; negative in vivo
“Although taurolidine is positive for genotoxicity in vitro regardless of metabolic activation (mouse lymphoma and Ames tests), it is negative in vivo.”
Carcinogenicity
Not conducted (not for systemic administration; negligible clinical exposure)
“Carcinogenicity studies were not needed for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
Reproductive & developmental
Not conducted; waived because the product is not for systemic administration
“Reproductive and developmental toxicology studies were waived for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
Safety pharmacology
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Genotox: Ames
Taurolidine positive in TA98 and TA100 with and without metabolic activation
“Taurolidine was mutagenic in TA98 and TA100 in the absence and presence of metabolic activation.”
Genotox: in vitro mammalian
Mouse lymphoma L5178Y TK assay: positive with and without metabolic activation
“Taurolidine-induced forward mutations at the thymidine kinase (TK) locus of L5178Y mouse lymphoma cells in the absence and presence of metabolic activation.”
Genotox: in vivo
Rat bone marrow micronucleus and liver comet assays: negative up to 600 mg/kg/day IV (MTD)
“Data from a study in rats demonstrated that micronuclei were not induced in bone marrow polychromatic erythrocytes, and DNA damage was not detected in liver cells in a comet assay when taurolidine was administered intravenously up to a maximum tolerated dose of 600 mg/kg/day for three days.”
Carcinogenicity model
Not conducted: not for systemic administration, negligible clinical exposure
“Carcinogenicity studies were not needed for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
Carcinogenicity timing
Not required: not for systemic administration, negligible clinical exposure
“Carcinogenicity studies were not needed for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
hERG / QT
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Defencath don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: No toxicity in rats given diluted product IV daily for 14 days (FDA multi-discipline review, p. 44)
NOAEL / key findings
No toxicity in rats given diluted product IV daily for 14 days
“A diluted solution of Defencath did not cause toxicity in rats when administered intravenously daily for 14 days.”
Risksopen answer page →
Immune & cytokine safety
Not irritating intradermally and nonsensitizing in guinea pigs
“Guinea pig studies with Defencath showed that the product was not irritating when injected intradermally and it was nonsensitizing in these animals.”
Biodistribution & persistence
Not studied; ADME/PK studies not conducted given negligible systemic exposure
“ADME/PK studies were not conducted with Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
Modality-specific risk
In vitro genotoxicity of taurolidine; risk judged low at clinical exposures
“At the levels where taurolidine exposure could be achieved in the clinic during use of the Defencath CLS, the risk of genotoxicity appears low.”
Anti-drug antibodies: animals
No immunogenicity evaluations conducted in the development program
“No immunogenicity/antigenicity evaluations were conducted as part of this development program.”
Anti-drug antibodies: patients
Not evaluated; no immunogenicity/antigenicity evaluations conducted
“No immunogenicity/antigenicity evaluations were conducted as part of this development program.”
Label warnings
- Heparin-Induced Thrombocytopenia
- Drug Hypersensitivity
ThrombocytopeniaHypersensitivity & infusion reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Defencath don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: No toxicity in rats given diluted product IV daily for 14 days (FDA multi-discipline review, p. 44)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
14-day IV rat study with diluted product (not adequate as pivotal); necropsy one day after last dose, no recovery phase
“Dosing began on Day 0 and animals were sacrificed on Day 14 (one day after the final dose was given).”
Pivotal GLP studies
None required; additional acute or repeat-dose general toxicology testing was not needed
“Thus, additional acute or repeat-dose general toxicology testing in animals was not required for the components of Defencath.”
DART package
Species: DART
Not conducted: waived, product not intended for systemic administration
“Reproductive and developmental toxicology studies were waived for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
Reproductive & developmental
Not conducted; waived because the product is not for systemic administration
“Reproductive and developmental toxicology studies were waived for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
PPND / ePPND: when
Not conducted: DART waived, product not intended for systemic administration
“Reproductive and developmental toxicology studies were waived for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
Carcinogenicity
Species: carcinogenicity
Not conducted (negligible systemic exposure)
“Carcinogenicity studies were not needed for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
Carcinogenicity model
Not conducted: not for systemic administration, negligible clinical exposure
“Carcinogenicity studies were not needed for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
Carcinogenicity timing
Not required: not for systemic administration, negligible clinical exposure
“Carcinogenicity studies were not needed for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
Safety marginopen answer page →
Safety margin at NOAEL
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
NOAEL / key findings
No toxicity in rats given diluted product IV daily for 14 days
“A diluted solution of Defencath did not cause toxicity in rats when administered intravenously daily for 14 days.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro antimicrobial activity of taurolidine against a panel of microorganisms
“The Applicant has demonstrated in vitro activity of taurolidine against the following microorganisms. This list will be included in the Microbiology section of labeling.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
In vitro taurolidine activity accepted for the Microbiology section of labeling
“The Applicant has demonstrated in vitro activity of taurolidine against the following microorganisms. This list will be included in the Microbiology section of labeling.”
Flexibilityopen answer page →
Flexibility accepted
OtherCriticised but acceptedBeyond the letter
No adequate general toxicology study: rat study with diluted product did not reach doses that explore taurolidine toxicity
Why: Previous clinical experience with taurolidine in catheter lock solutions judged adequate by medical reviewers · Human data
“A rat study conducted with a diluted solution of Defencath did not use high enough levels of the active ingredients to adequately explore the toxicity of taurolidine and identify possible target organs of toxicity (if any).”
“However, the medical reviewers found that previous clinical experience with taurolidine (particularly as a component of CLS) was adequate to support the clinical development of Defencath and the toxicology reviewer deferred to their judgement.”
DARTAcceptedBeyond the letter
Reproductive toxicity studies for taurolidine waived
Why: Product not intended for systemic administration · Pharmacology or kinetics
“Defencath is not intended for systemic administration, so the Division agreed to waive reproduction toxicity studies for taurolidine and deemed that these data were not needed for labeling.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies
Why: Not for systemic administration; negligible clinical exposure · Pharmacology or kinetics
“Carcinogenicity Carcinogenicity studies were not needed for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
GenotoxicityAcceptedBeyond the letter
Taurolidine positive in vitro (Ames and mouse lymphoma) but negative in vivo; accepted
Why: Negative in vivo; risk low at clinically achievable taurolidine exposure · Weight of evidence · Pharmacology or kinetics
“Although taurolidine is positive for genotoxicity in vitro regardless of metabolic activation (mouse lymphoma and Ames tests), it is negative in vivo.”
“At the levels where taurolidine exposure could be achieved in the clinic during use of the Defencath CLS, the risk of genotoxicity appears low.”
Similar precedents
ArtesunateSmall molecules · artesunate · Plasmodium (antimalarial)Rodent + dog or minipig · 4 wkBlujepaSmall molecules · gepotidacin · Bacterial topoisomerases (gyrase/topo IV)Rodent + dog or minipig · 13 wkBrexafemmeSmall molecules · ibrexafungerp · Fungal glucan synthaseRodent + dog or minipig · 26 wkCabenuvaSmall molecules · cabotegravir and rilpivirine · HIV-1 integrase; NNRTIMonkey + rodent · 39 wkEgatenSmall molecules · triclabendazole · Fasciola (tubulin)Rodent + dog or minipig · 13 wkExblifepSmall molecules · cefepime and enmetazobactam · PBPs; beta-lactamase (enmetazobactam)Rodent + dog or minipig · 13 wk