Byfavo
remimazolam
Species
MonkeyPig
Longest study
4 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey and minipig
“In general, findings in the pivotal repeat-dose toxicity studies with the API in monkey and minipig were limited to expected pharmacology and local toxicity.”
Why that species
Pivotal monkey and minipig studies used infusion dosing with the clinical formulation
“These two pivotal studies were selected for detailed review because the study investigated infusion dosing with the clinical formulation.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The repeat dose toxicity of remimazolam dosed by the intravenous route, as a bolus injection, at 5, 10 and 20 mg/kg/day once daily for 4 weeks has been conducted, including a 2-week recovery period.”
Species: general tox
Cynomolgus monkey and minipig
“In general, findings in the pivotal repeat-dose toxicity studies with the API in monkey and minipig were limited to expected pharmacology and local toxicity.”
Species: DART
Rat and rabbit (full DART battery); supplemental male reproductive tissue studies in minipig
“A full battery of developmental and reproductive toxicology (DART) studies for remimazolam in the rat and rabbit model were submitted in the NDA. The Applicant also conducted supplemental studies to characterize the effects of remimazolam on male reproductive tissues in minipigs.”
Species: carcinogenicity
Not conducted; not required for the acute indication
“Carcinogenicity studies were not conducted or required to support the safety of the proposed acute indication with remimazolam.”
Surrogate used in
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.
Study lengthopen answer page →
Longest pivotal study
4 (4-week minipig and monkey)
“Pivotal 4-week repeat-dose toxicity studies with 2-week recovery groups in minipig and monkey are reviewed in detail in sections 6.2.1 and 6.2.2.”
Pivotal GLP studies
4-week IV infusion studies in minipig and monkey with 2-week recovery
“Pivotal 4-week repeat-dose toxicity studies with 2-week recovery groups in minipig and monkey are reviewed in detail in sections 6.2.1 and 6.2.2.”
Route in tox
Intravenous (bolus and infusion)
“Repeated dose toxicity studies, up to 4 weeks duration, have been conducted in cynomolgus monkeys with administration of remimazolam by intravenous bolus and by intravenous infusion.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mouse lymphoma and in vivo rat micronucleus assays
“Genetic toxicology battery for the API was negative in the Ames assay, mouse lymphoma assay, and in vivo rat micronucleus test.”
Carcinogenicity
Not conducted
“Long-term animal studies have not been performed to evaluate the carcinogenic potential of remimazolam.”
Reproductive & developmental
Rat and rabbit EFD: no adverse embryo-fetal effects in surviving animals
“Regardless of these adverse effects to the pregnant female, in surviving animals, remimazolam had no adverse effects on embryo-fetal development up to 30 mg/kg/day in rat”
Safety pharmacology
Benzodiazepine-type sedation, respiratory depression and cardiovascular depression
“Remimazolam produced typical benzodiazepine-related pharmacodynamic effects including sedation, respiratory depression, and cardiovascular depression.”
Genotox: Ames
Negative
“Remimazolam showed no mutagenic potential in the bacterial reverse mutation assay.”
Genotox: in vitro mammalian
Mouse lymphoma assay: negative (mutation-frequency increases only with high cytotoxicity)
“Genetic toxicology battery for the API was negative in the Ames assay, mouse lymphoma assay, and in vivo rat micronucleus test.”
Genotox: in vivo
Rat micronucleus and comet assay: negative
“Remimazolam did not induce micronuclei in the rat. In the comet assay, there was no increase of %Tail DNA up to the maximum dose.”
Carcinogenicity model
Not conducted
“Remimazolam was not investigated in a carcinogenicity study.”
Carcinogenicity timing
Not required for the acute indication
“Carcinogenicity studies were not conducted or required to support the safety of the proposed acute indication with remimazolam.”
hERG / QT
hERG IC25 62 µM, IC50 207 µM, well above free clinical plasma levels
“estimated IC25 and IC50 values for remimazolam inhibition of hERG tail current were 62 and 207 μM, respectively, concentrations well above those required to activate GABAA receptors in vitro (0.36-1.38 μM) or free plasma levels reached in clinical studies.”
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 Byfavo 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: Local injection-site toxicity: thickened intima and partially recoverable endothelial fibrosis in monkey (FDA pharmacology/toxicology review, p. 7)
NOAEL / key findings
Local injection-site toxicity: thickened intima and partially recoverable endothelial fibrosis in monkey
“Local toxicities included thickened intima and partially recoverable endothelial fibrosis of blood vessels at 2.5 mg/mL in monkey.”
Risksopen answer page →
Immune & cytokine safety
No immune system findings
“There were no findings indicating an influence of remimazolam on the immune system.”
Biodistribution & persistence
Very limited placental transfer; readily enters breast milk
“Placenta penetration of remimazolam and/or its derivatives was very limited and did not lead to a sustained exposure of the fetus. Remimazolam and/or its derivatives easily accessed breast milk; the concentrations determined in milk were linked to maternal plasma concentrations.”
Modality-specific risk
Inadequate rat DART exposure margins (short boluses below human exposure)
“Of specific concern, data from the rat studies did not provide acceptable safety margins as the DART studies were conducted with short boluses that resulted in systemic exposures below that in humans.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
Label warnings
Boxed warning: Personnel and equipment for monitoring and resuscitation and risks from concomitant use with opioid analgesics
- Personnel and Equipment for Monitoring and Resuscitation
- Risks from Concomitant Use with Opioid Analgesics and Other Sedative-Hypnotics
- Hypersensitivity Reactions
- Neonatal Sedation and Withdrawal Syndrome
- Pediatric Neurotoxicity
Hypersensitivity & infusion reactionsNeurotoxicity
US prescribing information, Boxed Warning and 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 Byfavo 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: Local injection-site toxicity: thickened intima and partially recoverable endothelial fibrosis in monkey (FDA pharmacology/toxicology review, p. 7)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
4-week IV minipig and monkey studies with 2-week recovery
“Pivotal 4-week repeat-dose toxicity studies with 2-week recovery groups in minipig and monkey are reviewed in detail in sections 6.2.1 and 6.2.2.”
Pivotal GLP studies
4-week IV infusion studies in minipig and monkey with 2-week recovery
“Pivotal 4-week repeat-dose toxicity studies with 2-week recovery groups in minipig and monkey are reviewed in detail in sections 6.2.1 and 6.2.2.”
DART package
Species: DART
Rat and rabbit (full DART battery); supplemental male reproductive tissue studies in minipig
“A full battery of developmental and reproductive toxicology (DART) studies for remimazolam in the rat and rabbit model were submitted in the NDA. The Applicant also conducted supplemental studies to characterize the effects of remimazolam on male reproductive tissues in minipigs.”
Reproductive & developmental
Rat and rabbit EFD: no adverse embryo-fetal effects in surviving animals
“Regardless of these adverse effects to the pregnant female, in surviving animals, remimazolam had no adverse effects on embryo-fetal development up to 30 mg/kg/day in rat”
PPND / ePPND: when
Rat PPND judged inadequate; a new PPND study with all standard endpoints is a postmarketing requirement
“Conduct a pre-and post-natal development study testing the drug product formulation that evaluates all standard endpoints including learning, memory, and reproductive function of the F1 offspring and obtains adequate toxicokinetic data in a species and provides adequate exposures to support the proposed clinical exposures for the proposed maximum duration of use based on the clinical indication.”
Carcinogenicity
Species: carcinogenicity
Not conducted; not required for the acute indication
“Carcinogenicity studies were not conducted or required to support the safety of the proposed acute indication with remimazolam.”
Carcinogenicity model
Not conducted
“Remimazolam was not investigated in a carcinogenicity study.”
Carcinogenicity timing
Not required for the acute indication
“Carcinogenicity studies were not conducted or required to support the safety of the proposed acute indication with remimazolam.”
Safety marginopen answer page →
Safety margin at NOAEL
No systemic toxicity beyond pharmacology up to 120 mg/kg/day in monkey and minipig: >100x human AUC at MRHD
“There were no systemic toxicities identified in the repeat-dose toxicity studies that were not already identified in the safety pharmacology study up to 120 mg/kg/day in monkey and minipigs (safety margin >100x based on AUC at MRHD of 30 mg/kg/day).”
NOAEL / key findings
Local injection-site toxicity: thickened intima and partially recoverable endothelial fibrosis in monkey
“Local toxicities included thickened intima and partially recoverable endothelial fibrosis of blood vessels at 2.5 mg/mL in monkey.”
Efficacy evidenceopen answer page →
Efficacy evidence
Sedation in normal animals (rodents, monkeys), reversed by flumazenil; GABA-A benzodiazepine-site binding in vitro
“Flumazenil prevents or inhibits the sedative effects of remimazolam. Onset of sedation and recovery from sedation was rapid in all species tested compared to midazolam.”
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
FDA: high selectivity and specificity for GABA-A receptors; low risk of off-target pharmacological effects
“Multiple radioligand binding assays demonstrate the high electivity and specificity for remimazolam to bind GABAA receptors, suggesting a low risk of off-target pharmacological effects.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted with a conditionBeyond the letter
Rat fertility, EFD and PPND studies used short boluses giving exposures below human; DART battery incomplete
Why: Women of childbearing potential are pregnancy-tested before planned procedural sedation; male fertility, second-species EFD and PPND required as PMRs · Other reason
“Of specific concern, data from the rat studies did not provide acceptable safety margins as the DART studies were conducted with short boluses that resulted in systemic exposures below that in humans.”
“As per the clinical team, women of childbearing potential undergoing planned procedural sedation are usually tested for pregnancy prior to administration of the sedative drug product thereby excluding pregnant women. As such the less than adequate battery of DART studies will not preclude approval of remimazolam.”
Juvenile toxAccepted with a conditionBeyond the letter
No juvenile animal study on the developing brain before approval; required postmarketing
“In addition, a PMR for juvenile animal studies will be issued to further characterize the potential impact of the drug on the developing brain.”
OtherAcceptedBeyond the letter
Novel excipient Dextran 40: second-species (rat) EFD study replaced by literature-based justification
Why: Dextran 40 exposure to the embryo or fetus negligible · Weight of evidence · Pharmacology or kinetics
“In lieu of studies in a second species (rat), the Applicant provided a justification based on experimental evidence to demonstrate that Dextran 40 exposure to the embryo or fetus is negligible to support the safety of dextran.”
“The combined animal data and literature-based safety justification suggest limited concern that Dextran 40 would negatively impact embryo-fetal development.”
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