DRUG INTERACTIONS - summary

1. Opioid Analgesics and Other Sedative-Hypnotics-                                                        The sedative effect of intravenous BYFAVO can be accentuated by concomitantly administered CNS depressant medications, including opioid analgesics, other benzodiazepines, and propofol.

Continuously monitor vital signs during sedation and through the recovery period.

Titrate the dose of BYFAVO when administered with opioid analgesics and sedative-hypnotics to the desired clinical response.

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  26

ADVERSE REACTIONS-

The most common adverse reactions (>10%) in patients receiving BYFAVO for procedural sedation are hypotension, hypertension, diastolic hypertension, systolic hypertension, hypoxia, and diastolic hypotension.

CONTRAINDICATIONS

 Hypersensitivity to dextran 40.

WARNINGS AND PRECAUTIONS

­ Hypersensitivity Reactions:                                                                       Hypersensitivity reactions including anaphylaxis may occur. (5.3) Neonatal Sedation: Benzodiazepine use during pregnancy can result in neonatal sedation.Observe newborns for signs of sedation and manage accordingly. 

Pediatric Neurotoxicity:                                                                                                In developing animals, exposures greater than 3 hours cause neurotoxicity. Weigh benefits against potential risks when considering elective procedures in children under 3 years old. 

--------------------------USE IN SPECIFIC POPULATIONS-------------------­ Lactation: A lactating woman may pump and discard breast milk for 5 hours after treatment with BYFAVO. (8.2) Pediatric Use: BYFAVO should not be used in patients less than 18 years of age. (8.4) Geriatric Use: Sedating drugs, such as BYFAVO, may cause confusion and over-sedation in the elderly; elderly patients generally should be observed closely. (8.5) Severe Hepatic Impairment: In patients with severe hepatic impairment the dose of BYFAVO should be carefully titrated to effect. Depending on the overall status of the patient, reduced doses might be indicated. (8.6, 12.3) See 17 for PATIENT COUNSELING INFORMATION

 PATIENT COUNSELING INFORMATION

Alcohol and Current Medications-                                                                                  Advise patients to notify their healthcare provider about alcohol or medication use. Alcohol and other CNS depressants, such as opioid analgesics and benzodiazepines, can have an additive effect when administered with BYFAVO 

Pregnancy-                                                                                                      Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates.                                                                                                Advise mothers exposed to BYFAVO during pregnancy to monitor neonates for signs of sedation, respiratory depression, and feeding problems.

Instruct patients to inform their healthcare provider if they are pregnant during treatment with remimazolam 

Use in Specific Populations (

Effect of Anesthetic and Sedation-                                                                         Drugs on Early Brain Development Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains.

Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs.

Lactation -                                                                                                                  Advise women to consider reducing infant exposure by pumping and discarding breast milk for 5 hours after receiving BYFAVO during procedural sedation

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 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                        BYFAVO is a benzodiazepine. BYFAVO binds to brain benzodiazepine sites (gamma amino butyric acid type A [GABAA] receptors), while its carboxylic acid metabolite (CNS7054) has a 300 times lower affinity for the receptor. BYFAVO, like other benzodiazepines, did not show clear selectivity between subtypes of the GABAA receptor.

2. Pharmacodynamics-                                                                                           Dose finding studies determined the IV dosing recommendation of the initial 5 mg bolus, followed by 2.5 mg top-up doses. Median time to peak sedation, defined as the lowest Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score after the initial dose, in the Phase 3 trials was 3 to 3.5 minutes and median time to fully alert, defined as time to the first of three consecutive MOAA/S scores of five, following the last dose of BYFAVO was 11 to 14 minutes.

Cardiac Electrophysiology -                                                                                        In a thorough QT study, 57 healthy volunteers were given an IV push of 10 mg or 20 mg BYFAVO, intravenous midazolam (2.5 mg or 7.5 mg) or placebo, or a single tablet of moxifloxacin 400 mg given orally.

3. Pharmacokinetics                                                                                                      • BYFAVO has a terminal elimination half-life from plasma of 37 to 53 minutes.

• Mean distribution half-life (t1/2a) is between 0.5 and 2 minutes.                                      • Half-life (t1/2) is prolonged with increasing severity of hepatic impairment leading to a need for careful dose titration in patients with severe hepatic impairment.                        • Clearance (54 to 75 L/h) is not related to body weight.                                                  • In healthy subjects at least 80% and in colonoscopy patients 50% to 60% of dose is excreted in urine as inactive metabolite. 

Absorption-                                                                                                           BYFAVO is administered intravenously. BYFAVO overall maximum plasma concentration (Cmax) after IV administration of 0.01 to 0.5 mg/kg was 189 to 6,960 ng/mL, and overall area under the concentration versus time curve from time 0 to infinity (AUC0-8) was 12.1 to 452 ng·h/mL; BYFAVO cumulative dose versus BYFAVO total exposure (AUC0-8) suggested a close to dose-proportional relationship.

Metabolite Cmax was achieved approximately 20-30 minutes post dose. Metabolite AUC0-8 was 231 to 7,090 ng·h/mL.

Distribution-                                                                                                       BYFAVO volume of distribution (Vz) was 0.76 to 0.98 L/kg.                                            Plasma protein binding of BYFAVO was >91%, primarily to human serum albumin.

Elimination-                                                                                                         BYFAVO has a terminal elimination half-life from plasma of 37 to 53 minutes and mean distribution half-life (t1/2a) is between 0.5 and 2 minutes.

Metabolism-                                                                                                               The main route of metabolism of BYFAVO is via conversion to primary inactive metabolite CNS7054, which is then subject to hydroxylation and glucuronidation. Conversion to CNS7054 is mediated by tissue carboxylesterases (primarily type 1A), with no meaningful contribution by cytochrome P450 enzymes.

The t1/2 of the metabolite was 2.4 to 3.8 hours. Excretion In colonoscopy patients, approximately 0.003% BYFAVO is excreted unchanged in urine, and 50% to 60% is excreted in urine as the metabolite CNS7054.

Specific Populations-                                                                                          Pediatric Patients                                                                                                   There were no pediatric patients who received BYFAVO. 

Patients with Renal Impairment-                                                                                       The pharmacokinetics of BYFAVO were not altered in patients with mild to end stage renal disease not requiring dialysis.                                                                                    In a renal impairment study, BYFAVO PK parameters (e.g., AUC and Cmax) were not statistically different in subjects with varying degrees of renal function (from normal to severely impaired). Increased exposure to inactive metabolite CNS7054 was observed with increasing degree of renal impairment.

Patients with Hepatic Impairment-                                                                               A Phase 1 open-label, single-dose trial evaluated the PK and safety of BYFAVO given as an IV bolus of 0.1 mg/kg over 1 minute in subjects with hepatic impairment (8 moderately hepatically impaired subjects and 3 severely hepatically impaired subjects) and 9 matched healthy subjects.

Other Specific Populations-                                                                                      Age, sex, race, and weight had no clinically relevant effect on BYFAVO pharmacokinetics.

Drug Interactions-                                                                                                         BYFAVO and the metabolite CNS7054 caused no relevant inhibition of cytochrome P450 isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4.                                           

  There were no inducing effects on CYP1A2, 2B6, and 3A4. BYFAVO was not a relevant substrate of a panel of human drug transporters (OATP1B1, OATP1B3, BCRP).

No relevant inhibition of human drug transporters (OAT3, OCT2, OATP1B1, OATP1B3, OAT1, BCRP) was seen with BYFAVO or CNS7054.                                                   

Remifentanil did not influence the hydrolysis of BYFAVO by human liver S9 fractions, reducing the possibility of an interaction by competition for liver carboxylesterases. These results together show a very low potential of BYFAVO for pharmacokinetic drug interactions. 

USE IN SPECIFIC POPULATIONS- summary

­ Lactation: A lactating woman may pump and discard breast milk for 5 hours after treatment with BYFAVO. 

Pediatric Use: BYFAVO should not be used in patients less than 18 years of age. 

Geriatric Use: Sedating drugs, such as BYFAVO, may cause confusion and over-sedation in the elderly; elderly patients generally should be observed closely. 

Severe Hepatic Impairment: In patients with severe hepatic impairment the dose of BYFAVO should be carefully titrated to effect. Depending on the overall status of the patient, reduced doses might be indicated.

 USE IN SPECIFIC POPULATIONS - details

1. Pregnancy Risk Summary-                                                                              Infants born to mothers using benzodiazepines during the later stages of pregnancy have been reported to experience symptoms of sedation.

Although there are no data on the effects of BYFAVO use in pregnant women, available data from published observational studies of pregnant women exposed to other benzodiazepines have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes .

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% to 4% and 15% to 20%, respectively.

2 Lactation Risk Summary -                                                                                      There are no data on the effects of remimazolam in human milk, the effects on the breastfed infant or the effects on milk production. Remimazolam is present in animal milk  When a drug is present in animal milk, it is likely that it will be present in human milk. 

There are reports of sedation in infants exposed to benzodiazepines through breast milk. Monitor infants exposed to BYFAVO through breast milk for sedation, respiratory depression, and feeding problems.

A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 5 hours (approximately 5 elimination half-lives) after BYFAVO administration in order to minimize drug exposure to a breastfed infant.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BYFAVO and any potential adverse effects on the breastfed child from BYFAVO or from the underlying maternal condition.

3.Pediatric Use-                                                                                                     Safety and effectiveness in pediatric patients have not been established. No studies are available in any pediatric population and extrapolation of adult effectiveness data to the pediatric population is not possible.

4.Geriatric Use-                                                                                                            Of the total number of subjects treated with BYFAVO in clinical studies for procedural sedation, there were 649 subjects <65 years of age, 221 subjects >65 years of age, 171 subjects between 65­ 74 years of age, and 50 subjects >75 years of age.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Administer supplemental doses of BYFAVO slowly to achieve the level of sedation required for the procedure, and monitor all patients for cardiorespiratory complications. 

5. Hepatic Impairment-                                                                                                 In patients with severe hepatic impairment, the dose of BYFAVO should be carefully titrated to effect. Depending on the overall status of the patient, lower frequency of supplemental doses may be needed to achieve the level of sedation required for the procedure.

All patients should be monitored for sedation-related cardiorespiratory complications 

 DRUG ABUSE AND DEPENDENCE.                                                                              Abuse -BYFAVO contains the benzodiazepine, remimazolam. Benzodiazepines are a class of sedative drugs with a known potential for abuse. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

In a human abuse potential study conducted in recreational sedative abusers (n = 39), remimazolam (5 and 10 mg, IV) produced responses on positive subjective measures such as “Drug Liking,” “Overall Drug Liking,” “Take Drug Again,” and “Good Drug Effects” that were statistically similar to those produced by the sedative midazolam (2.5 and 5 mg), and statistically greater than the responses on these measures that were produced by placebo

3. Dependence -Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

In a monkey physical dependence study, chronic administration of remimazolam produced withdrawal signs such as tremors, muscle rigidity, restlessness, impaired motor activity, and a reduction in food consumption upon drug discontinuation.

One monkey of six in this study exhibited systemic convulsions and dissociation from the environment. These behaviors are consistent with benzodiazepine withdrawal, which suggests that remimazolam produces physical dependence.

OVERDOSAGE-                                                                                                    Clinical Presentation Overdose may lead to CNS depression, associated with drowsiness, confusion, and lethargy, with possible progression to ataxia, respiratory depression, and hypotension.

Management of Overdosage-                                                                                Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with BYFAVO is known or suspected.

Prior to the administration of flumazenil, institute necessary measures to secure the airway, and ensure adequate ventilation and oxygenation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose.

Flumazenil will only reverse benzodiazepine-induced effects and will not reverse the effects of other medications, such as opioid analgesics.

Consult the complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS, prior to use.

Monitor patients treated with flumazenil for re-sedation, respiratory depression, and other residual benzodiazepine effects.

Re-sedation by BYFAVO has not been observed after administration of flumazenil in clinical trials.