Byfavo (remimazolam) is indicated for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Byfavo was evaluated in three prospective, randomized, double-blind, multicenter, parallel group clinical studies in 630 patients undergoing colonoscopy (two studies) or bronchoscopy (one study). Colonoscopy Study 1 and the bronchoscopy study evaluated American Society of Anesthesiologists (ASA) physical status I to III patients, and Colonoscopy Study 2 evaluated ASA III and IV patients.

All three studies evaluated the safety of Byfavo compared to placebo with midazolam rescue and an open-label midazolam treatment arm. Patients were administered a total dose ranging from 5 to 30 mg of Byfavo. In these studies, the most common adverse reactions (incidence greater than 10%) following Byfavo administration were

• hypotension,
• hypertension,
• diastolic hypertension,
• systolic hypertension,
• hypoxia, and
• diastolic hypotension.

There were two patients who experienced an adverse reaction that led to discontinuation of study drug. One patient in the Byfavo arm in the bronchoscopy study discontinued treatment due to bradycardia, hypertension, hypotension, hypoxia, and respiratory rate increase. One patient in the open-label midazolam arm in Colonoscopy Study 2 discontinued due to respiratory acidosis. No deaths were reported during the studies.

Adverse reaction data from Colonoscopy Study 1 and the bronchoscopy study analyzed according to the cumulative dose of concomitant fentanyl (<100 mcg, 100-150 mcg and >150 mcg) suggest an increase in some adverse reactions with increasing fentanyl dose, such as hypotension, hypertension, bradycardia, hypoxia, and increased respiratory rate (see Table 4 and Table 5).

Byfavo contains remimazolam, a Schedule IV controlled substance (CIV).

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.

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.

• Individualize Byfavo dosing and titrate to desired clinical response.
• In clinical studies, fentanyl 25 to 75 mcg was administered for analgesia prior to the first dose of Byfavo. Supplemental doses of fentanyl were administered as needed for analgesia [see Clinical Studies].
• Recommended dosing guidelines:

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.

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.

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

There are no data on the effects of remimazolam in human milk, the effects on the breastfed infant or the effects on milk production. 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.