To assure safe and effective use of VERSED Syrup, the following information and instructions should be communicated to the patient when appropriate: 1. Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication and antibiotics, including drugs you buy without a prescription. Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment, 2. Inform your physician if you are pregnant or are planning to become pregnant, 3. Inform your physician if you are nursing, 4. Patients should be informed of the pharmacological effects of VERSED Syrup, such as sedation and amnesia, which in some patients may be profound. The decision as to when patients who have received VERSED Syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized, 5. VERSED Syrup should not be taken in conjunction with grapefruit juice, and 6. For pediatric patients, particular care should be taken to assure safe ambulation.
Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated.
Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered.
CNS Depressants: One case was reported of inadequate sedation with chloral hydrate and later with oral midazolam due to a possible interaction with methylphenidate administered chronically in a 2-year-old boy with a history of Williams syndrome. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate.
The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response.
No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed.
Midazolam is contraindicated in patients with a known hypersensitivity to the drug. Benzodiazepines are contraindicated in patients with acute narrow-angle glaucoma. Benzodiazepines may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with Midazolam; patients with glaucoma have not been studied.
Midazolam is not intended for intrathecal or epidural administration due to the presence of the preservative benzyl alcohol in the dosage form.