Pharmacodynamics

Pharmacodynamic properties of midazolam and its metabolites, which are similar to those of other benzodiazepines, include sedative, anxiolytic, amnesic and hypnotic activities. Benzodiazepine pharmacologic effects appear to result from reversible interactions with the γ-amino butyric acid (GABA) benzodiazepine receptor in the CNS, the major inhibitory neurotransmitter in the central nervous system. The action of midazolam is readily reversed by the benzodiazepine receptor antagonist, flumazenil.

Data from published reports of studies in pediatric patients clearly demonstrate that oral midazolam provides safe and effective sedation and anxiolysis prior to surgical procedures that require anesthesia as well as before other procedures that require sedation but may not require anesthesia. The most commonly reported effective doses range from 0.25 to 1.0 mg/kg in children (6 months to <16 years). The single most commonly reported effective dose is 0.5 mg/kg. Time to onset of effect is most frequently reported as 10 to 20 minutes.

The effects of midazolam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications.

Following premedication with oral midazolam, time to recovery has been assessed in pediatric patients using various measures, such as time to eye opening, time to extubation, time in the recovery room, and time to discharge from the hospital. Most placebo-controlled trials (8 total) have shown little effect of oral midazolam on recovery time from general anesthesia; however, a number of other placebo-controlled studies (5 total) have demonstrated some prolongation in recovery time following premedication with oral midazolam. Prolonged recovery may be related to duration of the surgical procedure and/or use of other medications with central nervous system depressant properties.

Partial or complete impairment of recall following oral midazolam has been demonstrated in several studies. Amnesia for the surgical experience was greater after oral midazolam when used as a premedicant than after placebo and was generally considered a benefit. In one study, 69% of midazolam patients did not remember mask application versus 6% of placebo patients.

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been reported in <1% of pediatric patients following premedication (eg, sedation prior to induction of anesthesia) with midazolam HCl syrup; the potential for such adverse events are markedly increased when oral midazolam is combined with other central nervous system depressing agents and in patients with abnormal airway anatomy, patients with cyanotic congenital heart disease, or patients with sepsis or severe pulmonary disease [see WARNINGS].

Concomitant use of barbiturates or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation or apnea, and may contribute to profound and/or prolonged drug effect. In one study of pediatric patients undergoing elective repair of congenital cardiac defects, premedication regimens (oral dose of 0.75 mg/kg midazolam or IM morphine plus scopolamine) increased transcutaneous carbon dioxide (PtcCO2), decreased SpO2 (as measured by pulse oximetry), and decreased respiratory rates preferentially in patients with pulmonary hypertension. This suggests that hypercarbia or hypoxia following premedication might pose a risk to children with congenital heart disease and pulmonary hypertension. In a study of an adult population 65 years and older, the preinduction administration of oral midazolam 7.5 mg resulted in a 60% incidence of hypoxemia (paO2<90% for over 30 seconds) at some time during the operative procedure versus 15% for the nonpremedicated group.

Pharmacokinetics

Absorption

Midazolam is rapidly absorbed after oral administration and is subject to substantial intestinal and hepatic first-pass metabolism. The pharmacokinetics of midazolam and its major metabolite, α- hydroxymidazolam, and the absolute bioavailability of midazolam HCl syrup were studied in pediatric patients of different ages (6 months to <16 years old) over a 0.25 to 1.0 mg/kg dose range. Pharmacokinetic parameters from this study are presented in Table 1. The mean Tmax values across dose groups (0.25, 0.5, and 1.0 mg/kg) range from 0.17 to 2.65 hours. Midazolam exhibits linear pharmacokinetics between oral doses of 0.25 to 1.0 mg/kg (up to a maximum dose of 40 mg) across the age groups ranging from 6 months to <16 years. Linearity was also demonstrated across the doses within the age group of 2 years to <12 years having 18 patients at each of the three doses. The absolute bioavailability of the midazolam HCl syrup in pediatric patients is about 36%, which is not affected by pediatric age or weight. The AUC0-∞ ratio of α-hydroxymidazolam to midazolam for the oral dose in pediatric patients is higher than for an IV dose (0.38 to 0.75 versus 0.21 to 0.39 across the age group of 6 months to <16 years), and the AUC0-∞ ratio of α-hydroxymidazolam to midazolam for the oral dose is higher in pediatric patients than in adults (0.38 to 0.75 versus 0.40 to 0.56).

Food effect has not been tested using midazolam HCl syrup. When a 15 mg oral tablet of midazolam was administered with food to adults, the absorption and disposition of midazolam was not affected. Feeding is generally contraindicated prior to sedation of pediatric patients for procedures.

Table 1: Pharmacokinetics of Midazolam Following Single Dose Administration of Midazolam Hydrochloride Syrup

Distribution

The extent of plasma protein binding of midazolam is moderately high and concentration independent. In adults and pediatric patients older than 1 year, midazolam is approximately 97% bound to plasma protein, principally albumin. In healthy volunteers, α-hydroxymidazolam is bound to the extent of 89%. In pediatric patients (6 months to <16 years) receiving 0.15 mg/kg IV midazolam, the mean steady-state volume of distribution ranged from 1.24 to 2.02 L/kg.

Metabolism

Midazolam is primarily metabolized in the liver and gut by human cytochrome P450 IIIA4 (CYP3A4) to its pharmacologic active metabolite, α-hydroxymidazolam, followed by glucuronidation of the α-hydroxyl metabolite which is present in unconjugated and conjugated forms in human plasma. The α- hydroxymidazolam glucuronide is then excreted in urine. In a study in which adult volunteers were administered intravenous midazolam (0.1 mg/kg) and α-hydroxymidazolam (0.15 mg/kg), the pharmacodynamic parameter values of the maximum effect (Emax) and concentration eliciting half- maximal effect (EC50) were similar for both compounds. The effects studied were reaction time and errors in tracing tests. The results indicate that α-hydroxymidazolam is equipotent and equally effective as unchanged midazolam on a total plasma concentration basis. After oral or intravenous administration, 63% to 80% of midazolam is recovered in urine as α-hydroxymidazolam glucuronide. No significant amount of parent drug or metabolites is extractable from urine before beta-glucuronidase and sulfatase deconjugation, indicating that the urinary metabolites are excreted mainly as conjugates.

Midazolam is also metabolized to two other minor metabolites: 4-hydroxy metabolite (about 3% of the dose) and 1,4-dihydroxy metabolite (about 1% of the dose) are excreted in small amounts in the urine as conjugates.

Elimination

The mean elimination half-life of midazolam ranged from 2.2 to 6.8 hours following single oral doses of 0.25, 0.5, and 1.0 mg/kg of midazolam HCl syrup. Similar results (ranged from 2.9 to 4.5 hours) for the mean elimination half-life were observed following IV administration of 0.15 mg/kg of midazolam to pediatric patients (6 months to <16 years old). In the same group of patients receiving the 0.15 mg/kg IV dose, the mean total clearance ranged from 9.3 to 11.0 mL/min/kg.

Pharmacokinetic-Pharmacodynamic Relationships

The relationship between plasma concentration and sedation and anxiolysis scores of midazolam HCl syrup (single oral doses of 0.25, 0.5, or 1.0 mg/kg) was investigated in three age groups of pediatric patients (6 months to <2 years, 2 to <12 years, and 12 to <16 years old). In this study, the patient’s sedation scores were recorded at baseline and at 10-minute intervals up to 30 minutes after oral dosing until satisfactory sedation (“drowsy” or “asleep but responsive to mild shaking” or “asleep and not responsive to mild shaking”) was achieved. Anxiolysis scores were measured at the time when the patient was separated from his/her parents and at mask induction. The results of the analyses showed that the mean midazolam plasma concentration as well as the mean of midazolam plus α-hydroxymidazolam for those patients with a sedation score of 4 (asleep but responsive to mild shaking) is significantly different than the mean concentrations for those patients with a sedation score of 3 (drowsy), which is significantly different than the mean concentrations for patients with a sedation score of 2 (awake/calm). The statistical analysis indicates that the greater the midazolam, or midazolam plus α-hydroxymidazolam concentration, the greater the maximum sedation score for pediatric patients. No such trend was observed between anxiolysis scores and the mean midazolam concentration or mean of midazolam plus α- hydroxymidazolam concentration, however, anxiolysis is a more variable surrogate measurement of clinical response.

Special Populations

Renal Impairment: Although the pharmacokinetics of intravenous midazolam in adult patients with chronic renal failure differed from those of subjects with normal renal function, there were no alterations in the distribution, elimination, or clearance of unbound drug in the renal failure patients. However, the effects of renal impairment on the active metabolite α-hydroxymidazolam are unknown.

Hepatic Dysfunction: Chronic hepatic disease alters the pharmacokinetics of midazolam. Following oral administration of 15 mg of midazolam HCl syrup, Cmax and bioavailability values were 43% and 100% higher, respectively, in adult patients with hepatic cirrhosis than adult subjects with normal liver function. In the same patients with hepatic cirrhosis, following IV administration of 7.5 mg of midazolam, the clearance of midazolam was reduced by about 40% and the elimination half-life was increased by about 90% compared with subjects with normal liver function. Midazolam should be titrated for the desired effect in patients with chronic hepatic disease.

Congestive Heart Failure: Following oral administration of 7.5 mg of midazolam HCl syrup, elimination half-life values were 43% higher in adult patients with congestive heart failure than in control subjects.

Neonates: Midazolam HCl syrup has not been studied in pediatric patients less than 6 months of age.

Drug-Drug Interactions

See PRECAUTIONS: Drug Interactions.

Inhibitors of CYP3A4 Isozymes

Table 2 summarizes the changes in the Cmax and AUC of midazolam when drugs known to inhibit CYP3A4 were concurrently administered with oral midazolam HCl syrup in adult subjects.

Table 2

Other drugs known to inhibit the effects of CYP3A4, such as protease inhibitors, would be expected to have similar effects on these midazolam pharmacokinetic parameters.

Inducers of CYP3A4 Isozymes

Table 3 summarizes the changes in the Cmax and AUC of midazolam when drugs known to induce CYP3A4 were concurrently administered with midazolam HCl syrup in adult subjects. The clinical significance of these changes is unclear.

Table 3

Although not tested, phenobarbital, rifabutin and other drugs known to induce the effects of CYP3A4 would be expected to have similar effects on these midazolam pharmacokinetic parameters.

Drugs that did not affect midazolam pharmacokinetics are presented in Table 4.

Table 4

Clinical Trials

Dose Ranging, Safety and Efficacy Study with Midazolam Hydrochloride Syrup in Pediatric Patients: The effectiveness of midazolam HCl syrup as a premedicant to sedate and calm pediatric patients prior to induction of general anesthesia was compared among three different doses in a randomized, double-blind, parallel-group study. Patients of ASA physical status I, II or III were stratified to 1 of 3 age groups (6 months to <2 years, 2 to <6 years, and 6 to <16 years), and within each age group randomized to 1 of 3 dosing groups (0.25, 0.5, and 1.0 mg/kg up to a maximum dose of 20 mg). Greater than 90% of treated patients achieved satisfactory sedation and anxiolysis at least one timepoint within 30 minutes posttreatment. Similarly high proportions of patients exhibited satisfactory ease of separation from parent or guardian and were cooperative at the time of mask induction with nitrous oxide and halothane administration. Onset time of satisfactory sedation or anxiolysis occurred within 10 minutes after treatment for >70% of patients who started with an unsatisfactory baseline rating. Whereas pairwise comparisons (0.25 mg/kg versus 0.5 mg/kg groups, and 0.5 mg/kg versus 1.0 mg/kg groups) on satisfactory sedation did not yield significant p-values (p=0.08 in both cases), comparative analysis of the clinical response between the high and low doses demonstrated that a higher proportion of patients in the 1.0 mg/kg dose group exhibited satisfactory sedation and anxiolysis as compared to the 0.25 mg/kg group (p<0.05).

Information for Patients

To assure safe and effective use of midazolam HCl 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, antibiotics, and protease inhibitors, 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 midazolam HCl syrup, such as sedation and amnesia, which in some patients may be profound. The decision as to when patients who have received midazolam HCl 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.

Midazolam HCl syrup should not be taken in conjunction with grapefruit juice.

6.

For pediatric patients, particular care should be taken to assure safe ambulation.

7.

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.

Pregnancy

Advise pregnant females that use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy).

Instruct patients to inform their healthcare provider if they are pregnant.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to midazolam HCl syrup during pregnancy (see Precautions, Pregnancy).

Nursing

Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs. A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant (see Precautions, Nursing Mothers).

Drug Interactions

Effect of Concomitant Use of Benzodiazepines and Opioids

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Monitor patients closely for respiratory depression and sedation.

Other 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 midazolam HCl syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of midazolam HCl syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see DOSAGE AND ADMINISTRATION].

No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed.

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 diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil were shown to significantly increase the Cmax 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 midazolam HCl syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions].

Inducers of CYP3A4 Isozymes

Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and cause a markedly decreased Cmax 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 midazolam HCl syrup to patients receiving these medications and if necessary dose adjustments should be considered.

Drug/Laboratory Test Interactions

Midazolam has not been shown to interfere with results obtained in clinical laboratory tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Midazolam maleate was administered with diet in mice and rats for 2 years at dosages of 1, 9, and 80 mg/kg/day. In female mice in the highest dose (10 times the highest oral dose of 1.0 mg/kg for a pediatric patient, on a mg/m2 basis) group there was a marked increase in the incidence of hepatic tumors. In high- dose (19 times the pediatric dose) male rats there was a small but statistically significant increase in benign thyroid follicular cell tumors. Dosages of 9 mg/kg/day of midazolam maleate (1 to 2 times the pediatric dose) did not increase the incidence of tumors in mice or rats. The pathogenesis of induction of these tumors is not known. These tumors were found after chronic administration, whereas human use will ordinarily be single or intermittent doses.

Mutagenesis

Midazolam HCl syrup did not have mutagenic activity in Salmonella typhimurium (5 bacterial strains), Chinese hamster lung cells (V79), human lymphocytes or in the micronucleus test in mice.

Impairment of Fertility

Male rats were treated orally with 1, 4, or 16 mg/kg midazolam (0.2, 0.6, and 2.6 times the dose of 1 mg/kg based on body surface area) beginning 62 days prior to mating with female rats treated with the same doses for 14 days prior to mating to Gestation Day 13 or Lactation Day 21. There were no adverse effects on either male or female fertility noted.

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including midazolam HCl syrup, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.

Risk Summary

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and Clinical Considerations). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data).

The 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 risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates. Monitor neonates exposed to midazolam HCl syrup during pregnancy and labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome).

Data

Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data

Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15). Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose. All doses produced slight to moderate ataxia. The high dose produced a 5% decrease in maternal body weight gain compared to control.

Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18). Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose. The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity.

Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21). All doses produced ataxia. The high dose produced a slight decrease in maternal body weight gain compared to control. There were no clear adverse effects noted in the offspring. The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits (see WARNINGS, Pediatric Neurotoxicity, PRECAUTIONS, Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY).

Nursing Mothers

Risk Summary

There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for midazolam HCl syrup and any potential adverse effects on the breastfed infant from midazolam HCl syrup or from the underlying maternal condition.

Clinical Considerations

Infants exposed to midazolam HCl syrup through breast milk should be monitored for sedation, poor feeding and poor weight gain. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant.

Pediatric Use

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Midazolam Hydrochloride Syrup 2 mg/mL, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data. [See WARNINGS; Pediatric Neurotoxicity, PRECAUTIONS; Pregnancy, and Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY].

Geriatric Use

The safety and efficacy of this product have not been fully studied in geriatric patients. Therefore, there are no available data on a safe dosing regimen. One study in geriatric subjects, using midazolam 7.5 mg as a premedicant prior to general anesthesia, noted a 60% incidence of hypoxemia (pO2<90% for over 30 seconds) at sometime during the operative procedure versus 15% for the nonpremedicated group. Until further information is available it is recommended that this product should not be used in geriatric patients.

Use in Patients With Heart Disease

Following oral administration of 7.5 mg of midazolam to adult patients with congestive heart failure, the half-life of midazolam was 43% higher than in control subjects. One study suggests that hypercarbia or hypoxia following premedication with oral midazolam might pose a risk to children with congenital heart disease and pulmonary hypertension, although there are no known reports of pulmonary hypertensive crisis that had been triggered by premedication. In the study, 22 children were premedicated with oral midazolam (0.75 mg/kg) or IM morphine plus scopolamine prior to elective repair of congenital cardiac defects. Both premedication regimens increased PtcCO2 and decreased SpO2 and respiratory rates preferentially in patients with pulmonary hypertension.