MIDAZOLAM IN SODIUM CHLORIDE- midazolam injection, solution

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

MIDAZOLAM (UNII: R60L0SM5BC) (MIDAZOLAM - UNII:R60L0SM5BC)

Available from:

WG Critical Care, LLC.

Administration route:

INTRAVENOUS

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Midazolam in Sodium Chloride Injection is indicated: Midazolam in Sodium Chloride Injection is contraindicated in patients with: Risk Summary Neonates born to mothers using benzodiazepines, including midazolam, late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.10), 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) . Available data from randomized controlled trials, cohort studies and case reports over several decades with midazolam use in pregnant women for anesthesia have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Most of the reported exposures to midazolam occurred at the time of cesarean delivery. Rare case reports of the prolonged use of midazolam in pregnant women for sedation in a critical care setting are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data). In pregnant rats and rabbits, midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons. Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans (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 background risk of major birth defects and 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 during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to midazolam during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.2)]. 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 and Precautions (5.8), Use in Specific Populations (8.4), Nonclinical Pharmacology (13.2)]. Risk Summary There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. Based on data from published studies, midazolam is present in human milk in low levels (see Data). There are no data on the effects of midazolam on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Midazolam in Sodium Chloride Injection and any potential adverse effects on the breastfed infant from Midazolam in Sodium Chloride Injection or from the underlying maternal condition. Clinical Considerations Infants exposed to midazolam 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. Data Published clinical lactation studies describe the presence of midazolam in human milk at low levels 4 to 8 hours after midazolam administration. These lactation studies have limitations including poor methodology and lack of validated analytical methods. Published study guidelines recommend pumping and discarding breast milk for a range of at least 4 to 8 hours after treatment with midazolam. No safety signals have been identified in breastfed infants exposed to midazolam. The safety and efficacy of midazolam for sedation/anxiolysis/amnesia following continuous infusion have been established in pediatric and neonatal patients. UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require closer monitoring. In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation. Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid intravenous administration, particularly, with concomitant use of fentanyl. Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Midazolam in Sodium Chloride Injection, 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 and Precautions (5.8) and Nonclinical Pharmacology (13.2)]. Because geriatric patients may have altered drug distribution and diminished hepatic and/or renal function, reduced doses of midazolam are recommended. Doses of Midazolam in Sodium Chloride Injection should be decreased for elderly and for debilitated patients [see Warnings and Precautions (5.6) and Dosage and Administration (2)] and subjects over 70 years of age may be particularly sensitive. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Administration of intravenous midazolam to elderly and/or high-risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially opioids [see Dosage and Administration (2)]. Midazolam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Midazolam in Sodium Chloride Injection contains midazolam, a Schedule IV controlled substance. Midazolam in Sodium Chloride Injection contains the benzodiazepine, midazolam. 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. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Both abuse and misuse may lead to addiction. Midazolam was actively self-administered in primate models used to assess the positive reinforcing effects of psychoactive drugs. Midazolam produced physical dependence of a mild to moderate intensity in cynomolgus monkeys after 5 to 10 weeks of administration. Available data concerning the drug abuse and dependence potential of midazolam suggest that its abuse potential is at least equivalent to that of diazepam. Midazolam may produce physical dependence after long-term use. 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. If Midazolam in Sodium Chloride Injection is administered long-term (i.e., for several days to weeks), abrupt discontinuation or rapid dosage reduction, or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.5)]. To reduce the risk of withdrawal reactions, after extended therapy, do not abruptly discontinue Midazolam in Sodium Chloride Injection. Gradually taper the dosage using a tapering schedule that is individualized to the patient. Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms have included abnormal involuntary movements, anxiety, blurred vision, cognitive disorder, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, homicidal thoughts, mania, psychosis, and suicidality Protracted Withdrawal Syndrome Protracted withdrawal syndrome is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. Tolerance Midazolam may produce tolerance after long-term use. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance may develop within days or weeks of the therapeutic effects of Midazolam; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

Product summary:

Midazolam in Sodium Chloride Injection is a clear, colorless solution supplied in single-dose bags with an aluminum overwrap available as: Total Strength per Total Volume Strength per mL 10 single-dose bags NDC Bag and Overwrap NDC *50 mg per 50 mL 1 mg/mL 44567-610-10 44567-610-01 100 mg per 100 mL 1 mg/mL 44567-611-10 44567-611-01 *Partial fill container 50 mL volume in 100 mL container Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from Freezing. Individual containers may be used up to 48 hours after initial penetration. Discard unused portion.

Authorization status:

New Drug Application

Summary of Product characteristics

MIDAZOLAM HYDROCHLORIDE- MIDAZOLAM HYDROCHLORIDE INJECTION, SOLUTION
WG CRITICAL CARE, LLC.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
MIDAZOLAM IN SODIUM
CHLORIDE INJECTION SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING
INFORMATION FOR MIDAZOLAM IN
SODIUM CHLORIDE INJECTION.
MIDAZOLAM IN SODIUM CHLORIDE INJECTION, FOR INTRAVENOUS USE, CIV
INITIAL U.S. APPROVAL: 1985
WARNING: PERSONNEL AND EQUIPMENT FOR MONITORING AND RESUSCITATION, AND
RISKS FROM CONCOMITANT USE WITH OPIOID ANALGESICS AND OTHER SEDATIVE-
HYPNOTICS
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
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RECENT MAJOR CHANGES
Warnings and Precautions (5.10) 01/2023
INDICATIONS AND USAGE
Midazolam in Sodium Chloride Injection is a benzodiazepine indicated
for: (1)
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DOSAGE AND ADMINISTRATION
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DOSAGE FORMS AND STRENGTHS
Injection: 50 mg per 50 mL (1mg/mL) and 100 mg per 100 mL (1 mg/mL) in
single-dose bags. (3) (3)
CONTRAINDICATIONS
Midazolam in Sodium Chloride Injection is contraindicated in patients
with: (4)
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WARNINGS AND PRECAUTIONS
Cardiorespiratory Adverse Reactions: Serious cardiorespiratory adverse
reactions have occurred,
sometimes resulting in death or permanent neurologic injury. (5.3) (5)
Paradoxical Behavior: Agitation, involuntary movements (including
tonic/clonic movements and muscle
tremor), hyperactivity and combativeness have been reported in both
adult and pediatric patients. (5.4)
ONLY PERSONNEL TRAINED IN THE ADMINISTRATION OF PROCEDURAL SEDATION,
AND NOT
INVOLVED IN THE CONDUCT OF THE DIAGNOSTIC OR THERAPEUTIC PROCEDURE,
SHOULD
ADMINISTER MIDAZOLAM INJECTION. (2.1, 5.1)
ADMINISTERING PERSONNEL MUST BE TRAINED IN THE DETECTION AND
MANAGEMENT OF
AIRWAY OBSTRUCTION, HYPOVENTILATION, AND APNEA, INCLUDING THE
MAINTENANCE OF A
PATENT AIRWAY, SUPPORTIVE VENTILATION, AND CARDIOVASCULAR
RESUSCITATION. (2.1, 5.1)
RESUSCITATIVE DRUGS, AND AGE- AND SIZE-APPROPRIATE EQUIPMENT FOR
BAG/VALVE/MASK
ASSISTED VENTILATION MUST BE IMM