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WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death [see WARNINGS and PRECAUTIONS].

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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

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Limit dosages and durations to the minimum required.

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Follow patients for signs and symptoms of respiratory depression and sedation.

Midazolam hydrochloride syrup has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. Midazolam hydrochloride syrup has been associated with reports of respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, most often when used concomitantly with other central nervous system depressants (eg, opioids). Midazolam hydrochloride syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, THAT CAN PROVIDE FOR CONTINUOUS MONITORING OF RESPIRATORY AND CARDIAC FUNCTION. IMMEDIATE AVAILABILITY OF RESUSCITATIVE DRUGS AND AGE- AND SIZE-APPROPRIATE EQUIPMENT FOR VENTILATION AND INTUBATION, AND PERSONNEL TRAINED IN THEIR USE AND SKILLED IN AIRWAY MANAGEMENT SHOULD BE ASSURED (see WARNINGS). For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

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 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 hydrochloride 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 pre-induction 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 non-premedicated group.

Pharmacokinetics:

Table 1

INHIBITORS OF CYP3A4 ISOZYMES:

Table 2 summarizes the changes in the Cmax and AUC of midazolam when drugs known to inhibit CYP3A4 which were concurrently administered with oral midazolam 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 oral midazolam 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:

Usage in Pregnancy

Although midazolam hydrochloride syrup has not been studied in pregnant patients, an increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) have been suggested in several studies. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus.

Usage in Preterm Infants and Neonates

Midazolam hydrochloride syrup has not been studied in patients less than 6 months of age.

Pediatric Neurotoxicity

Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, 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 three years of age in humans (See Precautions/ Pregnancy and Pediatric Use, and Animal Pharmacology and/or Toxicology).

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children and pregnant women needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

Use With Other CNS Depressants

The efficacy and safety of midazolam hydrochloride syrup in clinical use are functions of the dose administered, the clinical status of the individual patient, and the use of concomitant medications capable of depressing the CNS. Anticipated effects may range from mild sedation to deep levels of sedation with a potential loss of protective reflexes, particularly when coadministered with anesthetic agents or other CNS depressants. Care must be taken to individualize the dose of midazolam hydrochloride syrup based on the patient’s age, underlying medical/surgical conditions, concomitant medications, and to have the personnel, age- and size-appropriate equipment and facilities available for monitoring and intervention. Practitioners administering midazolam hydrochloride syrup must have the skills necessary to manage reasonably foreseeable adverse effects, particularly skills in airway management.

Use With Inhibitors of CYP3A4 Isozymes

Oral midazolam should be used with caution in patients treated with drugs known to inhibit CYP3A4 because inhibition of metabolism may lead to more intense and prolonged sedation (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug-Drug Interactions and WARNINGS). Patients being treated with medications known to inhibit CYP3A4 isozymes should be treated with lower than recommended doses of midazolam hydrochloride syrup and the clinician should expect a more intense and prolonged effect.

Information for Patients

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

 

Because some animal data suggest that the window of vulnerability includes the 3rd trimester of pregnancy, discuss with pregnant women the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs. (See Warnings/Pediatric Neurotoxicity)

 

Risks From Concomitant Use With Opioids: Inform patients and caregivers that potentially fatal additive effects may occur if midazolam is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider [see Warnings and Precautions; Drug Interactions].

Drug Interactions

Drug/ Laboratory Test Interactions

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

Carcinogenesis, Mutagenesis and Impairment of Fertility

Pregnancy

Labor and Delivery

In humans, measurable levels of midazolam were found in maternal venous serum, umbilical venous and arterial serum and amniotic fluid, indicating placental transfer of the drug.

The use of midazolam hydrochloride syrup in obstetrics has not been evaluated in clinical studies. Because midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonatal CNS depression, midazolam hydrochloride syrup is not recommended for obstetrical use.

Nursing Mothers

Midazolam is excreted in human milk. Caution should be exercised when midazolam syrup is administered to a nursing woman.

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 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 non-premedicated 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.

Table 5.

* This adverse event occurred precisely at the time of induction.

Table 6.

There were no deaths during the study and no patient withdrew from the study due to adverse events. Serious adverse events (both respiratory disorders) were experienced postoperatively by two patients: one case of airway obstruction and desaturation (SpO2 of 33%) in a patient given midazolam hydrochloride syrup 0.25 mg/kg, and one case of upper airway obstruction and respiratory depression following 0.5 mg/kg. Both patients had received intravenous morphine sulfate (1.5 mg total for both patients).

Other adverse events that have been reported in the literature with the oral administration of midazolam (not necessarily midazolam hydrochloride syrup), are listed below. The incidence rate for these events was generally <1%.

Respiratory: apnea, hypercarbia, desaturation, stridor.

Cardiovascular: decreased systolic and diastolic blood pressure, increased heart rate.

Gastrointestinal: nausea, vomiting, hiccoughs, gagging, salivation, drooling.

Central Nervous System: dysphoria, disinhibition, excitation, aggression, mood swings, hallucinations, adverse behavior, agitation, dizziness, confusion, ataxia, vertigo, dysarthria.

Special Senses: diplopia, strabiscmus, loss of balance, blurred vision.

Treatment of Overdosage

Treatment of midazolam hydrochloride syrup overdosage is the same as that followed for overdosage with other benzodiazepines. Respiration, pulse rate and blood pressure should be monitored and general supportive measures should be employed. Attention should be given to the maintenance of a patent airway and support of ventilation, including administration of oxygen. Should hypotension develop, treatment may include intravenous fluid therapy, repositioning, judicious use of vasopressors appropriate to the clinical situation, if indicated, and other appropriate countermeasures. There is no information as to whether peritoneal dialysis, forced diuresis or hemodialysis are of any value in the treatment of midazolam overdosage.

Gastrointestinal decontamination with lavage and/or activated charcoal once the patient’s airway is secure is also recommended.

Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of midazolam hydrochloride syrup and may be used in situations when an overdose with a benzodiazepine is known or suspected. There are anecdotal reports of adverse hemodynamic responses associated with midazolam hydrochloride syrup following administration of flumazenil to pediatric patients. Prior to the administration of flumazenil, necessary measures should be instituted to secure the airway, assure adequate ventilation, and establish adequate intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, should be consulted prior to use.

Monitoring

Midazolam hydrochloride syrup should only be used in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that can provide for continuous monitoring of respiratory and cardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured (see WARNINGS). For deeply sedated patients, a dedicated individual whose sole responsibility it is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. Continuous monitoring of respiratory and cardiac function is required.

Midazolam hydrochloride syrup must be given only to patients if they will be monitored by direct visual observation by a health care professional. Midazolam hydrochloride syrup should only be administered by persons specifically trained in the use of anesthetic drugs and the management of respiratory effects of anesthetic drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes, particularly when coadministered with anesthetic agents, other CNS depressants, and concomitant medications which may potentially cause a more intense and prolonged sedation (see PRECAUTIONS: Drug Interactions). This is especially true in pediatric patients. 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.

Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

Midazolam hydrochloride syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing CNS depression. Younger (<6 years of age) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring.

When midazolam hydrochloride syrup is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see WARNINGS and Monitoring subsection of DOSAGE AND ADMINISTRATION. 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.

The recommended dose for pediatric patients is a single dose of 0.25 to 0.5 mg/kg, depending on the status of the patient and desired effect, up to a maximum dose of 20 mg. In general, it is recommended that the dose be individualized and modified based on patients age, level of anxiety, concomitant medications, and medical need (see WARNINGS and PRECAUTIONS). The younger (6 months to <6 years of age) and less cooperative patients may require a higher than usual dose up to 1 mg/kg. A dose of 0.25 mg/kg may suffice for older (6 to <16 years of age) or cooperative patients, especially if the anticipated intensity and duration of sedation is less critical. For all pediatric patients, a dose of 0.25 mg/kg should be considered when midazolam hydrochloride syrup is administered to patients with cardiac or respiratory compromise, other higher risk surgical patients, and patients who have received concomitant narcotics or other CNS depressants. As with any potential respiratory depressant, these patients must be monitored for signs of cardiorespiratory depression after receiving midazolam hydrochloride syrup. In obese pediatric patients, the dose should be calculated based on ideal body weight. Midazolam hydrochloride syrup has not been studied, nor is it intended for chronic use.

Animal Pharmacology and/or Toxicology

Published studies in animals demonstrate that the use of anesthetic agents 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 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 exposure to an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but 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 neonates and young children who require procedures against the potential risks suggested by the nonclinical data (See Warnings/ Pediatric Neurotoxicity and Precautions/ Pregnancy and Pediatric Use)

Manufactured for:

Ranbaxy Pharmaceuticals Inc.

Jacksonville, FL 32216 USA

by:

Mikart, Inc.

Atlanta, GA 30318 USA

 

January 2017