Midazolam Epilepsy - Nasal Spray - An Overview

Drug Overview:

Midazolam nasal spray has been FDA-approved since 1985 for addressing emergencies by halting cluster seizures in adults and children aged 12 and above who are concurrently undergoing epilepsy treatment with other medications. Classified as a Benzodiazepine, Midazolam functions by mitigating abnormal brain overactivity, providing a calming effect.

For Patients:

What Are the Clinical Indications Of Midazolam?

Midazolam nasal spray is indicated for seizure-activity patients aged 12 or older.

What Is the Dosage of Midazolam?

It is administered as a nasal spray only in the quantity of five milligrams (mg); after a 10-minute gap, a five mg nasal spray is administered again in the opposite nostril only if the patient does not respond to the first spray.

What Are the Things to Inform the Doctor Before Taking the Drug?

The patient must inform the doctor if they are on other medications before starting this drug. They should also inform them about the below-mentioned conditions:

• Pregnancy.

• Heart disease.

• Liver disease.

• Migraines.

• Kidney diseases.

• Glaucoma.

• Stroke.

• Cancer.

• Depression.

• Breastfeeding.

• Diabetes.

How Is Midazolam Administered?

• Midazolam nasal spray is inhaled through the nose.

• Use exactly as directed; do not exceed or use more often than prescribed.

• If the first dose does not control a seizure, the doctor may advise a second dose.

• Follow the doctor's instructions for inhaling a second dose.

• Before prescribing, the doctor educates the patient and caregiver on recognizing seizure signs and administering the nasal spray.

• Keep Midazolam nasal spray available at all times for immediate use during seizures.

• Regular use may be habit-forming; the patient should stay within the

• prescribed dosage.

• Not for daily use; should be used at most five times a month or more often than every three days.

What Are the Side Effects of Midazolam?

• Drowsiness.

• Sore or irritated nose.

• Sore or irritated throat.

• Runny nose.

• Headache.

• Unusual taste in the mouth.

• Difficulty speaking.

• Watery or runny eyes.

Missed Dose:

Regular use is habit-forming; it is only taken when needed.

Overdose:

Symptoms of overdose may include:

• Drowsiness.

• Confusion.

• Loss of coordination.

• Slow reflexes.

• Coma (loss of consciousness for some time).

Call the doctor immediately in any such situation.

Storage:

Keeping the drug in its original package and container is necessary. It must be safely secured and out of the children's reach. This action ensures their safety. Since bathrooms have substantial moisture levels, never keep or store drugs there. It should always be kept for storage at the optimal room temperature.

For Doctors:

Indication:

Midazolam is prescribed for the immediate management of sporadic, stereotypical episodes involving frequent seizure activity, specifically addressing seizure clusters or acute repetitive seizures. This pertains to occurrences that deviate from the patient's typical seizure pattern, and it is intended for use in individuals aged 12 years and older with epilepsy.

Dose:

The recommended dose is five mg. Dosing Considerations:

• Administer Midazolam via the nasal route exclusively.

• Initial Dose: Administer one spray (five mg dose) into one nostril.

• Second Dose (if needed): Administer an extra spray (five milligrams) in the alternate nostril if there is no response to the initial dose after 10 minutes.

• Avoid a second Midazolam dose if the patient experiences difficulty breathing or excessive sedation during a seizure cluster episode.

• Maximum Dosage and Treatment Frequency: Do not exceed two doses of Midazolam for a single episode. Limit Midazolam to one episode every three days and no more than five monthly episodes.

What Are the Pharmacological Aspects of Midazolam?

Mechanism of Action: Midazolam is a benzodiazepine that acts on the central nervous system. Its mechanism of action involves enhancing the effect of gamma-aminobutyric acid (GABA), which is the primary inhibitory neurotransmitter in the brain.

• GABA Receptor Modulation: Midazolam binds to specific sites on the GABA-A (gamma-aminobutyric acid type A) receptors located in the brain. GABA-A receptors are ionotropic receptors that, when activated, allow the influx of chloride ions, leading to membrane hyperpolarization.

• Increased GABAergic Activity: Midazolam boosts the inhibitory effect of GABA by elevating the frequency of chloride channel opening when GABA binds. This results in an increased influx of chloride ions into the neurons.

• Neuronal Hyperpolarization: The increased chloride influx hyperpolarizes the neuronal cell membrane, making it more resistant to depolarization and less likely to generate an action potential. This hyperpolarization inhibits excessive electrical activity in the brain, characteristic of seizures.

• CNS Depression: Overall, the enhanced GABAergic activity induced by midazolam leads to central nervous system depression. This depressant effect helps reduce abnormal neuronal firing, providing a calming and anticonvulsant effect, particularly in seizure activity.

Pharmacodynamics:

Receptor Interaction:

• Midazolam primarily interacts with GABA-A receptors in the central nervous system.

• Binding to specific sites on these receptors modulates the response to gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter.

GABAergic Activity Enhancement:

• Midazolam enhances the inhibitory action of GABA by increasing the frequency of chloride channel opening in response to GABA binding.

• This augmentation results in an increased influx of chloride ions, leading to membrane hyperpolarization.

Neuronal Hyperpolarization:

• The heightened influx of chloride ions hyperpolarizes the neuronal cell membrane, reducing excitability.

• This effect makes neurons less likely to generate action potentials, contributing to an overall reduction in neuronal activity.

• Central Nervous System Depression:

• The cumulative impact of Midazolam's actions is central nervous system depression.

• This depression manifests as sedation, anxiolysis, muscle relaxation, and anticonvulsant effects, making it useful in various clinical scenarios.

Clinical Effects:

• Midazolam's pharmacodynamics result in anxiolysis (anxiety reduction), sedation, amnesia, and muscle relaxation.

• The drug's anticonvulsant properties are particularly beneficial in the management of seizures, including seizure clusters.

Dose-Response Relationship:

• The pharmacodynamic effects of Midazolam are dose-dependent, with higher doses generally producing more profound CNS depression and sedation.

Pharmacokinetics:

Population Pharmacokinetic Analysis:

• Plasma exposures (Cmax and AUC) of midazolam in epilepsy patients increase proportionally with the dose, from five mg to 15 mg.

Absorption:

• After nasal administration of a single Midazolam dose in healthy adults, absorption occurs with a median Tmax.

• The midazolam mean Cmax and AUC0 are reported.

• The mean absolute bioavailability is approximately a certain percentage.

Distribution:

• In adult and pediatric patients, approximately a certain percentage of Midazolam is bound to plasma proteins, primarily albumin.

• 1-hydroxy Midazolam is bound to the extent of a certain percentage in healthy volunteers.

• The calculated total volume of distribution for Midazolam equals a specific value.

• Midazolam crosses the placenta, enters the fetal circulation, and is detected in human milk and CSF.

Elimination:

• Median midazolam and 1-hydroxy-Midazolam elimination half-lives, independent of dose, are reported following NAYZILAM administration in clinical trials.

Metabolism:

• Liver and intestinal cytochrome P450 3A4 (CYP3A4) primarily metabolize Midazolam to its pharmacologically active metabolite, 1-hydroxy Midazolam.

• Two minor metabolites are 4-hydroxy metabolite and 1,4-dihydroxy metabolite.

• Studies suggest that 1-hydroxy-midazolam is at least as potent as the parent compound.

Excretion:

• The primary excreted product in urine is 1-hydroxy midazolam, a glucuronide conjugate.

• Smaller amounts of glucuronide conjugates of 4-hydroxy- and dihydroxymidazolam are also detected.

Clinical Studies and Efficacy:

• Epileptic patients aged 12 and older on stable antiepileptic drugs.

• Test Dose (tolerability assessment) and Comparative (randomized, double-blind, placebo-controlled).

• 292 patients received two five mg doses of Midazolam in the open-label Test Dose Phase.

• 201 patients treated a single seizure cluster episode with Midazolam 5 mg or placebo.

• Treatment success – seizure termination within 10 minutes and no recurrence within six hours.

• Midazolam-treated patients had a statistically longer time to the next seizure than the placebo group.

• Midazolam demonstrated significant efficacy in treating seizure clusters, with faster termination and reduced recurrence compared to placebo. Tolerability was assessed in the Test Dose Phase, supporting its potential as an effective option for acute seizure management in epilepsy patients aged 12 and older.

What Are the Contraindications of Midazolam?

Allergic Reaction:

• Individuals who have experienced an allergic reaction to midazolam should avoid its use.

• Symptoms of allergic reactions may include manifestations such as a rash, itching, swelling, profound dizziness, or challenges in breathing.

• It is crucial for individuals with a known allergy to Midazolam or its components to inform their healthcare provider to prevent adverse reactions.

Acute Narrow-Angle Glaucoma:

• Midazolam is contraindicated in individuals with acute narrow-angle glaucoma.

• In cases of narrow-angle glaucoma, heightened intraocular pressure is a defining condition. Midazolam's utilization in such situations can potentially exacerbate this pressure, possibly resulting in complications.

• Patients with a history of narrow-angle glaucoma should inform their healthcare provider to ensure appropriate alternative medications are considered, and potential risks are minimized.

Warnings and Precautions:

Risks from Concomitant Use of Opioids:

• Combining Midazolam and opioids may lead to severe sedation, respiratory depression, coma, and even death.

• Concomitant prescribing should be limited to cases where alternative treatments are insufficient.

• Observational studies show an increased risk of drug-related mortality with opioid and benzodiazepine use compared to opioids alone.

• If co-prescribing is necessary, use the lowest effective doses and durations, closely monitoring for respiratory depression and sedation.

Risks of Cardiorespiratory Adverse Reactions:

• Serious adverse reactions, including respiratory depression, airway obstruction, and cardiac events, have occurred with Midazolam.

• Hypotension risk increases, especially in patients premedicated with narcotics.

• Respiratory depression was observed in NAYZILAM trials; however, cardiac or respiratory arrest was not reported.

Central Nervous System Depression from Concomitant Use:

• Midazolam has a CNS depressant effect.

• Risks of increased CNS depression with alcohol, other depressants (e.g., opioids), or moderate/strong CYP3A4 inhibitors.

• Concomitant use with barbiturates or other depressants may heighten the risk of hypoventilation, airway obstruction, or prolonged drug effects.

Suicidal Behavior and Ideation:

• Antiepileptic drugs, including Midazolam, increase the risk of suicidal thoughts or behaviors.

• Pooled analyses show approximately twice the risk compared to placebo.

• Onset is observed as early as one week into treatment; risk persists for the duration of treatment.

Impaired Cognitive Function:

• Midazolam is associated with recall impairment for several hours after administration.

• Caution against operating machinery or vehicles until drug effects subside.

• Pediatric patients should be particularly cautious regarding safe ambulation.

Glaucoma:

• Benzodiazepines, including Midazolam, can increase intraocular pressure in glaucoma patients.

• Administer only to individuals with open-angle glaucoma if they are currently undergoing the correct treatment.

• Contradicted in narrow-angle glaucoma patients.

Other Adverse Reactions:

• When used for sedation, midazolam may cause reactions such as agitation, involuntary movements, hyperactivity, and combativeness.

• It is important to contemplate the potential for insufficient, excessive, or incorrect administration of Midazolam.

Specific Considerations

Pregnancy: Encouraging pregnant women prescribed Midazolam to participate in the North American Antiepileptic Drug (NAAED) pregnancy registry is advised. However, there is a notable absence of well-controlled studies on midazolam in pregnant women.

While current evidence on benzodiazepines as a class suggests no significant increase in congenital anomalies, clinical considerations underscore potential risks during midazolam exposure in the second and third trimesters. These risks include issues such as decreased fetal movement and "floppy infant syndrome," as well as the possibility of dependence and withdrawal. Consequently, the decision to use Midazolam during pregnancy should be carefully weighed, with the understanding that benefits to the mother must substantially outweigh potential risks to the fetus.

Lactation: Midazolam is excreted in human milk, and this raises concerns about potential effects on breastfed infants, including lethargy, somnolence, and poor sucking. When deciding to breastfeed while using Midazolam, it is essential to weigh the developmental and health advantages of breastfeeding against the clinical requirements of Midazolam for the mother.

Pediatric Use: The safety and effectiveness of Midazolam have been evaluated in individuals aged 12 to 17 based on an adequate and well-controlled study. However, data for pediatric patients below 12 is limited, and safety and effectiveness in this age group have yet to be conclusively established.

Geriatric Use: Studies assessing the safety and efficacy of Midazolam needed to include a sufficient number of subjects aged 65 and over. Geriatric patients may experience prolonged drug exposure due to longer elimination half-lives and altered drug distribution. Hence, close monitoring is strongly recommended, particularly for individuals aged 70 and above.

Renal Impairment: A population pharmacokinetic analysis indicates that individuals with mild renal impairment may exhibit similar pharmacokinetics to those with normal renal function. However, there is a lack of safety and efficacy data for individuals with severe renal impairment, and those with moderate impairment may experience slower elimination, resulting in prolonged drug exposure.

Congestive Heart Failure: Individuals suffering from congestive heart failure experience a slower elimination of Midazolam, resulting in an extended duration of drug exposure. This emphasizes the significance of meticulous evaluation and observation when administering Midazolam to individuals experiencing congestive heart failure.