midazolam intranasal (Rx)

Brand and Other Names:Nayzilam
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

intranasal solution: Schedule IV

  • 5mg/0.1mL per single-dose spray

Seizures

Indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy

Initial dose: 5 mg (1 spray) into 1 nostril

Second dose (if needed)

  • An additional 5 mg (1 spray) into the opposite nostril may be administered after 10 minutes if the patient has not responded to the initial dose
  • Do not administer second dose if the patient has breathing trouble or if excessive sedation occurs that is uncharacteristic of the patient during a seizure cluster episode

Maximum dose and frequency

  • Do not use >2 doses per single seizure episode
  • Do not treat more than 1 episode q3days and no more than 5 episodes/month

Dosing Considerations

For patients at increased risk of respiratory depression from benzodiazepines, administration under healthcare professional supervision should be considered before prescribing; this administration may be performed in the absence of a seizure episode

Instruct the individual who will administer midazolam intranasal on how to identify seizure clusters and use the product appropriately

Counsel patients and caregivers to carefully read instructions for use for complete directions on how to properly administer

Dosage Forms & Strengths

intranasal solution: Schedule IV

  • 5mg/0.1mL per single-dose spray

Seizures

Indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy aged ≥12 years

<12 years: Safety and efficacy not established

≥12 years

  • Initial dose: 5 mg (1 spray) into 1 nostril
  • Second dose (if needed)
    • An additional 5 mg (1 spray) into the opposite nostril may be administered after 10 minutes if the patient has not responded to the initial dose
    • Do not administer second dose if the patient has breathing trouble or if excessive sedation occurs that is uncharacteristic of the patient during a seizure cluster episode
  • Maximum dose and frequency
    • Do not use >2 doses per single seizure episode
    • Do not treat more than 1 episode q3days and no more than 5 episodes/month

Dosing Considerations

For patients at increased risk of respiratory depression from benzodiazepines, administration under healthcare professional supervision should be considered before prescribing; this administration may be performed in the absence of a seizure episode

Instruct the individual who will administer midazolam intranasal on how to identify seizure clusters and use the product appropriately

Counsel patients and caregivers to carefully read instructions for use for complete directions on how to properly administer

Safety and efficacy studies did not include sufficient numbers of participants aged ≥65 yr to determine whether they respond differently from younger individuals

Geriatric patients have longer elimination half-lives for midazolam and its metabolites, which may result in prolonged drug exposure

Geriatric patients may have altered drug distribution, diminished hepatic and/or renal function, and those aged >70 yr may be particularly sensitive

See adult dosing

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Interactions

Interaction Checker

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            Adverse Effects

            1-10% (Single 5-mg Dose)

            Somnolence (10%)

            Headache (7%)

            Nasal discomfort (5%)

            Abnormal taste (4%)

            Rhinorrhea (3%)

            Throat irritation (2%)

            Dysarthria (2%)

            Lacrimation increased (1%)

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            Warnings

            Black Box Warnings

            Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death

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

            Limit dosages and durations to the minimum required

            Monitor patients for signs and symptoms of respiratory depression and sedation

            Contraindications

            Known hypersensitivity

            Acute narrow-angle glaucoma

            Cautions

            Serious cardiorespiratory adverse reactions reported, including respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest, and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury; danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve

            Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication; pooled analyses of 199 placebo-controlled clinical trials of 11 different AEDs showed ~2 x risk of suicidal thinking or behavior in patients taking AEDs; should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms may be related to illness being treated

            May impair cognitive function; use associated with high incidence of partial or complete impairment of recall for several hours following dose

            Benzodiazepines can increase intraocular pressure in patients with glaucoma; may use in patients with open-angle glaucoma who are controlled with medication; contraindicated with narrow-angle glaucoma

            When midazolam was used for sedation, reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity, and combativeness reported

            Slower elimination and prolonged drug exposure of midazolam and its metabolites observed in patients with renal or hepatic impairment or congestive heart failure

            Benzodiazepines may be subject to abuse and dependence; abrupt withdrawal of chronic benzodiazepines may be associated with temporary increase in frequency and/or severity of seizures

            Drug interaction overview

            • Opioids and benzodiazepines: Concomitant use of benzodiazepines (including midazolam intranasal) and opioids may result in profound sedation, respiratory depression, coma, and death; only use in patients for whom alternative treatment options are inadequate; hypotension more likely if patient premedicated with a narcotic
            • CNS depressants: CNS depression reported with coadministration with other CNS depressants (eg, barbiturates, alcohol)
            • CYP3A4 inhibitors: Risk of prolonged sedation if coadministered with moderate or strong CYP3A4 enzyme inhibitors, owing to much higher midazolam exposures
            • CYP3A4 inducers: Midazolam exposure decreased 16-26% if coadministered with strong CYP3A4 inducers and by 8-15% by weak-to-moderate inducers
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            Pregnancy

            Pregnancy

            There are no adequate and well-controlled studies of midazolam intranasal in pregnant women

            Available data suggest benzodiazepines are not associated with marked increases in risk for congenital anomalies

            Clinical considerations

            • Exposure to benzodiazepines during the second and third trimesters of pregnancy or immediately prior to or during childbirth may increase risk for decreased fetal movement and/or fetal heart rate variability, floppy infant syndrome, dependence, and withdrawal
            • Clinical manifestations of withdrawal or neonatal abstinence syndrome may include hypertonia, hyperreflexia, hypoventilation, irritability, tremors, diarrhea, and vomiting

            Pregnancy registry

            • Encourage women prescribed midazolam intranasal during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or register at http://www.aedpregnancyregistry.org/

            Animal studies

            • Administration of midazolam to rats and rabbits during the period of organogenesis or to rats during late pregnancy and throughout lactation at doses greater than those used clinically did not result in any apparent adverse effects on development
            • However, published data for benzodiazepines suggest potential of neuronal cell death and long-term effects on neurobehavioral and immunological function in animals following prenatal or early postnatal exposure at clinically relevant doses

            Lactation

            Midazolam is excreted in human milk

            Studies assessing effects in the breastfed infant or on milk production/excretion have not been performed

            Postmarketing experience suggests that breastfed infants of mothers taking benzodiazepines may experience lethargy, somnolence, and poor sucking

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Binds receptors at several sites within the CNS, including the limbic system and reticular formation; effects may be mediated through GABA receptor system; increase in neuronal membrane permeability to chloride ions enhances the inhibitory effects of GABA; the shift in chloride ions causes hyperpolarization (less excitability) and stabilization of the neuronal membrane

            Absorption

            Absolute bioavailability: 44%

            Peak plasma time: 17.3 minutes

            Peak plasma concentration: 54.7 ng/mL

            AUC: 126.2 ng·hr/mL

            Distribution

            Vd: 226.5 L

            Protein bound: ~97%; 89% (1-hydroxy midazolam)

            Metabolism

            Primarily metabolized by liver and intestinal CYP3A4 to its pharmacologic active metabolite, 1-hydroxy midazolam (also termed alpha-hydroxymidazolam), which is at least as potent as the parent compound

            Also metabolized to 2 other minor metabolites: 4-hydroxy metabolite and 1,4-dihydroxy metabolite

            Elimination

            Half-life: 2.1-6.2 hr; 2.7-7.2 hr (major metabolite)

            Excretion: Primarily in urine as glucuronide conjugates of hydroxylated derivatives

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            Administration

            Intranasal Administration

            For nasal administration only as single-episode acute treatment of intermittent seizures

            Not for long-term, daily use as an anticonvulsant owing to potential for development of tolerance to midazolam’s therapeutic effects

            Do not open blister packaging until ready to use

            Do not test or prime before use

            Do not use if the nasal spray unit appears damaged

            Storage

            Store at controlled room temperature 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.