January 2016, Vol 4, No 1 - Inside Pediatric Health
Christine Echtenkamp, PharmDc
Stacie Lampkin, PharmD, BCACP, AE-C

Seizures are among the most common treatable and preventable medical conditions that require children to use emergency medical services. Optimizing home management of seizures in pediatric patients can significantly reduce morbidity and mortality in this population.1

An ideal agent for outpatient seizure management is a fast-acting medication with a broad spectrum of efficacy and minimal adverse effects, thus making benzodiazepines the first-line agents for this indication.2,3 In addition, the agent of choice should be easily administered via a socially acceptable route of administration.3

Diazepam and midazolam are 2 products commercially available in the United States for seizure management.2 Historically, diazepam rectal gel (Diastat) has been the standard of care, and is currently the only US Food and Drug Administration (FDA)-approved medication in the outpatient setting.4 Unfortunately, there are several disadvantages to the rectal dosage form regarding ease of administration and social acceptability.3 Although it is not FDA approved, midazolam administered by buccal and nasal routes may be an alternative for acute seizure management.2

These emerging treatment delivery options may provide an effective and more tolerable option to patients and their caregivers administering medication for acute seizure management.5,6 However, lack of healthcare provider knowledge regarding rescue benzodiazepine availability and proper use in pediatric patients presents a barrier to care for patients requiring rescue therapy.7

To optimize patient care, pharmacists and other healthcare providers should understand the role of rescue benzodiazepines used in the pediatric population, and have knowledge about their efficacy, safety, appropriate dosing, administration, and dispensing considerations.

Efficacy and Safety of Treatment Options

Diazepam was approved as an effective and safe rescue medication for acute seizure management in 2004.2 Notably, the nasal and buccal routes of administration for midazolam have proven to be effective and safe alternatives to rectal diazepam in randomized controlled trials conducted thus far.1,3,5,6

Three studies have evaluated the efficacy of intranasal midazolam compared with rectal diazepam in the home setting.8 In a pediatric study, Bhattacharyya and colleagues demonstrated that intranasal midazolam was significantly more effective than rectal diazepam, evaluating time to seizure cessation as a primary end point.9 Another study evaluated seizure episodes in children treated for episodes lasting >5 minutes, and the intranasal midazolam group in this study reported a median time to seizure cessation of 3 minutes versus 4.3 minutes in the rectal diazepam group.1 A study of seizure episodes in adults found no difference in the time to effect of these 2 drugs, although results were not significant.8

The administration method of intranasal midazolam varied throughout the studies reviewed, between using an atomizing device and administration by droplet. As the medication readily crosses the blood–brain barrier, delivery to the central nervous system is rapid through the nasal mucosa.1 However, administration without the atomizing device may not adequately coat the mucosa, resulting in medication being swallowed instead of nasally absorbed, and potentially reducing efficacy. Although the presence of increased nasal secretions in certain populations (eg, patients with an upper respiratory tract infection), and sneezing because of irritation may pre­sent a concern as to comparable efficacy, many studies did not find a difference in side effect occurrence.10

Similarly, a wealth of randomized controlled trials have demonstrated the efficacy and tolerability of buccal administration of midazolam in the acute treatment of seizures.4 Study authors in one study determined that buccal midazolam was more effective in achieving therapeutic success—defined as cessation of visible signs of seizure within 10 minutes of administration and lasting for ≥1 hours—than rectal diazepam.10 In another study, the investigators demonstrated that intranasal midazolam resulted in statistically significantly more patients achieving seizure termination within 10 minutes of benzodiazepine administration compared with rectal diazepam administration.11

With regard to safety, the most critical adverse effect associated with benzodiazepines is respiratory depression.2 This is dose-dependent and unlikely to occur at the doses prescribed for outpatient seizure management, with very few incidences being reported in clinical trials.3 Although it is unlikely, patients and caregivers should be aware of the risk and instructed to monitor the patient for 4 hours following administration, ensuring that they do not have any changes in breathing or skin color, or experience any side effects.12 Clinical trials have demonstrated little to no difference in side effect profile and occurrence of respiratory depression in the 3 dosage forms discussed in this article; however, local irritation is common with all of the medications, and burning upon administration has occurred commonly in patients receiving medication intranasally.3

Following administration of the medication that is alternatively used as a sedative, patients should expect drowsiness.2 Other adverse events that have been reported with single-dose benzodiazepine use include hypotension, dizziness, and headache.3,13 There are some theoretical concerns as to the risk of aspiration in patients receiving midazolam buccally.3 This has not presented as a legitimate safety issue in patients receiving the medication, because the volume of midazolam in this setting is minimal with respect to saliva production in the seizing individual.

Rectal Diazepam

Dosing
Rectal diazepam should be dosed in pediatric patients according to the following criteria: (1) aged 2 to 5 years, 0.5 mg/kg; (2) 5 to 11 years, 0.3 mg/kg; and (3) >12 years, 0.2 mg/kg, rounded to the next available 2.5-mg increment dose, with a maximum daily dose of 20 mg.2

Because pediatric dosing of this medication is variable with patient age and weight, it is critical that pharmacists check that dosing is appropriate each time the medication is filled; prescribing physicians may not see patients regularly enough to adjust dosing.

Dispensing Considerations
Rectal diazepam is dispensed as Diastat AcuDial rectal gel, a device that allows for storage and administration of the medication with convenient features, including a dosing window and ready band that indicates whether the dose has been locked.13 The pharmacy should ensure that the dose is locked in the administration device at the time of dispensing to avoid accidental overdose, and should dispense the product in the most convenient quantity for emergency use. Bear in mind that the Diastat AcuDial device can be dialed back to the appropriate number of milligrams calculated for the patient to ensure a safe, convenient, and individualized dose. For example, if the dose prescribed for a patient is 7.5 mg, it is appropriate to dispense the 10-mg Diastat AcuDial device and lock it at the prescribed dose of 7.5 mg.

Administration
Administration of rectal diazepam can be confusing and overwhelming for patients and caregivers. Therefore, providing patients with a demonstration and other instructions for use can help relieve anxiety regarding their use for patients and reduce emergency department visits.14 The Table has a link on detailed instructions for rectal administration.

Table

Intranasal Midazolam

Dosing
The dosing of intranasal midazolam established acute seizure management in randomized controlled trials is 0.2 mg/kg in children aged >6 months, which may be repeated once to a maximum total dose of 0.4 mg/kg. Currently, midazolam is only available as an intravenous vial, and comes in a variety of concentrations, including 1 mg/mL and 5 mg/mL.2

Dispensing Considerations
For administration, patients will need to draw up the appropriate dose into a syringe. Because of uncertainty regarding the stability of midazolam in a syringe, it is best practice for the pharmacy to dispense the medication in the manufacturer vial with an attached syringe premarked to the correct dose. Ensure that the patient is provided with all materials necessary for transfer and proper administration of the medication. This should include a premarked, needleless syringe, and, if applicable, an atomizer device.15 Because medication administered intranasally by droplet may result in reduced absorption into the central nervous system, it is best practice to, if possible, dispense the atomizer device, which is relatively inexpensive at about $4 per atomizer.1

Administration
When counseling on proper administration, there are 2 methods of delivery that have been studied, including using an atomizer device, or dropping the dose directly into the nares. Regardless of technique, administration of the medication requires that the dose be divided between nares.2

To draw the medication from vial to syringe, patients and caregivers will require instruction. When administering the medication by drop, the medication-filled syringe may be inserted into one nare, and the plunger pressed down to approximately half of the filled volume; this may then be repeated in the opposite nare by pressing the plunger to release the remaining midazolam. Alternatively, when administering with an atomizing device, the device may be attached by the luer lock or twisting mechanism once the medication is drawn up in the syringe at the appropriate dose. Once attached, the syringe may be—similarly to the vial method—inserted into one nare, and the plunger pressed to deliver approximately half of the midazolam, and repeated to deliver the remaining midazolam into the opposite nare.15 Although this method is preferable to rectal administration in the seizing child, it is important that instruction is given at the time of dispensing, and an understanding of both transfer from vial to syringe, as well as administration, is demonstrated by the patient and/or caregiver.6,15

Buccal Midazolam

Dosing
Dosing of buccal midazolam is based on weight (0.2-0.5 mg/kg in children aged >3 months) or age (infants 6-11 months, 2.5 mg; children 1-4 years, 5 mg; children 5-9 years, 7.5 mg; and children >9 years, 10 mg).16 Please note that although both dosing recommendations are legitimate and acceptable, the age-based dosing presented is drawn from the product information for Buccolam, which is approved for use in the European Union.3

Dispensing Considerations
Dispensing considerations are the same as those for nasal midazolam.

Administration
Similar to dispensing and education considerations for intranasal midazolam, patients and caregivers must be prepared to measure out the appropriate dose from the vial and administer the medication from a syringe. Buccal administration requires that caregivers transfer, by droplet, approximately half of the medication into each buccal cavity (ie, the space between the gum and the cheek).2 The pharmacist should instruct that the tip of the syringe be inserted into the buccal cavity, between the lower teeth and cheek, and the plunger pressed down to deliver approximately half of the medication into the space. This step should be repeated to deliver the remaining midazolam into the opposite buccal cavity.10,15

Additional Counseling Points and Considerations

As discussed in detail for each medication, patients should be instructed about, and demonstrate an understanding of, proper administration of the benzodiazepine prescribed to them, and what to expect following use.5 A critical element in the acute use of rescue benzodiazepines is an understanding of when administration of the medication is necessary. Generally, we can rely on 5 minutes from seizure start as the time period that warrants use of a rescue medication.14 However, this measure is highly patient-specific, and it is best practice for pharmacists to verify instructions for use with the prescriber if they are not indicated on the prescription.

Patients should be prepared for all courses of action in the event of a seizure beyond the use of their rescue medication, and the pharmacist, as an accessible provider, can play a critical role in patient preparedness. When creating this plan of action, patients and healthcare professionals should consider signs, symptoms, and types of seizures; basic first aid skills; when to administer medication; and when to call 911 or visit the emergency department.13 It is a good practice for patients to keep a record of seizure occurrence and medication use in case of emergency. See the Table for a customizable seizure preparedness guide; this preparedness guide can also be used to educate other caretakers who supervise the child. Parents of a child with epilepsy should consider situations where this may be a concern, such as at school or daycare, and when the child is with a babysitter, and ensure that the caregiver is prepared and comfortable with the child’s plan for seizure management.17

Lastly, when dispensing these controlled substances, it is advisable to provide patients with information regarding the proper disposal of unused medications. Ideally, diazepam and midazolam should be disposed of at a local collector registered with the Drug Enforcement Administration (Table).18 Patients may also be encouraged to take advantage of drug take-back programs in their area. If these methods are not readily available or convenient, patients may be advised to flush these medications down the sink while running hot water, because it is considered unsafe to dispose of them in the trash. Pharmacists should emphasize this point, because these controlled substances are dangerous if not used as prescribed, and have a high potential for abuse within the home.

Summary

Clinical evidence demonstrates that all 3 benzodiazepines available for acute seizure management in the community are safe and effective options for pediatric patients.1,3 Choice of therapy will often come down to patient and prescriber preference, as well as other factors, such as cost and availability. Pharmacists play a critical role in the optimization of at-home seizure management for these patients, and can significantly reduce risks of hospitalization and injury. Upon dispensing, care should be taken to ensure appropriate weight-based dosing, detailed instructions, and all necessary equipment have been provided, and that a preparedness plan has been discussed.




References

  1. Holsti M, Dudley N, Schunk J, et al. Intranasal mi­dazolam vs rectal diazepam for the home treatment of acute seizures in pediatric patients with epilepsy. Arch Pediatr Adolesc Med. 2010;164:747-753.
  2. Lexi-Comp Online, Lexi-Drugs Online, Hudson, OH: Lexi-Comp, Inc; 2015; June 24, 2015.
  3. Anderson M. Buccal midazolam for pediatric convulsive seizures: efficacy, safety, and patient acceptability. Patient Prefer Adherence. 2013;7:27-34.
  4. Humphries LK, Eiland LS. Treatment of acute seizures: is intranasal midazolam a viable option? J Pediatr Pharmacol Ther. 2013;18:79-87.
  5. Ulgey A, Aksu R, Bicer C. Nasal and buccal treatment of midazolam in epileptic seizures in pediatrics. Clin Med Insights Pediatr. 2012;6:51-60.
  6. Wilson MT, Macleod S, O’Regan ME. Nasal/buccal midazolam use in the community. Arch Dis Child. 2004;89:50-51.
  7. Shah MI, Macias CG, Dayan PS, et al. An evidence-based guideline for pediatric prehospital seizure management using GRADE methodology. Prehosp Emerg Care. 2014;18(Suppl 1):15-24.
  8. Kälviäinen R. Intranasal therapies for acute seizures. Epilepsy Behav. 2015;49:303-306.
  9. Bhattacharyya M, Kalra V, Gulati S. Intranasal mi­dazolam vs rectal diazepam in acute childhood seizures. Pediatr Neurol. 2006;34:355-359.
  10. McIntyre J, Robertson S, Norris E, et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomized controlled trial. Lancet. 2005;366:205-210.
  11. Fişgin T, Gurer Y, Teziç T, et al. Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study. J Child Neurol. 2002;17:123-126.
  12. Epilepsy Foundation. www.epilepsy.com. Accessed September 11, 2015.
  13. Diastat (diazepam rectal gel) [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America; 2014.
  14. Pascual FT, Hoang K, Hollen C, et al. Outpatient education reduces emergency room use by patients with epilepsy. Epilepsy Behav. 2015;42:3-6.
  15. Morgan HB, Miller GS. Home management of breakthrough seizures. In: Maria BL, ed. Current Management in Child Neurology. 4th ed. Shelton, CT: People’s Medical Publishing House - USA; 2008:148-152.
  16. Committee for Medicinal Products for Human Use. Buccolam. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002267/WC500112312.pdf. Published 2011. Accessed September 11, 2015.
  17. Frost S, Crawford P, Mera S, Chappell B. Implementing good practice in epilepsy care. Seizure. 2003;12:77-84.
  18. Office of Diversion Control. National take-back initiative. http://deadiversion.usdoj.gov/drug_disposal/takeback/index.html. Accessed September 11, 2015.
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