A Brief Introduction to Intranasal Medications

Joseph Lewis, M.D.Medical Director,

Honolulu EMS 2009

Intranasal Medications in the Prehospital Setting

WHY?

The problem!

• The CDC estimates: o600,000 percutaneous injuries each year involving contaminated sharps.

High Risk Patients in the field!

HIV+ patients = 4.1 to 8.3/100 transportsMarcus et al, Ann Em Med, 1995 *Hepatitis >10 patients /100 patients

• High risk environmentsoAltered patients, combativeoScene control issuesoMoving ambulance

Intranasal Medication Administration

• Intranasal Medication administration offers a truly “Needleless” solution to drug delivery.

Intranasal Medication Administration: Basic Concepts

Its easy and convenient because… • Almost everyone has a nose • No special training is required to deliver the

medication• No shots are needed• It is painless• It eliminates any risk of a needle stick to

you, the medical provider

Intranasal Medication Administration: Factors Affecting Drug Absorption

• Volume and concentration:• Best: Low volume & High concentration.• Too large a volume or too weak a

concentration may lead to failure because the drug cannot be absorbed in high enough quantity to be effective.

• Volumes over 1 ml per nostril are likely too dilute and may result in runoff out of the nostril.

Intranasal Medication Administration: Factors Affecting Drug Absorption

• Delivery system characteristics: oAtomization results in higher

bioavailability than either spray or drops.

oFor this reason, nasal drugs must use an atomized drug delivery system.

Intranasal Medication Administration: Factors Affecting Drug Absorption

• Nasal mucosal characteristics:o If there is something wrong with the nasal

mucosa it may not absorb medications effectively.

o Examples: Vasoconstrictors like cocaine prevent

absorption. Bloody nose, nasal congestion, mucous

discharge all can prevent mucosal contact of drug.

Destruction of nasal mucosa from surgery or cocaine abuse – no mucosa to absorb the drug.

Mucosal Atomization Device (MAD)

• MAD - Mucosal Atomization device:o Device designed to

allow emergency personnel to delivery nasal medications as an atomized spray.

o Broad 30-micron spray ensure excellent mucosal coverage.

Nasal Drug Delivery: What Medications?

• FDA approved: o A large number of medications ranging from

nasal steroids to antibiotics to opiate anesthetics are FDA approved.

• Non-FDA approved: o Many other medications are effective via the

nasal mucosa, but the pharmaceutical companies have not pursued FDA clearance for nasal delivery for a number of financial reasons as opposed to medical reasons.

Nasal Drug Delivery in EMS: What Medications?

• Drugs of interest to EMS systems:o Intranasal naloxone (Narcan)o Intranasal midazolam (Versed)o Nitroglycerineo Others

Intranasal (IN) Naloxone

• Backgroundo Absorption of IN naloxone almost as fast as

IV in both animal and human models Hussain et al, Int J Pharm, 1984 Loimer et al, Int J Addict, 1994 Loimer et al, J Psychiatr Res, 1992

o “Atomization” of medications show much better absorption via the IN route then IV

Thorsson et al, Br J Clin Pharmacol, 1999

The Denver Experience…

• Denver Health Paramedic Systemo Administering 600-800 doses of

naloxone (Narcan®) a year intravenously to patients

o Sheathed needles were not used properly

o No change in incidence of bloodborne exposures

Prehospital IN Naloxone

• Mucosal Atomizer Device (MAD)oSingle-useoDisposable oFits on standard syringe

Mucosal Atomizer Device (MAD)

The white plastic you see on this standard 2cc luer lock syringe is the atomizer and it costs about 23 cents.

IN Naloxone by Paramedics

IN Naloxone by Paramedics

Prehospital IN Naloxone• Results (cont.).

o 43/52 (83%) = “IN Naloxone Responders.” Mean time = 3.9 minutes (range 1-11 min.). Median time = 3 min. Mean time from first contact = 9.9 min. Median time from first contact = 8 min.

o 9/52 (17%) = “IN Non-responders.” 4 patients noted to have “epistaxis,” “trauma,”

or “septal abnormality.”

Prehospital IN Naloxone

• Results (cont.)o IN Naloxone Responders

12/43 (29%) got no IV in the field

7/43 (16%) required additional dose of IV naloxone “leakage from L nares” “aroused slowly” “recurrent somulence” “2mg IV given due to slow response” “lower IN dose - spilled filling syringe” “pt responded within 90-120 sec, but still had

decr LOC

Prehospital IN Naloxone

• Take away lessons for nasal naloxone: Dose and volume – higher concentration preferred so

use 1mg/ml IV solution. Delivery – immediately on decision to treat inject

naloxone into nose with MAD, then begin standard care.

Successful awakening eliminates the need for any IV or further ALS care.

Awakening is gradual, but adequate respiratory efforts occur as fast or faster than IV naloxone due to no delays with IV start.

Not 100% effective so failures with IN naloxone need to be followed with IV naloxone.

Prehospital IN Midazolam

• Why intranasal midazolam for seizures in the EMS setting?o No needles, no need for an IV in a seizing

patient.o Rapid delivery – No delays in IV attempts.o Socially acceptable: No need for rectal drug

administration.

IN Midazolam

• Supporting data:oNasal midazolam has been extensively

studied for over a decade with hundreds of studies published regarding its effectiveness for sedating children.

oVery effective for treating acute seizures and status epilepsy.

IN Midazolam

• Seizures.o Lahat et al, BMJ, 2000.

Prospective study: IN midazolam versus IV diazepam for prolonged seizures (>10 minutes) in children.

Similar efficacy in stopping seizures (app. 90%).

Time to seizure cessation: IV Valium: 8.0 minutes. IN Versed: 6.1 minutes.

IN Midazolam

• Lahat et al, BMJ, 2000 (cont):o Conclusions:

IV diazepam and IN midazolam have similar efficacy at controlling prolonged seizures in children.

IN midazolam controls seizures more rapidly because there is no delay in establishing an IV.

IN Midazolam

• Sheepers et al, Seizure, 2000. IN midazolam for treatment of severe epilepsy

in adults. Results: IN midazolam effective in 94% of

seizures. Conclusion: IN midazolam an effective method for

controlling seizures and is a “more acceptable and dignified route” than rectal diazepam.

IN MidazolamTake away lessons for nasal midazolam:• Dose and volume: Higher concentration

required - use 5mg/ml IV solution.• Dosing calculations are difficult: Use a

predefined age or weight based table to determine dose.

• Give max of 1 ml per nostril and 10 mg total.Give max of 1 ml per nostril and 10 mg total.• Deliver immediately on decision to treat:

Atomize into nose with MAD, then begin standard care.

• Efficacy: Not quite 100% effective so failures with nasal may need follow-up with IV therapy.

Dosage ChartsMidazolam 5mg/ml concentration Dosing chartTotal kg wt X 0.2 mg = total mg dose of Midazolam (maximum of 10 mlPatient age (years) Weight (kg) IN Midazolam volume in ml* Volume        Dose (mg)

Neonate 3  kg 0.3 ml             0.6 mg<1  yr 6  kg 0.4 ml             1.2 mg1  yr 10  kg 0.5ml              2.0 mg2  yr 14  kg 0.7 ml             2.8 mg3  yr 16  kg 0.8 ml             3.2 mg4  yr 18  kg 0.9 ml             3.6 mg5  yr 20  kg 1.0 ml             4.0 mg 6  yr 22  kg 1.0 ml             4.4 mg7  yr 24  kg 1.1 ml             4.8 mg8  yr 26  kg 1.2 ml             5.2 mg9  yr 28  kg 1.3 ml             5.6 mg10  yr 30  kg 1.4 ml             6.0 mg11  yr 32  kg 1.4 ml             6.4 mg12  yr 34  kg 1.5 ml             6.8 mgSmall teenager40  kg 1.8 ml             8.0 mgAdult or full-grown teenager> 50 kg 2.0 ml            10.0 mg

Example Standing orders IN Medications Hawaii State EMS

• Midazolam intranasal IN for seizure• Dose 0.2 mg/kg IN up to maximum of 10 mgup to maximum of 10 mg• Drug comes 5mg/ml• Patient weights 20 kg• Calculated Dose 4 mg versed• Give 0.8 ml via atomizer in one nare, which is

under the maximum of 1 ml per nare.

Example Standing orders IN Medications Hawaii State EMS

• Midazolam intranasal IN for seizure• Dose 0.2 mg/kg IN• Drug comes 5mg/ml• Patient weights 40 kg• Calculated Dose 8 mg versed• Give 1.6 ml via atomizer, 0.8 ml in each nare,

remembering that the desired upper limit is 1 ml per nostril.

Example Standing orders IN Medications Hawaii State EMS

• Midazolam intranasal IN for seizure• Dose 0.2 mg/kg IN• Drug comes 5mg/ml• Patient weights 80 kg• Calculated Dose 16 mg so give max dose of

10 mg only!• Give 2 ml via atomizer, 1 ml in each nare.

Dosage Charts Midazolam 5mg/ml concentration Dosing chartTotal kg wt X 0.2 mg = total mg dose of Midazolam (maximum of 10 mlPatient age (years) Weight (kg) IN Midazolam volume in ml* Volume        Dose (mg)

Neonate 3  kg 0.3 ml             0.6 mg<1  yr 6  kg 0.4 ml             1.2 mg1  yr 10  kg 0.5ml              2.0 mg2  yr 14  kg 0.7 ml             2.8 mg3  yr 16  kg 0.8 ml             3.2 mg4  yr 18  kg 0.9 ml             3.6 mg5  yr 20  kg 1.0 ml             4.0 mg 6  yr 22  kg 1.0 ml             4.4 mg7  yr 24  kg 1.1 ml             4.8 mg8  yr 26  kg 1.2 ml             5.2 mg9  yr 28  kg 1.3 ml             5.6 mg10  yr 30  kg 1.4 ml             6.0 mg11  yr 32  kg 1.4 ml             6.4 mg12  yr 34  kg 1.5 ml             6.8 mgSmall teenager40  kg 1.8 ml             8.0 mgAdult or full-grown teenager> 50 kg 2.0 ml            10.0 mg