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: 600,000 percutaneous injuries each year involving contaminated sharps.

High Risk Patients in the field! HIV+ patients = 4.1 to 8.3/100 transports Marcus et al, Ann Em Med, 1995 *Hepatitis >10 patients /100 patients High risk environments Altered patients, combative Scene control issues Moving 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: Atomization results in higher bioavailability than either spray or drops. For this reason, nasal drugs must use an atomized drug delivery system.

Intranasal Medication Administration: Factors Affecting Drug Absorption Nasal mucosal characteristics: If there is something wrong with the nasal mucosa it may not absorb medications effectively. 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: Device designed to allow emergency personnel to delivery nasal medications as an atomized spray. Broad 30-micron spray ensure excellent mucosal coverage.

Nasal Drug Delivery: What Medications? FDA approved: A large number of medications ranging from nasal steroids to antibiotics to opiate anesthetics are FDA approved. Non-FDA approved: 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: Intranasal naloxone (Narcan) Intranasal midazolam (Versed) Nitroglycerine Others

Intranasal (IN) Naloxone Background 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 “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 System Administering 600-800 doses of naloxone (Narcan®) a year intravenously to patients Sheathed needles were not used properly No change in incidence of bloodborne exposures

Prehospital IN Naloxone Mucosal Atomizer Device (MAD) Single-use Disposable Fits 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.). 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. 9/52 (17%) = “IN Non-responders.” 4 patients noted to have “epistaxis,” “trauma,” or “septal abnormality.”

Prehospital IN Naloxone Results (cont.) 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? No needles, no need for an IV in a seizing patient. Rapid delivery – No delays in IV attempts. Socially acceptable: No need for rectal drug administration.

IN Midazolam Supporting data: Nasal midazolam has been extensively studied for over a decade with hundreds of studies published regarding its effectiveness for sedating children. Very effective for treating acute seizures and status epilepsy.

IN Midazolam Seizures. 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): 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 Midazolam Take 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. 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 Charts Midazolam 5mg/ml concentration Dosing chart Total kg wt X 0.2 mg = total mg dose of Midazolam (maximum of 10 ml Patient 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 mg 1  yr 10  kg 0.5ml              2.0 mg 2  yr 14  kg 0.7 ml             2.8 mg 3  yr 16  kg 0.8 ml             3.2 mg 4  yr 18  kg 0.9 ml             3.6 mg 5  yr 20  kg 1.0 ml             4.0 mg 6  yr 22  kg 1.0 ml             4.4 mg 7  yr 24  kg 1.1 ml             4.8 mg 8  yr 26  kg 1.2 ml             5.2 mg 9  yr 28  kg 1.3 ml             5.6 mg 10  yr 30  kg 1.4 ml             6.0 mg 11  yr 32  kg 1.4 ml             6.4 mg 12  yr 34  kg 1.5 ml             6.8 mg Small teenager 40  kg 1.8 ml             8.0 mg Adult 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 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 chart Total kg wt X 0.2 mg = total mg dose of Midazolam (maximum of 10 ml Patient 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 mg 1  yr 10  kg 0.5ml              2.0 mg 2  yr 14  kg 0.7 ml             2.8 mg 3  yr 16  kg 0.8 ml             3.2 mg 4  yr 18  kg 0.9 ml             3.6 mg 5  yr 20  kg 1.0 ml             4.0 mg 6  yr 22  kg 1.0 ml             4.4 mg 7  yr 24  kg 1.1 ml             4.8 mg 8  yr 26  kg 1.2 ml             5.2 mg 9  yr 28  kg 1.3 ml             5.6 mg 10  yr 30  kg 1.4 ml             6.0 mg 11  yr 32  kg 1.4 ml             6.4 mg 12  yr 34  kg 1.5 ml             6.8 mg Small teenager 40  kg 1.8 ml             8.0 mg Adult or full-grown teenager > 50 kg 2.0 ml            10.0 mg