Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Recommendations

The working group consensus follows the Department of Health and Human Services PHEMCE Product Specific Requirements for new MCMs for nerve agent poisoning. The working group also agreed with repurposing of available drug formulations as nerve agent MCMs, using novel routes of administration, in line with the 2007 and 2011 PHEMCE requirements and procurement strategy.

The PHEMCE requirement document contains product-specific threshold criteria for new antimuscarinic MCMs:

1. (1) Centrally acting antimuscarinic agents, which more easily cross the blood-brain barrier than atropine

2. (2) Inhaled antimuscarinic (eg, dry powdered inhaled atropine) for delivery directly to the lungs to better treat both bronchorrhea and bronchoconstriction

3. (3) Effective antimuscarinics with a longer half-life

In summary, PHEMCE MCM strategy includes (a) new formulations of existing MCMs (parenteral atropine, parenteral diazepam), which are more easily administered or more readily absorbed; and (b) effective MCMs that can be used by untrained persons at risk, via intranasal or inhaled routes, and by first responders dealing with large numbers of exposed individuals. Table 3 describes the key advantages of (a) the contingency routes of administration and (b) the contingency pharmaceutical agents discussed in detail in the following sections.

Table 3

Advantages of Contingency Medical Countermeasures for NA Poisoning

IN – intranasal; IO – intraosseous; IM – intramuscular; IV – intravenous; IP – intraperitoneal; CNS – central nervous system; HCF – healthcare facility; MDI – metered-dose inhaler; SE – status epilepticus; SD – standard deviation; GI – gastrointestinal; RAD – reactive airways disease (asthma); C_max – peak plasma concentration; T_max – time post-administration to reach peak plasma concentration; mAchR – muscarinic acetylcholine receptor (where M# denotes receptor subtype/tissue distribution)

Ophthalmic Atropine Solution Administered Sublingual

Atropine sulfate ophthalmic solution, United States Pharmacopeia (USP) 1%, is an extremely potent formulation: each milliliter contains 10 mg of atropine sulfate. Investigators injected 2 mg/0.1 mL of atropine (2%) sublingually in 6 volunteers. Within 10 minutes, the sublingual administration resulted in a greater serum concentration (14 ng/mL) than the therapeutic peak of 6 to 8 ng/mL obtained with a 2-mg intramuscular dose at 30 minutes.Reference Rajpal¹⁴ That study does not directly inform our intended use of high concentration ophthalmic atropine preparations for sublingual administration by instillation of drops, nor do we advocate sublingual injection of atropine. However, the study highlights the rapid absorption and improved kinetics from the sublingual space compared with intramuscular administration into the vastus lateralis muscle of the thigh.

In practice, sublingual atropine drops have been used effectively in children (n=23) with severe sialorrhea.Reference Norderyd, Graf and Marcusson¹⁵ One drop of 1% atropine ophthalmic (10 mg/mL or approximately 1 mg) was administered sublingually once a day for 4 weeks, followed by twice a day for 4 weeks for palliation of drooling to improve perioral skin integrity and hygiene. Subjective improvement in drooling was reported by parents/caregivers on a visual analog scale; unstimulated saliva production in milliliters per minute (adsorbed to intraoral cotton balls that were weighed) significantly (P=0.032) decreased from baseline to the end of the study. The same approach has been used in cases of severe sialorrhea due to clozapine use.Reference Comley, Galletly and Ash¹⁶

Intranasal atropine administration may be an alternative route if an effective delivery device is used with a sufficiently concentrated preparation. Rajpal et alReference Rajpal¹⁴ administered 6 mg of atropine (0.6 mL) and 0.5% chitosan to 6 healthy supine adults by means of a nasal catheter to reach the posterior nasopharynx. The viscosity of the mixture was 14.465+0.17 pascal seconds, and clinically relevant blood concentrations of 8 ng/mL were reached in 5 minutes with a maximum concentration (C_max) of 49 ng/mL at 30 min. Chitosan is a bioadhesive polymer that improves mucosal absorption. In a parallel in vitro model of absorption using rat large intestinal mucosa, the authors showed their formulation’s cumulative drug release to be 0.684 mg/cm² over 90 minutes, two-thirds (0.4 mg) of which occurred in the first 30–35 minutes before a plateau was reached. Based on these data, the authors estimated the bioavailability of atropine/0.5% chitosan to be 0.40 with an improved time to therapeutic blood concentration and higher C_max than that with intramuscular administration.¹⁷

Also informative to the effectiveness of absorption from the nasal cavity are several case reports of iatrogenic systemic absorption of eye drops and one intraocular pharmacokinetic study documenting systemic absorption.Reference Kaila, Korte and Saari^11, Reference Shiuey and Eisenberg¹² In 6 volunteers, 30 µL of 1% atropine (0.3 mg) administered as an intraocular drop had a mean bioavailability of 0.63, and a mean C_max of 288 pg/mL at a mean time to maximum concentration (T_max) of 27 min.Reference Kaila, Korte and Saari¹¹ Absorption from the nasal mucosa after transiting the nasolacrimal duct was demonstrated in this study by Kaila et al,Reference Kaila, Korte and Saari¹¹ but volume limitations of the canthal space resulted in a delay in reaching T_max. The use of dilating eye drops in the outpatient setting for sustained miosis has been described in a human trial; 6 healthy volunteers exposed to sarin vapor (0.5 mg/m³ for 30 min) received 60 ul of 1% cyclopentolate intraocular.Reference Moylan-Jones and Thomas¹⁸ The authors did not note improvement in visual acuity, refraction, or pupil diameter, but concluded that full dark adaptation (preservation of night vision – a military consideration) or distressing ocular symptoms (pain) might be indications. In a real-world incident, miosis refractory to systemic antimuscarinic therapy is a significant impairment after nerve agent exposure, and mydriatic eye drops are effective therapy. Kato et alReference Kato and Hamanaka¹⁹ treated 96 patients for prolonged miosis with 0.5% ophthalmic tropicamide gtt for 3 to 21 days after the 1995 Tokyo subway sarin attack.

Ophthalmic Cyclopentolate Solution Administered Sublingual

Cyclopentolate 1% (1 mL=10 mg) is less potent than atropine but is centrally acting. One percent atropine ophthalmic preparations has been studied for pharmacokinetic profiles via the sublingual and intranasal routes, and 2 studies have examined 3 ophthalmic formulations of various potencies for efficacy against organophosphate pesticide-poisoned rats. Bryant et alReference Bryant, Rhee, Thompson and Aks²⁰ treated 40 rats (n=10 per group saline control, 0.3 mL; atropine sulfate solution, 10 mg/kg of body weight; 1% ophthalmic atropine, 10 mg/kg of body weight; 1% homatropine, 20 mg/kg of body weight) with intraperitoneal drug 10 minutes before an LD₅₀ dose of dichlorvos (10 mg/kg subcutaneous). Survival at 120 minutes (study end point) was 10/10 for atropine sulfate solution, 10/10 with 1% ophthalmic atropine preparation, 9/10 for homatropine, and 2/10 for the control group.Reference Bryant, Rhee, Thompson and Aks²⁰ A subsequent study by the same authors (2009) compared atropine 10 mg/kg, 1% tropicamide 20 mg/kg, and 1% cyclopentolate 20 mg/kg administered intraperitoneally 5 minutes before 15 mg/kg of dichlorvos was given subcutaneously. Survival was 90% in each treatment group (atropine, tropicamide, cyclopentolate) and 10% in controls. In addition to the comparative efficacy results, the authors emphasize the practicality of using high concentration ophthalmic antimuscarinic preparations as a high-capacity contingency: a 15-mL bottle of 1% concentration contains 150 mg of antimuscarinic agent. In their emergency department, the authors identified 125 mg of parenteral atropine in drug-dispensing cabinets and “crash” carts, and 40,000 mg of antimuscarinic agent collectively in ophthalmology preparations.Reference Bryant, Rhee and Thompson²¹

Parenteral Glycopyrrolate

Glycopyrrolate is 2–3 times as potent as atropine in reducing oral and respiratory secretions.Reference Mirakur, Jones and Dundee^22, Reference Gomez, Bellido, Sanchez and de la Cuesta^23, Reference Robenshtok, Luria, Tashema and Hourvitz²⁴ Glycopyrrolate is considered a non-selective parenteral muscarinic acetylcholine receptor antagonist used to dry secretions during operative procedures. However, glycopyrrolate may have a lower affinity at muscarinic-2 receptors and induce less tachycardia than atropine.Reference Gomez, Bellido, Sanchez and de la Cuesta²³ Glycopyrrolate does not cross the placenta and may be the antimuscarinic of choice in late-term pregnancy for organophosphate or nerve agent intoxication.Reference Robenshtok, Luria, Tashema and Hourvitz²⁴ There are 2 unblinded studies showing comparative efficacy of equipotent doses of atropine and glycopyrrolate in organophosphate poisoning.Reference Bardin and Van Eeden^25, Reference Arendse and Irusen²⁶ In 44 human pesticide poisoning cases randomized to either drug, there was no difference in outcome, intubation, or length of stay.Reference Bardin and Van Eeden²⁵ Arendse et alReference Arendse and Irusen²⁶ treated 53 human cases of organophosphate poisoning (2 fatal) with a combination of atropine and an equipotent dose of glycopyrrolate; the authors demonstrated a significant reduction in the incidence (12.2%) of central antimuscarinic toxicity when using glycopyrrolate versus their historical hospital experience treating organophosphate poisoning with atropine alone. Ali-Melkkila et al^17, Reference Ali-Melkkila, Kaila and Kanto²⁷ studied the pharmacokinetics of intramuscular (deltoid) glycopyrrolate in 6 ocular surgery patients: after 0.008 mg/kg intramuscularly, the T_max was 27.48±6.12 minutes with a predictable anti-secretory response; the C_max was 3.47±1.48 ug/L. The study included a third arm (n=6) dosed with 4 mg po; the absorption was so variable and the onset of clinical effects so unpredictable that the gastrointestinal route of administration is a poor pharmacokinetic/pharmacodynamic-based choice for administration.Reference Ali-Melkkila, Kaila and Kanto²⁷ Kaila et alReference Kaila, Ali-Melkkila, Lisalo and Kanto²⁸ dosed 3 gynecological surgery patients receiving spinal and epidural anesthesia with 0.008 mg/kg glycopyrrolate intramuscularly (deltoid); mean T_max=13.3 (10–15 minutes) and C_max=14.26 (12.02–16.97) µg/L. Cerebrospinal fluid concentrations were not detected with an assay level of detection of 140 ng/L.Reference Kaila, Ali-Melkkila, Lisalo and Kanto²⁸

Oral Propantheline

Propantheline bromide has a 1 to 1.25 times higher binding affinity than atropine at the muscarinic receptor and varies slightly by receptor subtype (M1-M4).Reference Huang, Buchwald and Browne²⁹ Propantheline has FDA indications for the treatment of peptic ulcer disease and hyperhidrosis; however, a parenteral formulation of propantheline is no longer produced. The absorption half-life after oral dosing is 8–30 minutes, C_max was 29 ng/mL, and the T_max was 3 hours (mean; n=6 healthy volunteers) after 30 mg po with a duration of effect of 4–6 hours.³⁰ Propantheline has not been studied as an oral MCM for mild nerve agent poisoning. Supplies of propantheline in a pharmacy or community are likely to be limited because of its infrequent use. Its pharmacokinetics after oral dosing might make a dose of propantheline an alternative treatment for patients with only mild symptoms (eg, sialorrhea, rhinorrhea, lacrimation, gastrointestinal cramping due to enhanced peristalsis), who might otherwise be treated with a single 2-mg dose of atropine, while they are observed for symptom progression.

Inhaled Ipratropium

The 200 inhalation unit dose of ipratropium bromide has a net weight of 12.9 g. After priming, each actuation of the inhaler delivers 21 µg of ipratropium bromide from the valve in 56 mg of solution and delivers 17 µg of ipratropium bromide from the mouthpiece.³¹ Ipratropium acts as an antimuscarinic at the neuromuscular junctions in the lung. The half-life of elimination is about 2 hours after inhalation. In 1 study, soman-exposed rats had improved minute ventilation and reduced lung edema after 21 µg of ipratropium, 120 µg of albuterol, 80 µg of budesonide, and 4.5 µg of formoterol administered 10 minutes after exposure; however, no effect on lethality was shown.Reference Perkins, Wong and Rodriguez³²

Inhaled Tiotropium

Tiotropium bromide has 23 times the potency of ipratropium for bronchodilation.Reference Barnes³³ Antimuscarinic blockade half-life is 540 minutes versus 81 minutes for ipratropium. Each inhaler actuation contains a dry powder consisting of 18 µg tiotropium (equivalent to 22.5 µg of tiotropium bromide monohydrate) blended with lactose monohydrate (which may contain milk proteins and therefore a risk for lactose-intolerant persons).Reference Barnes³³

Parenteral Midazolam

Midazolam is a lipid-soluble benzodiazepine that works as an agonist at the GABA-_A receptor and possesses anticonvulsant and sedative effects, as documented by pharmacokinetic data presented later.Reference Wermeling, Record and Kelly³⁴ Traditional routes of administration for midazolam are intravenous and intramuscular, and studies have demonstrated absorption and efficacy of intranasal administration. The data we present focus on the pharmacokinetics of anticonvulsant activity where applicable for the intramuscular and intranasal routes.

In a study by Wermeling et alReference Wermeling, Record and Kelly³⁴, intranasal midazolam was compared with intramuscular and intravenous formulations. The study used an open-label, 3-way crossover (separated by 1 week) design, comparing a 5-mg intravenous infusion over 15 minutes with 5 mg given intramuscularly and 5 mg given via the intranasal route. The median time to T_max was 10.3 min with intranasal administration, 12.4 minutes with intravenous, and 29.2 minutes with intramuscular. The C_max was 167 ng/mL with intravenous administration, 80 ng/mL with intranasal, and 59 ng/mL with intramuscular. Thus, although T_max was reached sooner with the drug given via the intranasal route, the intravenous route yielded a higher C_max. T_max and C_max were higher for the intravenous and intranasal formulations than for the intramuscular formulation. Bioavailability was 93% for intramuscular and 72% for intranasal administration compared with an assumed 100% for intravenous administration.Reference Wermeling, Record and Kelly³⁴ Although midazolam given via the intravenous route took longer to reach T_max than when given via the intranasal route, the concentration of midazolam given by either route was essentially the same at 5 minutes.Reference Wermeling, Record and Kelly³⁴

Another study by Bhattacharyya et alReference Bhattacharyya, Kalra and Gulati³⁵ compared the efficacy of intranasal midazolam with rectal diazepam for the prevention of seizures. In their study, in 46 children who had a total of 188 seizure episodes, 0.3 mg/kg of intranasal midazolam was superior to 0.2 mg/kg of rectal diazepam in terminating seizures within 10 minutes of drug administration, and the time to seizure cessation was 117±127 seconds for intranasal midazolam versus 178±179 seconds for rectal administration (P=0.005).Reference Bhattacharyya, Kalra and Gulati³⁵

The pivotal trial that investigated the efficacy of intramuscular midazolam was that of Silbergleit et al,Reference Silbergleit, Durkalski and Lowenstein³⁶ in which intramuscular midazolam was compared with intravenous lorazepam in the treatment of prehospital status epilepticus in adults and children. All patients weighing over 40 kg were randomized to either 10 mg intramuscular midazolam followed by a placebo infusion, or an intramuscular placebo injection followed by a 4-mg lorazepam infusion; patients 13–40 kg were given 5 mg of midazolam or 2 mg of lorazepam as previously. The study found that 73.4% of the midazolam group arrived at the emergency department without evidence of ongoing seizure compared with 63.4% in the lorazepam group. The median time to treatment was 1.2 minutes for the intramuscular midazolam group versus 4.8 minutes in the lorazepam group. Rates of endotracheal intubation and adverse effects were similar in the 2 groups.Reference Silbergleit, Durkalski and Lowenstein³⁶

McDonough et alReference McDonough, McMonagle and Copeland³⁷ compared 6 separate benzodiazepines in guinea pigs with status epilepticus induced by the nerve agent, soman. The drugs were given at the 5- and 40-minute mark. All benzodiazepines terminated convulsions, but midazolam was the most potent and rapid acting in terminating seizures at both times.Reference McDonough, McMonagle and Copeland³⁷

Intranasal Lorazepam

Lorazepam, like midazolam, is a lipid-soluble benzodiazepine that is an agonist at the GABA-_A receptor. Traditional routes of administration are intravenous and intramuscular, but reports support its use via the intranasal route. (Even rectal administration has been evaluated in human subjects; however, slow absorption has limited the drug’s usefulness when administered rectally.Reference Graves, Kriel and Jones-Saete³⁸)

In a study by Wermeling et alReference Wermeling, Miller and Archer³⁹, 11 healthy volunteers underwent an open, 3-arm crossover study in which each volunteer received 2 mg of lorazepam via intravenous, intramuscular, or intranasal routes after adequate washout periods between each administration. The median T_max for intravenous lorazepam was 6 (range 4.9–60) minutes; for intranasal, 30 (range 15–120) minutes; and for intramuscular, 180 (range 30–480) minutes. The C_max was 47.6 ng/mL for intravenous lorazepam, 22.6 ng/mL for intramuscular lorazepam, and 21.4 ng/mL for intranasal lorazepam. Bioavailability was 100% for intramuscular lorazepam and 78% for intranasal lorazepam, compared with an assumed 100% bioavailability for intravenous administration.Reference Wermeling, Miller and Archer³⁹ Thus, intranasal lorazepam yielded a C_max similar to intramuscular lorazepam, but it reached the C_max significantly earlier. However, because of less bioavailability with the intranasal route, the area under the curve still favored the intramuscular route.Reference Wermeling, Miller and Archer³⁹ Therefore, the clinician must weigh the importance of achieving rapid C_max versus total drug absorbed. The authors did not find a trial that directly compared intramuscular lorazepam with intranasal midazolam.

Parenteral Diazepam

Diazepam also is a benzodiazepine that is active at the GABA-_A receptor. As mentioned in the Working Group consensus (see Table 4), all parenteral benzodiazepines can terminate convulsions caused by a nerve agent. Historically, when AIs of benzodiazepines were introduced for the treatment of nerve-agent exposure, the benzodiazepine that was FDA-approved for the treatment of status epilepticus was diazepam, given intravenously. It followed that diazepam could be packaged in an AI for the treatment of nerve agent-induced convulsions.Reference McDonough⁴⁰ However, intramuscular diazepam is absorbed slowly, incompletely, and erratically from the site of administration.Reference Hung, Dyck and Varvel^41, Reference Divoll, Greenblatt, Ochs and Shader⁴² In a study of healthy volunteers, 5 mg of midazolam or 10 mg of diazepam were injected into opposite deltoid muscles. The C_max was 100.5±21 ng/mL for midazolam and 199±89.3 ng/mL for diazepam. The corresponding T_max was 17.5±6.5 minutes (midazolam) versus 33.8±7.5 minutes (diazepam).Reference Hung, Dyck and Varvel⁴¹ Intramuscular absorption was significantly more variable for diazepam than for midazolam.Reference Divoll, Greenblatt, Ochs and Shader⁴² Diazepam can be administered rectally, but the plateau state was reached more slowly than with midazolam given via the intramuscular route.Reference Rey, Tréluyer and Pons⁴³

As stated previously, intramuscular midazolam terminated soman-induced convulsions more rapidly than did other benzodiazepines, including diazepam, in guinea pigs.Reference McDonough, McMonagle and Copeland³⁷ This observation has led to a preference of intramuscular midazolam over intramuscular diazepam for the treatment of nerve-agent convulsions, despite the historical use of AI diazepam. Although diazepam AIs remain the conventional NA anticonvulsant stockpiled for the military and in national stockpile caches, additional pharmacokinetic studies support the opinion that intramuscular diazepam is not necessarily the foremost option for treatment of nerve agent-induced convulsions if intramuscular midazolam and intramuscular lorazepam are also available.