BENZODIAZEPINES

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Alprazolam (synonym)
2) Brotizolam (synonym)
3) Chlordiazepoxide (synonym)
4) Clobazam (synonym)
5) Clonazepam (synonym)
6) Clorazepate (synonym)
7) Diazepam (synonym)
8) Estazolam (synonym)
9) Flunitrazepam (synonym)
10) Flurazepam (synonym)
11) Halazepam (synonym)
12) Lorazepam (synonym)
13) Lormetazepam (synonym)
14) Medazepam (synonym)
15) Midazolam (synonym)
16) Nitrazepam (synonym)
17) Oxazepam (synonym)
18) Pinazepam (synonym)
19) Prazepam (synonym)
20) Temazepam (synonym)
21) Triazolam (synonym)
22) Zolazepam (synonym)
23) Black pearl (SLANG TERM) Diazepam
24) Blue bombers (SLANG TERM) Diazepam 10 mg
25) Blue boys (SLANG TERM) Valium 10 mg
26) Blue magoo's (SLANG TERM) Diazepam 10 mg
27) Blue thunder (SLANG TERM) Diazepam 10 mg
28) Bombers, blue (SLANG TERM) Diazepam 10 mg
29) Centurion (SLANG TERM) Benzodiazepine
30) Circles (SLANG TERM) Flunitrazepam (Rohypnol)
31) Date rape drug (SLANG TERM) Flunitrazepam (Rohypnol)
32) Downs (SLANG TERM) Flurazepam hydrochloride
33) Forget me drug (SLANG TERM) Flunitrazepam (Rohypnol)
34) Forget me pill (SLANG TERM) Flunitrazepam (Rohypnol)
35) Forget pill (SLANG TERM) Flunitrazepam (Rohypnol)
36) Getting roached (SLANG TERM) Using Rohypnol
37) Green and blacks (SLANG TERM) Librium capsules
38) Green apples (SLANG TERM) Libritabs
39) Jelly babies (SLANG TERM) Temazepam 20 mg capsules, the liquid is ingested orally or injected intravenously
40) La rocha (SLANG TERM) Flunitrazepam (Rohypnol)
41) Lunch money drug (SLANG TERM) Flunitrazepam (Rohypnol)
42) Magoo's, blue (SLANG TERM) Diazepam 10 mg
43) Mexican valium (SLANG TERM) Flunitrazepam (Rohypnol)
44) Pin (SLANG TERM) Clonazepam, favored by methadone patients
45) Pins (SLANG TERM) Clonazepam (Klonopin)
46) Pingus (SLANG TERM) Flunitrazepam (Rohypnol)
47) Pumpkin seeds (SLANG TERM) Benzodiazepines
48) R-2 (SLANG TERM) Flunitrazepam (Rohypnol)
49) Reynolds (SLANG TERM) Flunitrazepam (Rohypnol)
50) Rib (SLANG TERM) Flunitrazepam (Rohypnol)
51) Roach (SLANG TERM) Flunitrazepam (Rohypnol)
52) Roaches (SLANG TERM) Flunitrazepam (Rohypnol)
53) Roachies (SLANG TERM) Flunitrazepam (Rohypnol)
54) Robutal (SLANG TERM) Flunitrazepam (Rohypnol)
55) Rochas dos (SLANG TERM) Flunitrazepam (Rohypnol)
56) Roche (SLANG TERM) Flunitrazepam (Rohypnol)
57) Roches (SLANG TERM) Benzodiazepines
58) Roach-2 (SLANG TERM) Flunitrazepam (Rohypnol)
59) Roapies (SLANG TERM) Flunitrazepam (Rohypnol)
60) Rohypnol-date rape drug (SLANG TERM) Flunitrazepam (Rohypnol)
61) Roofie (SLANG TERM) (Rohypnol)
62) Roofies (SLANG TERM) Flunitrazepam (Rohypnol)
63) Rope (SLANG TERM) Flunitrazepam (Rohypnol)
64) Rophies (SLANG TERM) Flunitrazepam (Rohypnol)
65) Rophy (SLANG TERM) Flunitrazepam (Rohypnol)
66) Ropies (SLANG TERM) (flunitrazepam (Rohypnol)
67) Roples (SLANG TERM) Flunitrazepam (Rohypnol)
68) Row-shay (SLANG TERM) Flunitrazepam (Rohypnol)
69) Ruffes (SLANG TERM) Flunitrazepam (Rohypnol)
70) Ruffies (SLANG TERM) Flunitrazepam (Rohypnol)
71) Ruffles (SLANG TERM) Flunitrazepam (Rohypnol)
72) Thunder, blue (SLANG TERM) Diazepam 10 mg
73) Valleys (SLANG TERM) Valium
74) V - Valium (Roche) (SLANG TERM) diazepam
75) Wolfies (SLANG TERM) Flunitrazepam (Rohypnol)
76) Yellow eggs (SLANG TERM) Temazepam 20 mg capsules, the liquid is ingested orally or injected IV

Available Forms Sources

DRUG NAME	DOSAGE FORMS
Alprazolam	0.25, 0.5, 1 & 2 mg tablets
Bromazepam	1.5, 3 & 6 mg tablets
Chlordiazepoxide	5, 10 & 25 mg capsules; 100 mg injection
Clonazepam	0.5, 1 & 2 mg tablets
Clorazepate	3.75, 7.5 & 15 mg tablets and capsules
Diazepam	2, 5 & 10 mg tablets; 15 mg extended release tablets 5 mg/5ml & 5 mg/ml oral solution; 5 mg/ml injection
Estazolam	1 & 2 mg tablets
Flunitrazepam	1, 2, & 4 mg tablets
Flurazepam	15 & 30 mg capsules
Halazepam	20 & 40 mg tablets
Ketazolam	15 & 30 mg
Lorazepam	0.5, 1 & 2 mg tablets; 2 mg/ml oral solution 2 & 4 mg/ml injection
Lormetazepam	0.5, 1, & 2 mg capsules
Medazepam	10 mg tablets
Midazolam	1 mg/ml & 5 mg/ml injection
Nitrazepam	5 & 10 mg tablet
Oxazepam	10, 15 & 30 mg capsules
Prazepam	5 & 10 mg capsules; 5, 10 & 20 mg tablets
Quazepam	7.5 & 15 mg tablets
Temazepam	7.5, 15 & 30 mg capsules
Triazolam	0.125 & 0.25 mg tablets

2) TEMAZEPAM

a) Available as a liquid-filled capsule in the United Kingdom (Stark et al, 1987). The capsule may be taken by mouth or the liquid may be extracted and administered intravenously by the street user (Grahame-Smith, 1991).
b) STREET NAME(S)

1) Yellow eggs (Stark et al, 1987)
2) Jelly babies (Stark et al, 1987)

3) FLUNITRAZEPAM

a) Flunitrazepam (Rohypnol(R)) is a very potent benzodiazepine which produces sedation in 20 to 30 minutes that lasts for hours (Emergencynet, 1996).
b) STREET NAME

1) Roofies (Emergencynet, 1996)

4) ESTAZOLAM

a) A Chinese product known as "Sleeping Buddha" is being marketed as a dietary supplement, promoted as a treatment for insomnia and restlessness, and is sold as an herbal alternative to prescription sedatives. The FDA has determined that the product actually contains prescription-strength estazolam and is warning consumers against purchasing this product. The U.S. distributor, Treasure Box Products, Inc, has initiated a voluntary recall of this product in the United States (FDA, 1998).

1) Benzodiazepines are generally used as sedative/hypnotics, muscle relaxants, antianxiety agents, and anticonvulsants (USPDI, 1999).
2) ZOLAZEPAM is used for general anesthesia in veterinary medicine (S Sweetman , 2001).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Benzodiazepines are used as anxiolytics, muscle relaxants, procedural sedation agents, and sedative-hypnotics to treat withdrawal states (ie, ethanol, benzodiazepines) and many hyperadrenergic/stimulated conditions (eg, seizures, serotonin syndrome, neuroleptic malignant syndrome, sympathomimetic overdose, psychiatric conditions).
B) PHARMACOLOGY: They act on the benzodiazepine binding site on the chloride channel of the gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter receptor in the CNS, and increase the frequency of chloride channel opening. This hyperpolarizes the cell and prevents nerve firing/stimulation, resulting in generalized depression of spinal reflexes and the reticular activating system causing CNS depression.
C) TOXICOLOGY: Toxicity is an extension of the pharmacology, increased GABA activity causing CNS depression. While coma and respiratory depression are rare, they may occur with large overdoses or coingestions.
D) EPIDEMIOLOGY: Benzodiazepine overdose is common and usually occurs in combination with other drug ingestions. Outcomes are generally good.
E) WITH THERAPEUTIC USE

1) Adverse effects of benzodiazepines in therapeutic doses usually reflect the drug's pharmacology and include sedation, slurred speech, and ataxia. Some IV forms of benzodiazepines (namely, diazepam (Valium(R)) and lorazepam (Ativan(R))) contain propylene glycol as a diluent. Large doses and prolonged infusions may cause the accumulation of propylene glycol and a resultant anion gap metabolic acidosis. This is best avoided by using midazolam (Versed(R)) infusions since they are water soluble and do not contain propylene glycol.
2) Physical and/or psychological dependence may develop, and a withdrawal syndrome similar to ethanol withdrawal (ie, hypertension, tachycardia, tremulousness, seizures, low grade fever, and, in severe cases, delirium) may develop after abrupt discontinuation in dependent individuals.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: CNS depression is the most common finding after overdose. Respiratory depression may also occur, but is more common with coingestion of other sedative-hypnotics.
2) SEVERE TOXICITY: Respiratory depression/arrest may occur with large overdoses or following rapid IV injection with short-acting benzodiazepines. Severity of respiratory effects depends on the amount ingested and absorbed, type of benzodiazepine ingested (worse for lipophilic agents (eg, diazepam or flunitrazepam) compared with polar (eg, lorazepam)), and coingestants. In high doses, patients may manifest coma, respiratory depression, hypotension, hypothermia, and rhabdomyolysis. Otherwise, benzodiazepines are remarkably safe as single agents.

0.2.3)

A) Respiratory depression, hypotension, bradycardia, and hypothermia have been reported in overdose.

0.2.20)

A) Flurazepam, temazepam, and triazolam are classified as FDA pregnancy category X, while alprazolam, chlordiazepoxide, clonazepam, diazepam, lorazepam, midazolam and oxazepam are classified as FDA pregnancy category D. Clobazam has been classified as FDA pregnancy category C. The FDA pregnancy category rating is not available for clorazepate. The use of benzodiazepine drugs during pregnancy has been associated with an increased risk of congenital malformations and other developmental abnormalities. Non-teratogenic risks may also be associated with benzodiazepine use during pregnancy. Additionally, there may be some risk of withdrawal symptoms in the infant during the postnatal period due to the mother receiving benzodiazepines regularly during late pregnancy. Administration of benzodiazepines prior to delivery may produce signs of poisoning in the neonate. A condition called "floppy infant syndrome", characterized by hypotonia that may last several days, may occur following maternal diazepam use. Benzodiazepines have been shown to be excreted in breast milk and may produce effects in the nursing infant.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) SUPPORT

1) Supportive care with attention to the airway, breathing, and circulation is the mainstay of treatment. Overdose of a benzodiazepine as a single agent may cause coma but generally does not cause loss of airway reflexes. However, when combined with other sedating drugs (eg, ethanol, opioids, muscle relaxants, antipsychotics, anticonvulsants), airway protection may be necessary. Even with large overdoses, patients generally remain hemodynamically stable.

B) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Supportive care.

C) MANAGEMENT OF SEVERE TOXICITY

1) Coma and respiratory depression require intubation. Hypotension responds to fluids and rarely vasopressors. Anion gap metabolic acidosis from prolonged, high-dose lorazepam or diazepam can be treated with medication cessation.

D) DECONTAMINATION

1) PREHOSPITAL: Activated charcoal is usually not necessary unless the patient has a dangerous co-ingestant. Avoid if the patient is too sedated.
2) HOSPITAL: Activated charcoal may be beneficial if dangerous co-ingestants were consumed and the patient is intubated or can protect their airway. Gastric lavage and whole bowel irrigation are usually not indicated as severe toxicity is very rare.

E) AIRWAY MANAGEMENT

1) Although respiratory depression is rare, some patients may require airway management.

F) ANTIDOTE

1) Flumazenil is a specific benzodiazepine receptor antagonist that can rapidly reverse the benzodiazepine effect. However, it is rarely indicated except for iatrogenic oversedation or respiratory depression. In addition, flumazenil may cause withdrawal states and result in seizures, adrenergic stimulation, or autonomic instability in patients chronically taking benzodiazepine, or in those with ventricular dysrhythmias and seizures who are concomitantly using cocaine or tricyclic antidepressants. The starting dose is 0.1 to 0.2 mg IV over 15 to 30 seconds and repeated as needed to a maximum of 1 mg. Continuous IV infusion from 0.1 to 1 mg/hr in 0.9% NaCl or D5W may also be used.

G) ENHANCED ELIMINATION

1) There is no role for diuresis, dialysis, or hemoperfusion.

H) PATIENT DISPOSITION

1) HOME CRITERIA: Healthy children with unintentional ingestions of 1 to 2 tablets may be observed at home if the family is responsible. If significant ataxia or drowsiness develops, refer the patient to the hospital. Asymptomatic adults with unintentional ingestions and a good social situation may remain at home.
2) OBSERVATION CRITERIA: All patients with intentional ingestion or significant ataxia, drowsiness, or respiratory depression should be referred to the hospital for observation. Patients with unreliable social situations may also need observation. Patients may be discharged when asymptomatic.
3) ADMISSION CRITERIA: Admit patients with severe symptoms (ie, coma, respiratory failure, or hypotension unresponsive to IV fluids) or if a danger to themselves. Discharge when asymptomatic and when psychiatric issues have been addressed.

I) PITFALLS

1) Profound coma, respiratory failure, and significant hemodynamic instability suggest a co-ingestant and indicate the need for further investigation. Indiscriminate flumazenil administration to comatose patients may cause seizures or dysrhythmias.

J) PHARMACOKINETICS

1) Most benzodiazepines are rapidly absorbed (greater than 80%), highly protein bound (80% to 100%), and have small volumes of distribution (less than 1.5 L/kg) but vary in onset, time to peak serum level, and duration. Agents that have a fast onset of action include clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, midazolam, and triazolam. Peak plasma levels usually occur within 2 hours with some taking up to 6 hours. Agents with active metabolites have longer half-lives and duration of action and include chlordiazepoxide, clorazepate, diazepam, flurazepam, and quazepam.

K) PREDISPOSING CONDITIONS

1) Benzodiazepines co-ingested with other sedating agents increase the risk for respiratory compromise. Obese patients have longer elimination half-lives and prolonged drug effect. Sleep apnea patients and those with other underlying chronic pulmonary diseases may be at increased risk for respiratory depression.

L) DIFFERENTIAL DIAGNOSIS

1) Various sedative-hypnotics, including ethanol, antidepressants, anticonvulsants, antipsychotics, barbiturates, and opioids, can cause sedation and minimal vital sign changes in overdose.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) Respiratory depression, hypotension, bradycardia, and hypothermia have been reported in overdose.

3.3.2)

A) Respiratory depression may occur (Hojer et al, 1989).
B) Respiratory arrest may occur in the three hours after an overdose of flunitrazepam alone or with ethanol.

3.3.3)

A) Hypothermia may occur. In one study, hypothermia was reported in 15% of patients (Michaud et al, 2001; Hojer et al, 1989).

3.3.4)

A) Hypotension may occur (Greenblatt et al, 1977; Meredith & Vale, 1985), more commonly when other drugs are ingested concomitantly (Hojer et al, 1989).
B) Cardiovascular effects are generally mild or absent. Changes suggest the presence of other agents (Osborn & Goldfrank, 1994).

3.3.5)

A) BRADYCARDIA: Severe bradycardia occurred in 2 of 153 patients (Mignee et al, 1980). Bradycardia may be observed after an overdose of flunitrazepam.

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) SUMMARY: For pure benzodiazepine ingestions, effects should be minimal, but may include mydriasis, nystagmus, and divergence paralysis.
2) MYDRIASIS: Dilated pupils may be present with benzodiazepine intoxication (Trappler & Bezeredi, 1982; Wiley & Wiley, 1995).
3) NYSTAGMUS: Has been reported following overdose of chlordiazepoxide and ethanol (Bailey, 1984). Nystagmus was reported in 5 of 66 cases of benzodiazepine overdose (Meredith & Vale, 1985).
4) DIVERGENCE PARALYSIS: Horizontal diplopia at greater than one meter was reported in an elderly patient taking 2 mg of diazepam 3 times a day (Arai & Fujii, 1990).
5) MIOSIS: Pinpoint, equal pupils have been reported in overdose (Welch et al, 1977; Wiley & Wiley, 1995).
6) DIPLOPIA: May occur (Osborn & Goldfrank, 1994).

Cardiovascular

3.5.2)

A) CARDIAC ARREST

1) Four deaths due to "cardiac complications" (2) and cardiorespiratory arrest (2) have been reported to the US Food and Drug Administration (FDA) after the therapeutic use of midazolam (Versed(R)) (Anon, 1986). No further details were available.
2) A 2-year-old, 13.5-kg girl ingested 70 mg diazepam. Three hours after ingestion, she developed irregular bradycardia ending in cardiac arrest. She was successfully resuscitated (Berger et al, 1975).

B) HYPOTENSIVE EPISODE

1) Hypotension may occur (Meredith & Vale, 1985; Quail et al, 1999); hypotension may be more common when other drugs are ingested concomitantly (Hojer et al, 1989).

C) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) Serious bradycardia occurred in 2 of 153 acute overdose patients (1.3%) (Mignee et al, 1980).

D) ECTOPIC BEATS

1) WITH THERAPEUTIC USE

a) Three young adult patients scheduled for elective surgery developed ventricular irritability (bigeminy and trigeminy) and tachycardia 45 minutes following preoperative intramuscular injection of midazolam. No anticholinergic or analgesic premedication was given (Arcos, 1987).

3.5.3)

A) ANIMAL STUDIES

1) ARTERITIS

a) Dogs receiving bretazenil at more than 250 times the normal human dose developed necrotizing arteritis and periarteritis (Schlaeppi et al, 1991).

Respiratory

3.6.2)

A) HYPOVENTILATION

1) WITH POISONING/EXPOSURE

a) Respiratory depression requiring ventilatory support has occurred in benzodiazepine overdose (Lukasik-Glebocka et al, 2016; Sullivan, 1989; Olson et al, 1985; Hojer et al, 1989; Minder, 1989).
b) INCIDENCE: In a retrospective study of 144 patients admitted to a medical intensive care unit for overdose of benzodiazepine only, 53 patients (37%) required orotracheal intubation for airway protection and 18 (12%) required mechanical ventilation. In the same study, 558 patients had ingested benzodiazepines combined with ethanol or other drugs. Of these, 275 (49%) required intubation for airway protection and 106 (19%) required mechanical ventilation.(Hojer et al, 1989).
c) In another study, 16% of 131 patients with alprazolam overdose required ventilation compared with 8% of 823 patients with diazepam overdose and with 10.8% of patients with overdose of other benzodiazepines (Isbister et al, 2004).

B) APNEA

1) MIDAZOLAM: Three deaths from respiratory arrest and two deaths from cardiopulmonary arrest have been reported to the US Food and Drug Administration (FDA) after the therapeutic administration of midazolam (Versed(R)) (Anon, 1986).
2) Respiratory depression has been reported with intravenous flunitrazepam, leading to significant decreases in arterial oxygen tension. Depressant effects on respiration are more pronounced with rapid injections; apnea has been reported with rapid administration of 2 mg (Mattila & Larni, 1980).
3) FLUNITRAZEPAM: Respiratory arrest may also occur after overdose of flunitrazepam alone or with ethanol.

C) ACUTE LUNG INJURY

1) TRIAZOLAM: Non-cardiogenic pulmonary edema was reported in a 24-year-old former heroin user following ingestion of triazolam (total dose, 1 mg). Although the patient denied any other drug intake, the authors speculated that the occurrence of pulmonary edema may have been due to either heroin use or a synergistic effect of triazolam with other drugs (Chan et al, 1995).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH THERAPEUTIC USE

a) INCIDENCE: Some degree of CNS depression is common including drowsiness, fatigue, and ataxia (Prod Info diazepam oral tablets, 2006; Prod Info alprazolam oral tablets, 2006; Whyte, 2004). Even after large doses, patients may exhibit only sleepiness. However, stupor may develop (Hojer et al, 1989; McCormick et al, 1985; Svenson, 1987; Wiley & Wiley, 1995).

1) Initial phases may produce minor extrapyramidal signs with some excitement.

B) COMA

1) WITH POISONING/EXPOSURE

a) Coma occurred in 11% of a total of 66 cases of benzodiazepine poisoning (Meredith & Vale, 1985).
b) In another study of benzodiazepine overdose, coma (Glasgow Coma score less than 9) developed in 12.2% of 131 alprazolam overdoses, 6.9% of 823 diazepam overdoses, and 9.7% of other benzodiazepine overdoses (n=1109) (Isbister et al, 2004).
c) One patient developed deep coma with asymmetrical neurologic signs suggesting a structural brainstem lesion after ingesting 50 mg flunitrazepam. He regained consciousness 2 days after admission and a repeat EEG at that time was normal. Recovery was complete with no neurologic deficits reported (Deleu & DeKeyser, 1987).
d) In a long-term, clinical trial, it was reported that 49% of all benzodiazepine-only admissions presented with grade 3 or 4 coma, 14 of which persisted for 24 hours and 5 of which persisted for 48 hours (Hojer et al, 1989).
e) Analysis of acute benzodiazepine overdoses in relation to the incidence of coma indicate that short-acting benzodiazepines, such as midazolam and triazolam, and intermediate-acting flunitrazepam have a higher acute toxicity compared with longer-acting benzodiazepines, such as diazepam, lorazepam and nitrazepam (Meier et al, 1993).

1) Flurazepam and temazepam may also have a greater toxicity (Serfaty & Masterton, 1994). The same observation for temazepam was made in a study of 303 patients (Buckley et al, 1995).

f) CASE REPORT: Following ingestion of triazolam 5 mg, one patient presented unconscious, apneic, cyanotic, and hypotensive. Eight hours later, she awoke and was extubated without sequelae (Olson et al, 1985).
g) CASE REPORT: Alpha coma was reported in a patient following an overdose of 100 mg lorazepam. By the second day, the patient's mental status cleared and neurologic examination was normal (Guterman et al, 1981).
h) CASE REPORT (CHILD): A cyclical coma has been reported in a clonazepam overdose in a child (Welch et al, 1977).
i) CASE REPORT: An 83-year-old woman became comatose after accidentally ingesting approximately 52.5 mg temazepam. The patient recovered following flumazenil administration (Verghese & Merino, 1999).
j) CASE REPORT: A 30-year-old woman became unconscious (Glasgow Coma score, 10) and severely hypotensive after intentional intravenous administration of a veterinary tranquilizer containing zolazepam and tiletamine. The patient recovered with supportive care (Quail et al, 1999).
k) CASE REPORT(FLUBROMAZOLAM): A 27-year-old man, with a history of substance abuse, presented in a coma (Glasgow Coma Scale [GCS] of 3) and was intubated and mechanically ventilated due to respiratory failure. He was tachycardic and hypotensive, with cyanosis of his hands and feet, generalized hypotonia, absent plantar responses and decreased reflexes. Treatment included IV fluids and a continuous norepinephrine infusion. Suspecting opioid intoxication, naloxone was administered; however, the patient was neurologically unresponsive. A urinalysis, obtained at admission, was positive for benzodiazepines, and flumazenil was administered with a brief spontaneous return of consciousness (GCS 10); however, 30 minutes later, the patient deteriorated to a GCS of 3. Over the next 2 days, the patient's level of consciousness fluctuated, and a brain CT was performed, revealing hypoxic-ischemic changes in the frontal and left temporal region. With continued supportive care, the patient's neurological status gradually improved and he was extubated on hospital day 4. With continued rehabilitation and antibiotic therapy, due to the development of pneumonia, the patient was eventually transferred to the Department of Neurology for further therapy. Interview of the patient revealed that he had ingested a total of 5 mg of flubromazolam, a designer benzodiazepine, up to 19 hours prior to admission (Lukasik-Glebocka et al, 2016).

C) DYSKINESIA

1) WITH THERAPEUTIC USE

a) Benzodiazepines may worsen or induce dyskinesia in susceptible patients (Francis, 1983; Rosenbaum & De La Fuente, 1979). Orofacial dyskinesias have been associated with low dosage benzodiazepine treatment (Sandyk, 1986; Kaplan & Murkofsky, 1978).

D) DYSTONIA

1) Two cases of acute dystonic reactions associated with diazepam ingestions were reported. Both resolved with diphenhydramine (Hooker & Danzil, 1988).

E) SEIZURE

1) WITH THERAPEUTIC USE

a) WITHDRAWAL SEIZURES: Have occurred following abrupt discontinuation of benzodiazepines (Prod Info alprazolam oral tablets, 2006; Prod Info diazepam oral tablets, 2006; Breier et al, 1984; Schneider et al, 1987; Essig, 1966).

F) DISTURBANCE IN SPEECH

1) WITH THERAPEUTIC USE

a) DYSARTHRIA: Has been reported (Bailey, 1984).
b) CASE REPORT: Dysarthria was reported in a 34-month-old girl who was given a total of 37.5 mg IV diazepam over a 15-hour period. The dysarthria continued for 180 hours after the last dose of diazepam. Other medications this patient received included buprenorphine, dopamine, cefazolin, furosemide, and carbazochrome, so drug interaction may have played a role (Ishikawa et al, 1988).

G) RESTLESSNESS AND AGITATION

1) WITH THERAPEUTIC USE

a) Paradoxical Excitement

1) Midazolam may produce paradoxical excitement with therapeutic use and has been more commonly associated with children, particularly autistic children, the elderly, or patients with a history of alcohol dependence or violence. Other benzodiazepines may have the same effect (Whyte, 2004).

H) DELIRIUM

1) WITH THERAPEUTIC USE

a) CASE REPORT (ADULT): A 57-year-old man developed short-term memory loss and visual and auditory hallucinations 8 to 12 hours after ingesting a "handful" of triazolam tablets (Trappler & Bezeredi, 1982).
b) PEDIATRIC: Visual and auditory hallucinations have occurred in children following lorazepam ingestion (Vlachos et al, 1978).

I) AMNESIA

1) WITH THERAPEUTIC USE

a) TRIAZOLAM

1) Triazolam, as well as other benzodiazepines, have been implicated in next-day memory impairment/amnesia in as many as 40% of patients (Huff & Plunkett, 1989; Bixler et al, 1991; Kales, 1991; Verwey et al, 2000). Single doses of triazolam (0.125 to 0.25 mg) have been associated with amnestic episodes for up to 24 hours after ingestion (Shader & Greenblatt, 1983).

a) In a randomized, placebo-controlled study, single 0.5-mg doses of triazolam did not impair memory 30 minutes after ingestion, but did significantly impair recall memory 13.5 hours after ingestion compared with placebo and temazepam (Scharf et al, 1988).
b) A parallel, double-blind, placebo-controlled study was conducted comparing triazolam 0.25 mg with flurazepam 15 mg, temazepam 15 mg, and placebo. Triazolam alone significantly impaired memory recall at 24 hours post-ingestion (Greenblatt et al, 1989).

Gastrointestinal

3.8.2)

A) VOMITING

1) WITH POISONING/EXPOSURE

a) Nausea and vomiting were noted in 9% of children presenting with lorazepam intoxication (Garnier et al, 1984).

B) DRUG-INDUCED ILEUS

1) WITH POISONING/EXPOSURE

a) Absent bowel sounds were reported in 1 case of clonazepam overdose in a child (Welch et al, 1977).

Acid-Base

3.11.2)

A) ACIDOSIS

1) LORAZEPAM

a) CASE REPORT (ADOLESCENT): Anion gap metabolic acidosis with an osmolar gap widening was associated with a high-dose lorazepam infusion (containing 40% volume/volume propylene glycol and 3% benzyl alcohol in the vehicle), at a rate of 500 mcg/kg/hr, in a 13-year-old girl. The acidosis resolved after the lorazepam infusion was lowered to 250 mcg/kg/hr. It is believed that the propylene glycol and the benzyl alcohol were responsible for the anion gap acidosis and the osmolar gap in this patient (Pali & Kallas, 2000).
b) CASE REPORT (ADULT): Severe hyperosmolar metabolic acidosis (pH, 6.9; bicarbonate 6.2 mmol/L; anion gap, 17.8 mmol/L) was reported in a 34-year-old woman, who had preexisting metabolic acidosis and who was receiving increasing doses of intravenous lorazepam containing polyethylene glycol (PEG-400) and benzyl alcohol (total lorazepam dose, within 78 hours, of 1696 mg and cumulative PEG-400 dose of 153 mL). The patient's pH and bicarbonate levels gradually improved following three hemodialysis sessions (Tayar et al, 2002).

2) TRIAZOLAM

a) CASE REPORT: Arterial blood gases revealed mixed metabolic and respiratory acidosis, with a pH of 6.9, in a 24-year-old man with a history of heroin abuse after ingesting 2 tablets of triazolam (0.5 mg each) (Chan et al, 1995).

Dermatologic

3.14.2)

A) BULLOUS ERUPTION

1) WITH POISONING/EXPOSURE

a) Bullae have been reported following overdose with nitrazepam, oxazepam, and temazepam (Ridley, 1971; Moshkowitz et al, 1990; Verghese & Merino, 1999).

B) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 62-year-old woman developed erythemato-bullous eruption with extensive erosions and 65% skin detachment after beginning phenytoin and oxazepam therapy 6 weeks and 2 weeks earlier, respectively. Histopathology showed extensive epidermal necrosis and detachment. The patient recovered following two separate 3-day series of dexamethasone pulse therapy of 1.5 mg/kg infused over 30 to 60 minutes (van der Meer et al, 2001).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Acute rhabdomyolysis occurred in a patient with prolonged coma after ingesting lorazepam 60 mg, perphenazine 240 mg, and amitriptyline 1500 mg (Caruana et al, 1983).

B) ARTERIAL THROMBOSIS

1) WITH POISONING/EXPOSURE

a) INTRAARTERIAL INJECTION

1) Acute arterial occlusion with subsequent tissue necrosis has followed accidental intraarterial administration of injectable diazepam in adults (Ruddel et al, 1985) and in children (Gould & Lingam, 1977).
2) Muscle necrosis and subsequent fatal fulminant gas gangrene was reported following intraarterial injection of crushed triazolam and cyclizine tablets (suspended in water) in a suspected HIV positive man (Haiart et al, 1992).
3) Intraarterial injection of a suspension of crushed temazepam, diazepam, and codeine phosphate tablets resulted in an occluded radial artery and subsequent above elbow amputation in a 26-year-old man. Two years later, the same patient underwent emergency disarticulation of the left leg secondary to extensive vascular thrombosis caused by intraarterial injection of crushed triazolam tablets dissolved in water (Cooper et al, 1992).
4) Limb and digital ischemia and necrosis and compartment syndrome with rhabdomyolysis were reported following intentional intraarterial injections of temazepam by intravenous drug abusers (Eddey & Westcott, 2000).

Endocrine

3.16.2)

A) INCREASED HORMONAL ACTIVITY

1) WITH THERAPEUTIC USE

a) CORTISOL: In a study of 10 normal subjects given 5 and 10 mg oral diazepam, the baseline cortisol levels did not change. However, after application of controlled stress, the change in measured cortisol levels in control subjects was significantly higher than that of the subjects given 10 mg diazepam (Roy-Byrne et al, 1988).

Immunologic

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) Severe anaphylactic reactions following administration of IV diazepam have been reported (Faulk, 1977; Milner, 1977).

Reproductive

3.20.1)

3.20.2)

A) LACK OF INFORMATION

1) CLOBAZAM

a) At the time of this review, no data were available to assess the teratogenic potential of this agent in humans (Prod Info ONFI(R) oral tablets, oral suspension, 2014)

B) CONGENITAL ANOMALY

1) The use of benzodiazepine drugs during pregnancy has been associated with an increased risk of congenital malformations and other developmental abnormalities (Prod Info VALIUM(R) oral tablets, 2008).
2) In a meta-analysis reviewing outcomes of children born to mothers exposed to any benzodiazepine during their first trimester, mixed results were found. When only cohort studies were considered, no significant association between benzodiazepine use and either major malformations or oral cleft malformations was observed. However, data from case control studies showed a small, but significant, increased risk for major malformations (p=0.008) and for cleft lip (p=0.01) (Dolovich et al, 1998).
3) Severe dysmorphism, malformations, intrauterine and extrauterine growth retardation, and CNS dysfunction have been described in 7 infants born following maternal benzodiazepine use during pregnancy (Laegreid et al, 1987).
4) A case report described aplasia cutis congenita in a neonate born to a mother who had used lorazepam and diazepam or chlordiazepoxide in the early part of her pregnancy; however, a direct causal relationship could not be clearly established nor other causes ruled out (Martinez-Lage et al, 2002).
5) Mixed results were found in a meta-analysis of cohort and case-control studies that reported on the occurrence of major malformations in infants exposed to any benzodiazepine during at least the first trimester of pregnancy. When only cohort studies were pooled, no significant association between benzodiazepine use and major malformations were noted (odds ratio 0.90; 95% confidence interval 0.61 to 1.35; p=0.62); data pooled from case-control studies, however, showed a positive association with major malformations (odds ratio 3.01; 95% confidence interval 1.32 to 6.84; p=0.008). Similar observations were made with regard to oral cleft; the pooled cohort study data did not substantiate an association with drug use (odds radio 1.19; 95% confidence interval 0.34 to 4.15; p=0.997), whereas the case-controlled data did (odds ratio 1.79; 95% confidence interval 1.13 to 2.82; p=0.01). Finally, the meta-analysis found 2 case-controlled studies that each provided conflicting evidence of any association between benzodiazepine exposure and cardiac malformations, and 1 study failed to find an association between exposure and central nervous system defects (Dolovich et al, 1998a).
6) The controversy over prescribing benzodiazepines during pregnancy is discussed in an extensive review (Weber, 1985). Both animal data and human epidemiological studies suggest benzodiazepines are teratogens. Attack on the CNS by benzodiazepines can occur during organogenesis, during early differentiation of neural anlagen (hereditary factor) after neural tube closing, or during biochemical differentiation of the brain. However, other researchers have presented letters citing their own data which show benzodiazepines to be free of teratogenic potential (Winter, 1987), (Czeizel & Lendvay, 1987; Gerhardsson & Alfredsson, 1987).
7) CLORAZEPATE

a) Clorazepate dipotassium is a derivative of benzodiazepine and effects on congenital malformations have not been adequately studied (Prod Info TRANXENE T-TAB(R) oral tablets, 2010). In a single case of first-trimester maternal overdose with clorazepate, extensive malformations and neonatal death resulted (Patel & Patel, 1980). Neurologic depression in 4 exposed newborns has also been reported (Bavous, 1981).

C) ANIMAL STUDIES

1) CHLORDIAZEPOXIDE

a) RATS: In animal studies, no congenital anomalies or teratogenic effects were observed in rats administered oral doses of either 2.5 mg/kg chlordiazepoxide hydrochloride with 1.25 mg/kg clidinium bromide or 25 mg/kg chlordiazepoxide hydrochloride with 12.5 mg/kg clidinium bromide during 2 successive matings. A slight decrease in the number of pups surviving during lactation was observed in rats receiving the highest dose during the first mating. A slight decrease in the number of pregnant females as well as the number of pups surviving until weaning was observed during the second mating (Prod Info LIBRAX(R) oral capsules, 2009).
b) RATS: In animal studies, there was no evidence of congenital anomalies in rats administered chlordiazepoxide hydrochloride 10, 20 or 80 mg/kg/day followed by breeding. In a similar study, rats administered chlordiazepoxide hydrochloride 100 mg/kg/day experienced a significant decrease in fertilization rate and decreased body weight and viability of offspring. Major skeletal defects were observed in 1 neonate from both the first and second mating receiving chlordiazepoxide hydrochloride 100 mg/kg/day. During 2 reproduction studies in rats administered clidinium bromide 2.5 and 10 mg/kg/day, respectively, there was no incidence of congenital anomalies or teratogenic effects (Prod Info LIBRAX(R) oral capsules, 2009).

2) CLOBAZAM

a) In animal studies, clobazam caused fetal malformations and increased embryofetal mortality in rats and rabbits. The offspring of rats given oral clobazam (150, 450, or 750 mg/kg/day) during organogenesis showed higher incidences of fetal skeletal variations and embryofetal mortality. Plasma exposures at the low dose (150 mg/kg/day) were lower than those in humans at the maximum recommended human dose of 40 mg/day. The offspring of rabbits given oral clobazam (10, 30, or 75 mg/kg/day) during organogenesis showed decreased fetal body weights and increased incidences of fetal malformations (visceral and skeletal) at mid to high doses and increased incidences of embryofetal mortality at the high dose. All doses resulted in increased fetal variations and risk of maternal toxicity (ataxia and decreased activity) increased at the highest dose, and the risk of embryofetal developmental toxicity was increased with the lowest effective dose. Plasma exposures at the low dose (10 mg/kg/day) were lower than those in humans at the maximum recommended human dose. The offspring of rats given oral clobazam (50, 350, or 750 mg/kg/day) throughout pregnancy and lactation showed increased embryofetal mortality at the high dose, decreased pup survival rate at the mid and high dose, and alterations in offspring behavior at all doses. Plasma exposures at the low dose (50 mg/kg/day) were lower than those in humans at the maximum recommended human dose (Prod Info ONFI(R) oral tablets, oral suspension, 2014).

3) DIAZEPAM

a) MICE, HAMSTERS: In animal studies, diazepam was teratogenic in mice and hamsters at oral daily doses of 100 mg/kg or greater (approximately 8 times the maximum recommended human dose (MRHD) of 1 mg/kg or greater on a mg/m(2) basis). Cleft palate and encephalopathy were the most commonly reported malformations (Prod Info VALIUM(R) oral tablets, 2008).

3.20.3)

A) LACK OF INFORMATION

1) CLOBAZAM

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info ONFI(R) oral tablets, oral suspension, 2014).

B) PREGNANCY CATEGORY

1) The following agents are classified as FDA pregnancy category X: flurazepam, temazepam, and triazolam (Prod Info DALMANE(R) oral capsules, 2007a; Prod Info RESTORIL(TM) oral capsules, 2008; Prod Info HALCION(R) oral tablets, 2008), and alprazolam, chlordiazepoxide, clonazepam, diazepam, lorazepam, midazolam and oxazepam as FDA pregnancy category D (Prod Info alprazolam oral tablets, 2007; Prod Info LIBRIUM(R) oral capsules, 2005a; Prod Info KLONOPIN(R) TABLETS, KLONOPIN(R) WAFERS oral tablets, orally disintegrating tablets, 2010; Prod Info TRANXENE(R) T-TAB(R) oral tablets, 2005; Prod Info VALIUM(R) oral tablets, 2008; Prod Info Ativan(R) Injection, 2002; Prod Info midazolam hcl injection, 2005; Prod Info oxazepam oral capsules, 2007). The manufacturer has classified clobazam as FDA pregnancy category C (Prod Info ONFI(TM) oral tablets, 2011)The manufacturer package insert does not provide the FDA pregnancy category rating for clorazepate (Prod Info TRANXENE T-TAB(R) oral tablets, 2010).

C) PREGNANCY REGISTRY

1) CLOBAZAM: If pregnancy occurs while receiving clobazam therapy, encourage patients or their caregivers to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry (1-888-233-2334 or www.aedpregnancyregistry.org) (Prod Info ONFI(R) oral tablets, oral suspension, 2014).

D) PLACENTAL TRANSFER

1) LORAZEPAM

a) Lorazepam crosses the placenta and may cause fetal damage when administered during pregnancy. Placental transfer has been indicated in blood levels obtained from umbilical cords in humans. Infants whose mothers ingested benzodiazepines for several weeks or more prior to delivery, reportedly experienced withdrawal symptoms during the postnatal period. Neonates whose mothers ingested benzodiazepines during the late phase of pregnancy or at delivery, experienced symptoms such as hypoactivity, hypotonia, hypothermia, respiratory depression, apnea, trouble feeding and impaired metabolic response to cold stress (Prod Info lorazepam concentrated oral solution, 2008; Prod Info lorazepam IM, IV injection, 2008; Prod Info lorazepam oral tablets, 2008).

E) NEONATAL EFFECTS

1) The use of benzodiazepine drugs during pregnancy has been associated with nonteratogenic risks. Neonatal flaccidity, respiratory and feeding difficulties, and hypothermia have been reported in infants born to mothers who have been treated with benzodiazepines late in pregnancy (Prod Info ONFI(R) oral tablets, oral suspension, 2014; Prod Info VALIUM(R) oral tablets, 2008; Prod Info alprazolam oral tablets, 2006; Prod Info HALCION(R) oral tablets, 2008; Prod Info KLONOPIN(R) TABLETS, KLONOPIN(R) WAFERS oral tablets, orally disintegrating tablets, 2010).
2) DIAZEPAM

a) Administration of benzodiazepines to women prior to delivery may produce signs of poisoning in the neonate (ie, difficulties in sucking and respiratory arrest requiring assisted ventilation) within the first hours or days after delivery. In neonates, a condition, called "floppy infant syndrome", may occur, following maternal diazepam consumption, and is characterized by hypotonia that may last over several days (Autret et al, 1985; Autret et al, 1987).

3) LORAZEPAM

a) High dose IV lorazepam therapy has been shown to cause "floppy infant" syndrome (McBride & Dundee, 1979; Whitelaw & Cummings, 1981). Fifty-three neonates born to 51 mothers treated with lorazepam were followed for 5 days. Maternal plasma levels were higher than corresponding cord levels. Cord levels greater than 45 mcg/L necessitated ventilation at birth in 40 infants (75%). Conjugated lorazepam was measurable for up to 7 days following birth. Preterm neonates had a high incidence of low Apgar scores, need for ventilation, hypothermia, and poor suckling. Full term neonates whose mothers received oral lorazepam showed no complications other than delay in feeding (Whitelaw & Cummings, 1981). Lorazepam use during labor has been associated with an increased, while not statistically significant, occurrence of respiratory depression in the newborn (McAuley & O'Neill, 1982).

F) NEONATAL WITHDRAWAL SYNDROME

1) There may be some risk of withdrawal symptoms in the infant during the postnatal period due to the mother receiving benzodiazepines regularly during late pregnancy (Prod Info VALIUM(R) oral tablets, 2008; Prod Info lorazepam oral tablets, 2008; Prod Info HALCION(R) oral tablets, 2008). Withdrawal symptoms lasting several days have occurred in neonates born to women chronically receiving benzodiazepines prior to delivery (Prod Info alprazolam oral tablets, 2006).
2) ALPRAZOLAM

a) Alprazolam has been reported to result in symptoms of neonatal withdrawal in cases of maternal use of alprazolam during breastfeeding in addition to antepartum use (Anderson & McGuire, 1989).

3) DIAZEPAM

a) A case report described neonatal drug withdrawal in an infant whose mother's epilepsy was being treated with diazepam was accompanied by SIADH. Because of poor feeding, IV infusion of a 5% glucose solution was instituted on day 1 after birth. Oliguria was recognized (urine output less than 0.5 mL/kg/hr) on day 1, and fluid was then restricted to 65 mL/kg/day and a diuretic given. After day 3, urine output increased and urine osmolality decreased. Oliguria did not recur. At 60 days, there was no evidence of abnormalities of the brain; development at 6 months of age was normal (Nako et al, 2000).

G) LACK OF EFFECT

1) CLORAZEPATE

a) After single dose administration during labor, no clinical repercussions were noted in the neonate; however, the authors cautioned that chronic clorazepate use in pregnancy caused accumulation of nordiazepam in the fetus (Rey, 1979; Rey, 1979a)

H) ANIMAL STUDIES

1) DIAZEPAM

a) RODENT: Rodent studies have demonstrated long-term changes in cellular immune responses, brain neurochemistry, and behavior at maternal doses of diazepam similar to those used clinically (Prod Info VALIUM(R) oral tablets, 2008).

3.20.4)

A) BREAST MILK

1) Benzodiazepines are excreted in breast milk and may produce effects in the nursing infant (Prod Info VALIUM(R) oral tablets, 2008).
2) In a study conducted to determine the serum concentrations of benzodiazepines and antidepressants in nursing infants (n=35) whose mothers were taking antidepressants or benzodiazepines while breastfeeding, 74% had serum medication levels below the laboratory limit of detection. Twenty-six percent of the infants with detectable serum medication levels were also exposed to the medication during pregnancy (Birnbaum et al, 1999).
3) CLOBAZAM

a) Clobazam is known to be excreted in human breast milk (Prod Info ONFI(R) oral tablets, oral suspension, 2014). According to the World Health Organization, clobazam is safe for short-term use during breastfeeding (Anon, 1995).

4) CLORAZEPATE

a) Nordiazepam (desmethyldiazepam), a metabolite of clorazepate, has been found in breast milk and in the blood of neonates exposed via breast milk after maternal ingestion of the parent drug during labor (Prod Info Tranxene(R), 1997). Milk concentrations of up to 15 ng/mL were measured following a single 20 mg IM injection of clorazepate, representing 15% to 30% of maternal serum concentrations. No data are available on milk concentrations with oral clorazepate therapy (Rey, 1979a).

5) DIAZEPAM

a) Breastfed infants whose mothers are administered diazepam, may become lethargic and lose weight; labeling advises against nursing while on benzodiazepines (Prod Info Xanax XR(R), 2003; Prod Info Xanax(R), 2001).

6) DIAZEPAM/OXAZEPAM

a) CASE REPORT: Milk and plasma concentrations of diazepam, N-desmethyldiazepam, temazepam, and oxazepam in the breast milk of a 22-year-old mother were observed during withdrawal from diazepam and oxazepam combination therapy. Milk to plasma ratios of diazepam and N-desmethyldiazepam were 0.2 and 0.13, respectively, and the calculated infant's dose was 4.7% of that ingested by the mother. While serum concentrations of diazepam were not detected in the infant, low levels of the metabolite and concomitant temazepam were present. No adverse effects were noted in this infant (Dusci et al, 1990).

7) LORAZEPAM

a) Lorazepam is distributed into breast milk in low concentrations, and the amount ingested by the breastfed infant is pharmacologically insignificant (Whitelaw et al, 1981). Conjugation and elimination of lorazepam are slow in the infant (Cummings & Whitelaw, 1981). A slight delay in establishing breastfeeding between infant and mother has resulted from the presence of lorazepam in breast milk (Johnstone, 1981). However, the volume of milk consumed and the duration of nursing sessions were not significantly affected by maternal ingestion of lorazepam (Johnstone, 1982). One report suggested that lorazepam is safe for oral premedication in breastfeeding mothers, since the concentration found in breast milk was low (8 to 9 ng/mL) (Summerfield & Nielsen, 1985).

B) NEONATAL WITHDRAWAL SYMPTOMS

1) ALPRAZOLAM

a) CASE REPORT: A case of neonatal alprazolam withdrawal, possibly due in part to breastfeeding, was reported. Milk concentrations were not measured (Anderson & McGuire, 1989a).

C) LACK OF EFFECT

1) LORAZEPAM

a) In one case, a nursing woman took 2.5 mg lorazepam twice daily for 5 days after delivery with no evidence of sedation in the neonate (Whitelaw et al, 1981).

3.20.5)

A) LACK OF EFFECT

1) At the time of this review, no adverse effects on fertility or offspring viability were observed at a diazepam dose of 80 mg/kg/day (approximately 13 times the MRHD)(Prod Info VALIUM(R) oral tablets, 2008).

B) ANIMAL STUDIES

1) RATS

a) DIAZEPAM: In animal studies, rats given an oral diazepam dose of 100 mg/kg/day (approximately 16 times the maximum recommended human dose (MRHD) on a mg/m(2) basis) prior to and during mating and throughout gestation and lactation showed decreases in the number of pregnancies and in the number of surviving offspring. No adverse effects on fertility or offspring viability were observed at a diazepam dose of 80 mg/kg/day (approximately 13 times the MRHD) (Prod Info VALIUM(R) oral tablets, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Serum glucose, venous blood gases, ECG, and pulse oximetry may be useful.
B) Urine drug tests do not detect all benzodiazepines; in particular, midazolam, chlordiazepoxide, and flunitrazepam are not detected on many urinary assays, so a negative screen does not rule out a benzodiazepine ingestion.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Qualitative testing for the presence of benzodiazepine is helpful to confirm presence, especially when overdose history is sketchy. Quantitative levels are typically not clinically useful. For summary of therapeutic and toxic levels of most benzodiazepines, see (Cardoni, 1985).
2) Detection in plasma is usually only performed in specialized analytical toxicology laboratories.
3) Patients with prolonged coma after ingesting benzodiazepines should have CPK determination to rule out rhabdomyolysis (Caruana et al, 1983).

B) LABORATORY INTERFERENCE

1) Visine(R), hand soap, Drano(R), and bleach caused false-negative tests for benzodiazepines (Mikkelsen & Ash, 1988).

a) Urine containing benzodiazepines up to 0.78 mg/L were falsely negative with Visine(R) at 107 mL/L.
b) Drano(R) or bleach at 125 mL/L interfered when drug concentrations were less than 3 mg/L.
c) Soap at concentrations of 42 mL/L interfered when drug concentrations were less than 6.5 mg/L.

2) FLUMAZENIL: Flumazenil does not interfere with commonly used urine, plasma, or serum qualitative and quantitative tests for benzodiazepines (EMIT(R)-dau assay (urine), EMIT(R)-TOX and EMIT(R)-ST (serum/plasma), Benzodiazepine TDX(R) (urine)) (Doem & Unger, 1988; Martens et al, 1990).

4.1.3)

A) URINALYSIS

1) Patients with prolonged coma after ingesting benzodiazepines should have a urinalysis performed to rule out rhabdomyolysis (Caruana et al, 1983).

Methods

1) Semiquantitative and qualitative EMIT(R) homogeneous enzyme immunoassays and a fluorescence polarization immunoassay are available for measurement of benzodiazepines in urine, serum or plasma (Verstraete et al, 1998).

a) Drugs and metabolites detected include diazepam, chlordiazepoxide, oxazepam, midazolam (Fraser et al, 1991), N-desmethyldiazepam, flurazepam, desalkylflurazepam, and lorazepam.

2) However, urine drug tests do not detect all benzodiazepines; in particular, midazolam, chlordiazepoxide, and flunitrazepam are not detected on many urinary assays, so a negative screen does not rule out a benzodiazepine ingestion (Moeller et al, 2008).
3) Assay responses are cumulative of the parent drug and its metabolites.
4) The detection limit (sensitivity) of the semiquantitative urine assay is 0.7 mcg/mL for oxazepam or its equivalent; the detection limit of the qualitative urine assay is 0.5 mcg/mL for oxazepam.

a) The semiquantitative serum assay measures drug concentrations in the range of 0.3 to 2 mcg/mL for diazepam; the qualitative serum assay's detection limit is 0.5 mcg/mL for diazepam.
b) The detection limit of the fluorescence polarization immunoassay is 12 nanograms/mL for nordiazepam (Verstraete et al, 1998).

5) Serum assays correlate well with gas-liquid chromatography (GLC), and the urine assay compares favorably with GLC, thin-layer chromatography, high performance liquid chromatography, and radioimmunoassay.
6) FALSE-NEGATIVE RESULTS

a) CASE REPORT: A 58-year-od woman presented to the emergency department after intentionally ingesting 24 mg of lorazepam over a 24-hour period. Two qualitative urine immunoassays, performed approximately 4 hours apart, were negative for benzodiazepines. Because of the discrepancies between the patient's history and the results of the immunoassays, the two urine samples were reanalyzed via gas chromatography/mass spectrometry. Both samples were positive, with lorazepam levels of more than 20,000 nanograms/mL.

1) The authors have suggested possible reasons for the initial false-negative results. One theory is that direct, rapid precipitation of immune complexes may have occurred. The complexes may have consisted of either reagent antibodies and abundant drug, or of free drug, reagent antibodies, and microparticles. Another theory is that an undetected inhibitor, that could either change the microparticle aggregation time or rate, may have been present (Wenk, 2006).

b) False-negative results using an EMIT(R) II urine immunoassay have also been reported with bromazepam. Bromazepam has two major metabolites: 3-hydroxybromazepam (3HB) and 2-amino-3-hydroxy-5-bromobenzoylpyridine (AHBBP). Only 3HB appeared to cross-react with the antibody within the EMIT(R) II urine immunoassay, but AHBBP did not. However, gas chromatography/mass spectrometry (GC/MS) was able to detect the presence of AHBBP, suggesting that AHBBP screening by GC/MS should be performed in order to avoid false-negative results (El-Haj et al, 2007).

1) TEMAZEPAM: Temazepam has been quantified in human plasma by high performance liquid chromatography (Ho et al, 1983).
2) Benzodiazepines can be detected in body fluids using an high performance liquid chromatography method with photodiode array detection (Minder et al, 1987; Minder et al, 1987a; Minder et al, 1988; Ahrens et al, 2000) and with ultraviolet detection (Verstraete et al, 1998).

a) The detection limit, using the high performance liquid chromatography method with ultraviolet detection, is approximately 5 to 10 nanograms/mL (Verstraete et al, 1998).

3) Negative ion chemical ionization gas chromatography/mass spectrometry has been used for the determination of flunitrazepam and its metabolite, 7-aminoflunitrazepam, in the hair of 10 healthy volunteers following ingestion of a single 2-mg dose of flunitrazepam. Using this method, the limits of detection were 0.5 picograms (pg)/mg and 0.2 pg/mg for flunitrazepam and 7-aminoflunitrazepam, respectively. The limits of quantitation were 2.5 picograms (pg)/mg and 0.5 pg/mg for flunitrazepam and 7-aminoflunitrazepam, respectively (Negrusz et al, 2001).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Admit patients with severe symptoms (ie, coma, respiratory failure, or hypotension unresponsive to IV fluids) or if they are a danger to themselves. Discharge when asymptomatic and when psychiatric issues have been addressed.

6.3.1.2) HOME CRITERIA/ORAL

A) Healthy children with unintentional ingestions of 1 to 2 tablets may be observed at home if the family is responsible. If significant ataxia or drowsiness develops, refer the patient to the hospital. Asymptomatic adults with unintentional ingestions and a good social situation may remain at home.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) All patients with intentional ingestion or significant ataxia, drowsiness, or respiratory depression should be referred to the hospital for observation. Patients with unreliable social situations may also need observation. Patients may be discharged when asymptomatic.

Monitoring

Oral Exposure

6.5.1)

A) PREHOSPITAL: Activated charcoal is usually not necessary unless the patient has a dangerous co-ingestant. Avoid if the patient is too sedated.
B) EMESIS/CONTRAINDICATED

1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression.

C) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

3) In a randomized, crossover study, administration of activated charcoal, 30 minutes after ingestion of 10 mg temazepam, reduced the peak plasma concentration of temazepam by 29% (Lapatto-Reiniluoto et al, 2000).

6.5.3)

A) AIRWAY MANAGEMENT

1) Treat respiratory depression with assisted ventilation and/or flumazenil if available.

B) MONITORING OF PATIENT

1) Serum glucose, venous blood gases, ECG, and pulse oximetry may be useful.
2) Urine drug tests do not detect all benzodiazepines; in particular, midazolam, chlordiazepoxide, and flunitrazepam are not detected on many urinary assays, so a negative screen does not rule out a benzodiazepine ingestion.

C) FLUMAZENIL

1) SUMMARY: A benzodiazepine agonist/antagonist, flumazenil, has reversed coma and respiratory depression in severely poisoned patients. Flumazenil has also been reported to reverse cardiovascular depression secondary to benzodiazepine use (Coates et al, 1991).
2) Flumazenil is a competitive antagonist of benzodiazepines, and reverses all central effects (Prod Info ROMAZICON(R) injection, 2007; Amrein et al, 1988). It also antagonizes the depressive effect of benzodiazepine analogs like zolpidem (Wyss et al, 1996).
3) DURATION: The duration of effect depends on the type and dose of benzodiazepine ingested, the dose of flumazenil, and the time interval between ingestion of the benzodiazepine and administration of flumazenil; it is usually 1 to 4 hours. It is also directly proportional to dosage; 3-mg doses produce the longest duration (Danton et al, 1988).
4) INDICATIONS

a) For benzodiazepine or benzodiazepine analogs overdose and reversal of conscious benzodiazepine sedation (Prod Info ROMAZICON(R) injection, 2007).

1) Flumazenil has been used as a diagnostic tool for comatose patients with unknown overdose ingestions. However, flumazenil should not be used if tricyclic antidepressant ingestion is suspected or if the patient has any other contraindication to flumazenil. There is no known benefit of treatment with flumazenil in a mixed drug overdose patient who is in critical condition (Prod Info ROMAZICON(R) injection, 2007; Burkhart et al, 1989; Burkhart & Kulig, 1990; Hodgkinson & Driscoll, 1991; Ahmad et al, 1991; Hojer et al, 1990; Hojer & Baehrendtz, 1988; Sprenger et al, 1994; Weinbroum et al, 1996; Winkler et al, 1993).
2) EFFICACY: Flumazenil has been found to be effective in reducing coma in patients admitted with probable or known benzodiazepine overdoses (Ritz et al, 1990; Skielboe et al, 1991; Martens et al, 1990; O'Sullivan & Wade, 1987; Knudsen et al, 1988; Ume & Gelb, 1988; Chern et al, 1995; Proudfoot, 1995; Weinberg et al, 1994).

5) REVERSAL OF CONSCIOUS SEDATION

a) ADULT

1) INTRAVENOUS: Recommended initial IV dose is 0.2 mg (2 mL), administered over 15 seconds. If adequate consciousness is not obtained within 45 seconds, a further dose of 0.2 mg (2 mL) may be repeated at 60-second intervals to a maximum total dose of 1 mg (10 mL). Most patients will respond to 0.6 to 1 mg; titrate each case as needed (Prod Info ROMAZICON(R) injection, 2007).

a) Can be diluted in D5W, normal saline, or lactated Ringers solution. Secure the airway and have venous access prior to flumazenil administration (Prod Info ROMAZICON(R) injection, 2007).
b) RESEDATION: In this event, repeated doses may be administered at 20-minute intervals. No more than 1 mg (given as 0.2 mg/mL) should be administered at any one time, and no more than 3 mg should be given in any one hour. In general, if a patient shows no sign of sedation within 2 hours after a 1 mg-dose of flumazenil, serious resedation at a later time is unlikely (Prod Info ROMAZICON(R) injection, 2007).
c) CONTINUOUS INFUSION: The use of continuous flumazenil maintenance infusion over 5 to 24 hours seems of therapeutic value in the event of resedation after initial response (Winkler et al, 1993; Weinbroum et al, 1996; Brammer et al, 1998).

1) CASE REPORT: Continuous intravenous flumazenil infusion was initiated, at a rate of 1.0 mg/hour, in a 24-year-old female who presented with coma (Glasgow Coma score of 8) and clinical hypoventilation after an overdose ingestion of flunitrazepam tablets (total dose of 100 mg). Prior to initiation of the infusion, the patient had received several intravenous boluses of flumazenil which increased her Glasgow Coma score to 15 with normalization of ventilation. After initiation of the infusion, the patient continually maintained a Glasgow Coma score of 15. Discontinuation of the flumazenil infusion, fourteen hours later, resulted in resedation and hypoventilation of the patient. The infusion was restarted at 1 mg/hr and, 30 hours later, was discontinued without recurrence of resedation or hypoventilation (Brammer et al, 2000).
2) CASE REPORT: Continuous infusion of flumazenil 0.5 to 1 mg/hr was used to treat a patient with CNS depression attributed to accumulation of chlordiazepoxide and its active metabolites (Maxa et al, 2003).
3) EXPERIMENTAL ROUTE OF ADMINISTRATION: A study was conducted to determine if therapeutic plasma concentrations of flumazenil can be achieved with endotracheal administration. Six elective surgical patients received 1 mg flumazenil in 10 mL of saline intratracheally during general anesthesia. Therapeutic blood levels of flumazenil were attained within 1 minute after flumazenil administration and there were no adverse effects reported among the 6 patients (Palmer et al, 1998).

b) PEDIATRIC

1) For reversal of the sedative effects of benzodiazepines after conscious sedation, the usual dose of flumazenil in children 1 year or older is 0.01 mg/kg (up to 0.2 mg) administered intravenously over 15 seconds. If adequate anesthesia reversal does not occur after waiting an additional 45 seconds, further injections of 0.01 mg/kg (up to 0.2 mg) may be repeated at 1-minute intervals as needed, up to 4 times. The maximum total dose is 0.05 mg/kg or 1 mg, whichever is lower (Prod Info ROMAZICON(R) injection, 2007).

a) The safety and efficacy of flumazenil have not been established in pediatric patients less than one year of age for reversal of sedative effects of benzodiazepines after conscious sedation (Prod Info ROMAZICON(R) injection, 2007).
b) RESEDATION: The safety and efficacy of administering repeated doses of flumazenil in pediatric patients in the case of resedation have not been established (Prod Info ROMAZICON(R) injection, 2007).
c) In a study conducted to determine the safety and efficacy of flumazenil for the reversal of benzodiazepine-induced conscious sedation in children, flumazenil was given in incremental doses of 0.01 mg/kg (0.2-mg maximum dose) at 1-minute intervals, to a maximum total dose of 0.05 mg/kg (1-mg maximum dose).

1) One hundred out of 107 children (96%) who received flumazenil partially or completely responded to the flumazenil by 10 minutes after administration. The most frequently occurring adverse effects included abnormal crying, agitation, and aggressiveness which were possibly related to flumazenil administration (Shannon et al, 1997).

6) TREATMENT OF BENZODIAZEPINE OVERDOSE

a) ADULT

1) Recommended initial intravenous dose is 0.2 mg (2 mL), administered over 30 seconds. If adequate consciousness is not obtained within 30 seconds, a further dose of 0.3 mg (3 mL) may be administered over 30 seconds (Prod Info ROMAZICON(R) injection, 2007).
2) Further doses of 0.5 mg (5 mL) may be administered at 1 minute intervals up to a maximum total dose of 3 mg (30 mL). Most patients will respond to 1 to 3 mg; doses beyond 3 mg do not usually produce additional effects (Prod Info ROMAZICON(R) injection, 2007).
3) Occasionally, patients with partial response at 3 mg may require a 5-mg total dose for full response. If a patient has not responded within 5 minutes of administration of a 5-mg total dose, the major cause of sedation is not likely to be benzodiazepines (Prod Info ROMAZICON(R) injection, 2007).
4) Many clinicians have found that higher doses, 1 to 10 mg in an adult, may be necessary to treat the profound coma in some overdose cases (Lheureux & Askenasi, 1988; Personal Communication, 1992; Mapelli et al, 1988; Prischl et al, 1988; Rouzioux et al, 1988).

b) PEDIATRIC

1) Administer an initial dose of 0.01 mg/kg (up to 0.2 mg) in children 1-year-old or older; repeat as necessary at 60-second intervals, up to a maximum total dose of 0.05 mg/kg or 1 mg, whichever is less (Prod Info ROMAZICON(R) injection, 2007).
2) Flumazenil has also been used in children, 4, 7, and 13 years of age, who overdosed on benzodiazepines in doses of 10 mcg/kg intravenously for 2 doses (Wood et al, 1988) and in a 3-year-old girl following an overdose ingestion of lorazepam (total amount ingested was approximately 15 mg) (Clark et al, 1995).
3) NEONATES: Flumazenil administration consisted of 0.02 mg/kg intravenous loading dose followed by 0.05-mg/kg/hour maintenance infusion of 6 hours duration in a neonate following maternal benzodiazepine ingestion (Richard et al, 1991).

a) A woman received 20 mg of diazepam intravenously 1 hour prior to the caesarean section delivery of an apneic, blue, hypotonic male infant. The infant received flumazenil 10 mcg/kg intravenously with vigorous movement and respiratory effort following in 1 minute. A flumazenil infusion of 10 mcg/kg/hour was continued for 6 hours with no further episodes of apnea or desaturation. An uneventful recovery ensued (Cone et al, 1993).

4) FETAL: Administration of flumazenil (0.3 mg), to a 22-year-old primipara (36 weeks gestation) who overdosed on diazepam, restored the normal beat-to-beat variation and periodic oscillations of amplitude of fetal heart rate. No adverse effects or withdrawal symptoms were reported (Stahl et al, 1993).

7) CONTRAINDICATIONS

a) Flumazenil should not be used in patients with serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, seizure), dysrhythmias (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), or cardiovascular collapse at presentation. Flumazenil should not be used until the effects of neuromuscular blocking agents have worn off (Prod Info ROMAZICON(R) injection, 2007).
b) Flumazenil should not be used in patients who are benzodiazepine-dependent or who have been given benzodiazepines for control of a life-threatening condition (Prod Info ROMAZICON(R) injection, 2007).

1) In a small, 10-week study of benzodiazepine overdose patients (n=22) who presented to an emergency department, 21 of the patients were NOT eligible to receive flumazenil due to daily benzodiazepine use (Thomson et al, 2006).

c) There is no known benefit of treatment with flumazenil in a mixed drug overdose patient who is in critical condition. Flumazenil should NOT be used in cases where seizures are likely, from any cause (Prod Info ROMAZICON(R) injection, 2007).

1) Precipitation of seizures may occur in epileptic patients or those coingesting epileptogenic agents (Bismuth et al, 1985). Seizure has also been reported after flumazenil administration in a pediatric patient (McDuffee & Tobias, 1995).

d) TRICYCLIC ANTIDEPRESSANTS: Flumazenil is NOT recommended for use when patients show signs of tricyclic antidepressant toxicity; the patient should be allowed to remain sedated (with respiratory and other support) until the tricyclic signs abate. Concurrent ingestion of large doses of tricyclic antidepressants may predispose patients to seizures upon flumazenil administration (Prod Info ROMAZICON(R) injection, 2007).

1) Deaths have occurred after flumazenil treatment in mixed overdose patients who have ingested large doses of tricyclic antidepressants.
2) CASE REPORT: A 42-year-old female who ingested 80 mg of clonazepam and 1 g of imipramine, had a generalized tonic-clonic seizure 5 minutes after receiving 1 mg of flumazenil (0.25 mg/minute). The seizure stopped during injection of 10 mg of diazepam and did not recur (Mordel et al, 1992).
3) ANIMAL DATA: Flumazenil 5 mg/kg did not cause seizures in mice overdosed with diazepam and either imipramine or maprotiline. Flumazenil also did not cause acute withdrawal from large doses of diazepam (Geller et al, 1991).
4) ANIMAL DATA: Flumazenil 0.2 mg/kg was given to 6 dogs overdosed on amitriptyline and midazolam. Four of six dogs developed seizures within 4 minutes. The author suggested that seizures were not reported in other animal studies due to the slight anticonvulsant effect of the higher doses of flumazenil (5 mg/kg) used in those studies (Lheureux et al, 1992).

8) ADVERSE EFFECTS

a) Adverse effects have included fatigue, nausea and vomiting, agitation, confusion, and rarely seizures and cardiac arrhythmias. Heart block has been reported in one elderly patient given flumazenil following possible benzodiazepine and acetaminophen overdose (Herd & Clarke, 1991). Panic attacks may occur in patients under psychiatric care; signs associated with head trauma may be exacerbated in some patients.

1) Be prepared to treat any of these signs; most seizures have responded to treatment with benzodiazepines, phenytoin, or barbiturates.
2) Deaths have occurred in patients treated with flumazenil; most of these occurred with severe underlying disease states or overdoses of large amounts of non-benzodiazepines (Bodenham, 1989; Lim, 1989).
3) In clinical studies, most adverse reactions were an extension of the pharmacologic effects of flumazenil in reversing benzodiazepine effects (Prod Info ROMAZICON(R) injection, 2007).
4) WITHDRAWAL: Withdrawal syndromes have been reported after single overdoses of benzodiazepines (Lopez & Rebollo, 1990); be prepared to treat for this possibility (signs may include seizures).
5) FLUMAZENIL OVERDOSE: Large intravenous doses of flumazenil administered to healthy volunteers with no benzodiazepine on board did not cause any serious adverse effects. Animal toxicology studies reveal that the risk in man given therapeutic doses or even accidental/intentional overdoses is extremely small. The agent has a wide margin of safety (Schlappi et al, 1988).

9) THERAPEUTIC INDEX: 3000

a) CLINICAL TRIALS

1) Use of flumazenil to reverse midazolam-induced sedation in subjects who had taken diazepam or triazolam was effective and caused no significant changes in laboratory values, vital signs, or EKG (Danton et al, 1988).

b) In a double-blind study including 18 patients in whom a benzodiazepine intoxication was suspected, flumazenil (Lanexat(R), RO-15,4513) was compared with placebo. There was a highly significant effect on consciousness; all patients awakened, usually within minutes. No adverse effects were observed. In 2 patients, the clinical condition deteriorated 1 to 2 hours after the antagonist was given (Aarseth et al, 1988).
c) A two-phase study (a controlled, randomized, double-blind study followed by a prospective, open study) was performed. Unconscious patients (n=110) suspected of benzodiazepine overdose were treated with flumazenil. The first 31 patients were studied in a double-blind fashion while the others were studied according to an open protocol. Patients who remained unconscious among the double-blind patients and those who relapsed into coma after the first dose of flumazenil were later treated in the open phase portion of the study.

1) Fourteen of 17 double-blind patients regained consciousness after an average administration of flumazenil 8 mg compared with 1 of 14 placebo patients (p less than 0.001). Twenty-five percent of patients did not regain consciousness due to ingestions of high concentrations of non-benzodiazepine drugs. Sixty percent of the responders remained awake for 72 +/- 37 minutes. Forty percent relapsed into coma after 18 +/- 7 minutes and various CNS depressant drugs were detected in their blood in addition to benzodiazepines.
2) Flumazenil adverse effects included 5 cases of transient hypertension and tachycardia and 27 cases of mild anxiety, restlessness, and aggression (Weinbroum et al, 1996)

d) A prospective study was conducted to determine the cardiovascular response and stress reaction following flumazenil administration to patients sedated with a midazolam infusion. The patients' level of consciousness increased significantly after administration of flumazenil and returned to baseline within 30 minutes. The patients did not experience any significant stress reactions to the flumazenil; however, there were transient elevations in heart rate, blood pressure, systolic pulmonary artery pressure, and pulmonary artery occlusion pressure (Kamijo et al, 2000).

D) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

E) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE

1) Administration of dexamethasone pulse therapy, 1.5 mg/kg IV infused over 30 to 60 minutes and given for 3 consecutive days, resulted in complete re-epithelization in a patient who experienced toxic epidermal necrolysis several weeks after beginning phenytoin and oxazepam therapy (van der Meer et al, 2001).

F) DRUG WITHDRAWAL

1) Initial management should be administration of phenobarbital as a replacement for diazepam. 30 mg of phenobarbital is equivalent to 5 mg of diazepam or 25 mg of chlordiazepoxide. One-fourth of this calculated dose should be administered and increased as necessary to relieve abstinence symptoms.
2) A gradual taper of phenobarbital can be instituted as soon as the patient has become stable for 48 hours. Taper at a rate of 10% per day.
3) Alternatively, the benzodiazepines may be administered and then tapered by 10% per day for 10 days. Relative potency of the benzodiazepine being withdrawn from should be considered when estimating the appropriate dose of the benzodiazepine chosen for treatment of withdrawal (Schneider et al, 1987; Albeck, 1987).
4) Propranolol 20 mg three to four times daily starting on day 5 and continuing for 2 weeks has been shown to be of use in benzodiazepine withdrawal (Smith & Wesson, 1983; Wilbur & Kulik, 1983).
5) Benzodiazepine withdrawal was managed by giving one-half of the reported daily dose in diazepam, decreasing the dose by approximately 10% each day in one study (Harrison et al, 1984).
6) A case report described acute manic-like behavior after abrupt withdrawal of lorazepam 2 mg at bedtime. The authors recommended slow tapering of the shorter half-life benzodiazepine compounds (Lapierre & Labelle, 1987).
7) Slow triazolam withdrawal (Singh et al, 1986) and conversion from triazolam to flurazepam or diazepam (Fleming et al, 1986) have been advocated to withdraw patients from triazolam.
8) A 53-year-old male with a 3 month addiction to 5 mg/day of triazolam showed psychosis and delirium following abrupt withdrawal from the drug. The withdrawal was effectively treated with lorazepam (Heritch et al, 1987).

G) FETAL BENZODIAZEPINE SYNDROME

1) Recurrent apnea converted to normal respirations following administration of flumazenil to a neonate with presumed prenatal benzodiazepine exposure (Richard et al, 1991). Flumazenil administration consisted of a 0.02-mg/kg intravenous loading dose followed by a 0.05-mg/kg/hour maintenance infusion of 6 hours duration.
2) A case report described the use of aminophylline to treat diazepam intoxication in a neonate. At 2 hours postdelivery, aminophylline 2 mg/kg was given IV; within 5 minutes, muscle tone returned, and spontaneous movements were observed. Respirations normalized. Aminophylline 2 mg/kg/dose was repeated every 6 hours for the next 24 hours (Kumar et al, 1987).

H) CONTRAINDICATED TREATMENT

1) Stimulants are contraindicated in treatment of benzodiazepine poisonings.
2) AMINOPHYLLINE

a) Intravenous aminophylline has been reported to reverse benzodiazepine-induced sedation, although experience is limited (Marrosu et al, 1985; Stirt, 1981). Flumazenil, a specific benzodiazepine antagonist, is the drug of choice for reversing benzodiazepine-induced sedation and respiratory depression.

Enhanced Elimination

1) Forced diuresis or hemodialysis are ineffective.

Abstracts

Case Reports

1) ALPRAZOLAM: Two overdoses (20 to 30 mg and 60 mg) resulting in only mild toxicity (lethargy and combative) have been reported (McCormick et al, 1985).
2) BROTIZOLAM: Brotizolam is a bromotricyclobenzodiazepine with hypnotic activity. Animal studies in mice, rats, monkeys, and rabbits indicate a wide margin of safety. There were no significant teratogenic effects in animals. Toxicology findings of significance were first recorded at doses of 7 to 10 mg/kg (1000 times the intended human therapeutic dose) (Hewett et al, 1986). Other animal studies suggest that brotizolam may not cause significant motor impairment at therapeutic dosage in humans (Lehr et al, 1986).
3) CLOBAZAM: Clobazam overdose (390 mg) produced extreme drowsiness without coma or significant respiratory depression in a 44-year-old man (Anon, 1980).
4) CLONAZEPAM: Clonazepam overdose in children has produced drowsiness and ataxia without circulatory or respiratory collapse (Bladin, 1973; Barnett, 1973).
5) DIAZEPAM: Respiratory arrest developed in a 56-year-old man with chronic obstructive pulmonary disease, angina, and hypertension who received a 10-mg IV bolus of diazepam during a spermatocele repair. The patient was awake and responsive after 15 minutes, but was amnestic for the procedure (Hall & Ovassapian, 1977).
6) DIAZEPAM: Prolonged coma (7 days) occurred in a patient with hypoalbuminemia treated with diazepam and phenobarbital. Elimination half-life of diazepam was reduced from 195 hours to 18 hours with multiple dose charcoal. Hypoalbuminemia may have increased the free fraction of diazepam, increasing CNS depression and making more drug available to diffuse into the gastrointestinal tract and adsorb to charcoal (Traeger & Haug, 1986).
7) FLUNITRAZEPAM: A flunitrazepam overdose may mimic asymmetrical neurological signs which can suggest a structural brainstem lesion. Flunitrazepam should be considered to cause alpha pattern coma. In one case, a 60-year-old man developed symptoms that simulated a structural brainstem lesion following a 50-mg intentional overdose of flunitrazepam; following supportive care, neurological recovery was complete (Deleu & DeKeyser, 1987).
8) FLUNITRAZEPAM: A flunitrazepam overdose (40 mg) in an 11.5 kg child produced hypotonia, hypotension, bradycardia, respiratory, and CNS depression. Vital signs and mental status improved with flumazenil, which was continued as needed for 48 hours after ingestion (Roald & Dahl, 1989).
9) FLUNITRAZEPAM: Flunitrazepam (Rohypnol(R); "Roofies") has become popular as a drug of abuse, often combined with alcohol, marijuana, or cocaine to produce an intense "high". It has been used as a "date rape" drug, both for its properties of lowering inhibitions and because it can cause retrograde amnesia. When taken together with alcohol or other depressant drugs, there is a risk of respiratory depression and aspiration of gastric contents (Emergencynet, 1996).
10) FLURAZEPAM: A prolonged coma (13 days) with respiratory depression was reported in a 48-year-old woman after ingestion of 1.5 g chlordiazepoxide and 2.4 g flurazepam (Ruff et al, 1981).
11) FLURAZEPAM: Adult respiratory distress syndrome developed in a 60-year-old woman after a mixed ingestion that included flurazepam and phenazone (Stringer, 1985).
12) LORAZEPAM: A case report describes a 60-year-old woman who developed an orofacial dyskinesia 2 weeks after starting lorazepam 3 mg three times daily. The movements gradually abated over 4 weeks following stoppage of lorazepam(Sandyk, 1986). Delirium and persecutory delusions developed in a patient receiving IV lorazepam and morphine and topical silver sulfadiazine after sustaining 30% body surface area burns (Stanford & Pine, 1988).
13) MIDAZOLAM: Three case reports describe ventricular dysrhythmias associated with the use of midazolam as a surgical premedicant. These recurred approximately 45 minutes after IV infusion. The author does not mention the possibility of 1% lidocaine causing this reaction, although it would be rare (Arcos, 1987).
14) MIDAZOLAM: A 59-year-old man with hypertension, diabetes mellitus, organic brain syndrome, and chronic renal insufficiency sustained cardiorespiratory arrest one hour after receiving midazolam 2.5 mg, meperidine 50 mg, and glycopyrrolate 0.2 mg IM (Taylor & Simon, 1990).
15) NITRAZEPAM: A 55-year-old man with chronic bronchitis and emphysema died following overdose with approximately 150 mg nitrazepam and ethanol (Torry, 1976).
16) NITRAZEPAM: Two adult fatalities have been associated with nitrazepam ingestion. An unknown amount of nitrazepam had been ingested in each case and one of the cases had concomitant ethanol ingestion. Postmortem levels were noted(Giusti & Chiarotti, 1979).
17) OXAZEPAM: A 45-year-old man developed deep coma and respiratory depression following ingestion of an unknown amount of oxazepam. Oxazepam interfered with glucose testing, giving spuriously elevated levels (1680 mg/dL) (Zileli et al, 1971).
18) OXAZEPAM: A 16-year-old adolescent developed grade I coma with absent deep tendon reflexes after ingesting 900 mg of oxazepam (Granguli, 1970).
19) OXAZEPAM: A 2-year-old girl developed lethargy, ataxia, absent deep tendon reflexes, and facial edema after ingesting 90 mg of oxazepam. Some facial edema and indifference to various sensory stimuli persisted two weeks later, several days after oxazepam was no longer detectable in blood (Shimkin & Shaivitz, 1966).
20) TRIAZOLAM : Extreme drowsiness developed in an adult after ingestion of 7.5 mg triazolam despite therapeutic blood triazolam levels three hours post-ingestion (Price & Giannini, 1986).
21) TRIAZOLAM: Ingestion of 2 to 20 mg of triazolam has been reported to cause apnea, lethargy, and coma within one hour of ingestion (Olson et al, 1985). Ataxia, lethargy, and slurred speech are common.
22) TRIAZOLAM: Ingestion of approximately 28.5 mg of triazolam in a 75-year-old woman resulted in fatality. The patient had a therapeutic blood level of orphenadrine, 76 nanomoles/L triazolam, and was negative for other drugs (Sunter et al, 1988).
23) TRIAZOLAM: An 83-year-old woman developed respiratory depression requiring 36 hours of ventilatory support following a single 0.5-mg dose of triazolam. No serum levels or toxicology screen results were reported. The patient was in her eighth day of treatment with erythromycin ethylsuccinate 400 mg four times daily for symptoms of mild bronchitis which may have contributed to the prolonged triazolam effects (Sullivan, 1989).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) BROMAZEPAM

a) The recommended dose is 3 to 12 mg orally two or three times daily; recommended MAXIMUM DOSE: 60 mg/day (Prod Info LEXOTAN(R) oral tablets, 2009).

2) CHLORDIAZEPOXIDE

a) ANXIETY: The recommended oral dose is 5 to 25 mg 2 to 4 times daily, depending on the severity of symptoms (Prod Info LIBRIUM(R) oral capsules, 2005a)
b) PREOPERATIVE ANXIETY: The recommended IM dose is 50 to 100 mg given 1 hour prior to surgery (Prod Info LIBRIUM(R) oral capsules, 2005a).

3) CLOBAZAM

a) 30 KG BODY WEIGHT OR LESS: Initial dose is 5 mg orally once daily. The dose may be increased to 10 mg/day, in two divided doses, starting on day 7, and to 20 mg/day, in two divided doses, starting on day 14 (Prod Info ONFI(R) oral tablets, suspension, 2012).
b) GREATER THAN 30 KG BODY WEIGHT: Initial dose is 10 mg/day orally, in two divided doses. The dose may be increased to 20 mg/day, in two divided doses, starting on day 7, and to 40 mg/day, in two divided doses, starting on day 14 (Prod Info ONFI(R) oral tablets, suspension, 2012).
c) GERIATRIC PATIENTS: Initial dose is 5 mg orally once daily. The dose may be titrated no faster than every 7 days to 10 to 20 mg/day, in two divided doses, depending on weight. If tolerated, the dose may be titrated to a MAXIMUM DOSE of 20 to 40 mg/day (depending on weight), starting on day 21 (Prod Info ONFI(R) oral tablets, suspension, 2012).

4) CLONAZEPAM

a) SEIZURE DISORDER: The recommended initial oral dose is 1.5 mg/day divided into 3 doses, The dose may be increased every 3 days as needed; MAXIMUM DOSE: 20 mg/day (Prod Info KLONOPIN(R) oral tablets, orally disintegrating tablets, 2009).
b) PANIC DISORDER: The recommended target oral dose is 1 mg/day; typically divided into 2 doses. The dose may be increased as needed; MAXIMUM DOSE: 4 mg/day (Prod Info KLONOPIN(R) oral tablets, orally disintegrating tablets, 2009).

5) CLORAZEPATE DIPOTASSIUM

a) ANXIETY: For the treatment of anxiety, the recommended dose is 15 to 60 mg/day in divided doses or 15 mg as a single daily dose at bedtime (Prod Info TRANXENE(R) T-TAB, SD, SD HALF STRENGTH oral tablets, 2005).
b) PARTIAL SEIZURES: As adjunctive therapy for the management of partial seizures, the recommended initial dose is 7.5 mg three times daily, and may be increased by no more than 7.5 mg on a weekly basis as needed; MAXIMUM DOSE: 90 mg/day (Prod Info TRANXENE(R) T-TAB, SD, SD HALF STRENGTH oral tablets, 2005)

6) DIAZEPAM

a) ORAL: Depending on the indication, the recommended oral dose ranges from 2 to 10 mg administered 2 to 4 times daily (Prod Info VALIUM(R) oral tablets, 2008a).
b) INJECTION: The recommended dose is 2 to 20 mg administered IM or IV, depending on the indication and the severity (Prod Info diazepam injection, 2004).

7) ESTAZOLAM

a) The recommended initial dose is 1 to 2 mg orally as a single dose at bedtime (Prod Info estazolam oral tablets, 2008).

8) FLURAZEPAM

a) The recommended oral dose is 15 to 30 mg as a single dose at bedtime (Prod Info DALMANE(R) oral capsules, 2007).

9) LORAZEPAM

a) ORAL

1) The recommended dose is 2 to 6 mg/day orally in divided doses (Prod Info ATIVAN(R) oral tablets, 2007a).

b) INTRAMUSCULAR

1) For use as a preanesthetic agent, the usual recommended dose is 0.05 mg/kg intramuscularly; MAXIMUM DOSE: 4 mg (Prod Info ATIVAN(R) intramuscular, intravenous injection, 2006)

c) INTRAVENOUS

1) PREANESTHETIC: The usual recommended initial intravenous dose is 2 mg total or 0.044 mg/kg, whichever is smaller (Prod Info ATIVAN(R) intramuscular, intravenous injection, 2006).
2) STATUS EPILEPTICUS: For treatment of status epilepticus, the recommended dose is 4 mg given intravenously at a rate of 2 mg/minute. If seizures recur, another 4-mg dose may be given (Prod Info ATIVAN(R) intramuscular, intravenous injection, 2006)

10) MIDAZOLAM

a) INTRAMUSCULAR INJECTION: For preoperative sedation/anxiolysis/amnesia, the recommended dose for patients less than 60 years of age is 5 mg (0.07 to 0.08 mg/kg) administered up to 1 hour prior to surgery. For patients 60 years of age or older, the recommended dose is 2 to 3 mg (0.02 to 0.05 mg/kg) (Prod Info midazolam hcl IV injection, 2004).
b) INTRAVENOUS INJECTION: For sedation/anxiolysis/amnesia, the recommended dose for patients less than 60 years of age is 1 to 2.5 mg administered over a period of at least 2 minutes, up to a maximum total dose of 5 mg. For patients 60 years of age or older, 1 to 2.5 mg administered over a period of at least two minutes, up to a maximum total dose of 3.5 mg (Prod Info midazolam hcl IV injection, 2004).
c) CONTINUOUS INTRAVENOUS INFUSION: A loading dose of 0.01 to 0.05 mg/kg (approximately 0.5 to 4 mg) may be administered slowly over several minutes, followed by a maintenance infusion rate of 0.02 to 0.1 mg/kg/hour (1 to 7 mg/hour) (Prod Info midazolam hcl IV injection, 2004).

11) OXAZEPAM

a) The recommended dose is 10 to 30 mg orally 3 or 4 times daily, depending on the indication (Prod Info oxazepam oral capsule, 2007).

12) QUAZEPAM

a) The recommended dose is 7.5 mg orally as a single dose at bedtime. The dose may be increased if necessary. MAXIMUM DOSE: 15 mg/day (Prod Info DORAL(R) oral tablets, 2013).

13) TEMAZEPAM

a) The recommended dose is 7.5 to 30 mg orally as a single dose at bedtime (Prod Info RESTORIL(TM) oral capsules, 2008a).

14) TRIAZOLAM

a) The usual recommended dose is 0.25 mg orally as a single dose at bedtime. The MAXIMUM DOSE is 0.5 mg (Prod Info HALCION(R) oral tablets, 2008a).

7.2.2)

A) SPECIFIC SUBSTANCE

1) BROMAZEPAM

a) Safety and efficacy in pediatric patients have not been established (Prod Info LEXOTAN(R) oral tablets, 2009).

2) CHLORDIAZEPOXIDE

a) For children 6 years of age or older, the usual dose is 5 to 10 mg orally 2 to 4 times daily (Prod Info LIBRIUM(R) oral capsules, 2005a).

3) CLOBAZAM

a) 2 YEARS AND OLDER, 30 KG OR LESS: Initial dose is 5 mg orally once daily. The dose may be increased to 10 mg/day, in two divided doses, starting on day 7, and to 20 mg/day, in two divided doses, starting on day 14 (Prod Info ONFI(R) oral tablets, suspension, 2012)
b) 2 YEARS AND OLDER, GREATER THAN 30 KG: Initial dose is 10 mg/day orally, in two divided doses. The dose may be increased to 20 mg/day, in two divided doses, starting on day 7, and to 40 mg/day, in two divided doses, starting on day 14 (Prod Info ONFI(R) oral tablets, suspension, 2012)
c) Safety and efficacy in pediatric patients less than 2 years of age have not been established (Prod Info ONFI(R) oral tablets, suspension, 2012).

4) CLONAZEPAM

a) SEIZURE DISORDER: For infants and children up to 10 years of age or 30 kg of body weight, the initial dose is 0.01 to 0.03 mg/kg/day, given in 2 or 3 divided doses. The dose may be increased up to a maintenance dose of 0.1 to 0.2 mg/kg/day given in 3 divided doses (Prod Info KLONOPIN(R) oral tablets, orally disintegrating tablets, 2009).
b) PANIC DISORDER: Safety and efficacy in pediatric patients have not been established (Prod Info KLONOPIN(R) oral tablets, orally disintegrating tablets, 2009).

5) CLORAZEPATE DIPOTASSIUM

a) CHILDREN 9 TO 12 YEARS OF AGE: As adjunctive therapy for the management of partial seizures, the recommended initial dose is 7.5 mg two times daily, and may be increased, as needed, by no more than 7.5 mg on a weekly basis; MAXIMUM DOSE: 60 mg/day (Prod Info TRANXENE(R) T-TAB, SD, SD HALF STRENGTH oral tablets, 2005)
b) CHILDREN OLDER THAN 12 YEARS OF AGE: As adjunctive therapy for the management of partial seizures, the recommended dose is 7.5 mg three times daily with an increase in dose every week, as needed; MAXIMUM DOSE: 90 mg/day (Prod Info TRANXENE(R) T-TAB, SD, SD HALF STRENGTH oral tablets, 2005).

6) DIAZEPAM

a) ORAL

1) INFANTS AND CHILDREN 6 MONTHS OF AGE AND OLDER: The usual recommended dose is 1 to 2.5 mg orally 3 or 4 times daily (Prod Info VALIUM(R) oral tablets, 2008a).

b) INTRAVENOUS

1) INFANTS AND CHILDREN 30 DAYS OF AGE TO LESS THAN 5 YEARS OF AGE: For treatment of status epilepticus, the recommended dose is 0.2 to 0.5 mg administered slowly intravenously every 2 to 5 minutes; MAXIMUM DOSE: 5 mg (Prod Info diazepam injection, 2004).
2) CHILDREN 5 YEARS OF AGE OR OLDER: For treatment of status epilepticus, the recommended dose is 1 mg administered slowly intravenously every 2 to 5 minutes; MAXIMUM DOSE: 10 mg (Prod Info diazepam injection, 2004)

7) ESTAZOLAM

a) Safety and efficacy in pediatric patients have not been established (Prod Info estazolam oral tablets, 2008).

8) FLURAZEPAM

a) Safety and efficacy in pediatric patients have not been established (Prod Info DALMANE(R) oral capsules, 2007).

9) LORAZEPAM

a) ADJUNCT TO ANTIEMETIC THERAPY FOR CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING: 0.025 to 0.05 mg/kg IV or orally every 6 to 12 hours as needed. Maximum 3 mg/dose (Dupuis & Nathan, 2003; None Listed, 1999).
b) ANXIETY

1) LESS THAN 12 YEARS OF AGE: 0.025 to 0.05 mg/kg/dose IV or orally, up to every 4 hours as needed. Maximum 3 mg/dose (Ratcliff et al, 2006; Robert et al, 2000; McCall et al, 1999).
2) 12 YEARS OF AGE AND OLDER: Initial, 2 to 3 mg/day orally, divided twice daily to three times daily. Usual range is 2 to 6 mg/day, with daily doses ranging from 1 to 10 mg/day. A larger dose may be taken before bedtime (Prod Info LORAZEPAM INTENSOL(TM) oral solution, 2007; Prod Info ATIVAN(R) oral tablets, 2007).

c) INSOMNIA (12 YEARS OF AGE AND OLDER): A single daily dose of 2 to 4 mg orally, usually given at bedtime (Prod Info LORAZEPAM INTENSOL(TM) oral solution, 2007; Prod Info ATIVAN(R) oral tablets, 2007)
d) PROCEDURAL SEDATION/AMNESIA: 0.05 mg/kg (range, 0.02 to 0.09 mg/kg) orally/sublingually/IV 30 to 60 minutes prior to procedure. Maximum 2 mg/dose (Ratcliff et al, 2006; Hopkins et al, 1999; Henry et al, 1991; Burtles & Astley, 1983).
e) SEDATION, PICU

1) Intermittent dosing: 0.025 to 0.05 mg/kg IV every 2 to 4 hours. Maximum starting dose of 2 mg (Tobias, 1999).
2) Continuous infusion: Initial, 0.025 mg/kg/hour IV, with increases up to 0.2 mg/kg/hour. Maximum 2 mg/hour (Tobias, 1999).

f) STATUS EPILEPTICUS: 0.1 mg/kg IV push (range 0.05 to 0.1 mg/kg), may repeat dose in 5 to 10 minutes if seizure continues. Maximum dose 4 mg (Sreenath et al, 2009; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).

10) MIDAZOLAM

a) INTRAMUSCULAR: For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, the usual dose is 0.1 to 0.15 mg/kg, up to 0.5 mg/kg in patients with more severe anxiety. The total MAXIMUM DOSE should not exceed 10 mg/day (Prod Info midazolam hcl IV injection, 2004).
b) INTRAVENOUS BY INTERMITTENT INJECTION

1) CHILDREN 6 MONTHS TO 5 YEARS OF AGE: For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, the recommended initial dose is 0.05 to 0.1 mg/kg, up to a total dose of 0.6 mg/kg, not to exceed a MAXIMUM DOSE of 6 mg (Prod Info midazolam hcl IV injection, 2004).
2) CHILDREN 6 TO 12 YEARS OF AGE: For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, the recommended initial dose is 0.025 to 0.05 mg/kg, up to a total dose of 0.4 mg/kg, not to exceed a MAXIMUM DOSE of 10 mg (Prod Info midazolam hcl IV injection, 2004).

c) CONTINUOUS INTRAVENOUS INFUSION

1) NEONATES: For patients who are intubated, a continuous intravenous infusion of midazolam should be initiated at a rate of 0.03 mg/kg/hour (0.5 mcg/kg/minute) in neonates less than 32 weeks and 0.06 mg/kg/hour (1 mcg/kg/minute) in neonates greater than 32 weeks. A loading dose should NOT be used (Prod Info midazolam hcl IV injection, 2004).
2) CHILDREN (NON-NEONATES): For patients who are intubated, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over a 2 to 3 minute period should be initiated, followed by a continuous intravenous infusion at a rate of 0.06 to 0.12 mg/kg/hour (1 to 2 mcg/kg/minute) (Prod Info midazolam hcl IV injection, 2004).

d) ORAL

1) 0.3 to 0.75 mg/kg orally prior to procedure; a dose up to 1 mg/kg may be necessary in younger children (less than 6 years of age) or when midazolam is used alone for sedation. Maximum total dose 20 mg (Prod Info midazolam hcl oral syrup, 2007; Krauss & Green, 2006; Bauman & McManus, 2005; Lee-Kim et al, 2004; Aydintug et al, 2004; Cravero & Blike, 2004; Kogan et al, 2002; Cote et al, 2002; Howell et al, 2002; Algren & Algren, 1996; Connors & Terndrup, 1994).

e) INTRANASAL:

1) 0.2 to 0.5 mg/kg intranasally prior to procedure, with half of the dose given in each nostril. Maximum 10 mg (Mazaheri et al, 2008; Krauss & Green, 2006; Mittal et al, 2006; Lee-Kim et al, 2004; Kogan et al, 2002; Acworth et al, 2001; Ljungman et al, 2000; Algren & Algren, 1996; Connors & Terndrup, 1994; Theroux et al, 1993).

f) RECTALLY:

1) 0.25 to 0.75 mg/kg rectally prior to procedure (Krauss & Green, 2006; Aydintug et al, 2004; Kanegaye et al, 2003; Kogan et al, 2002; Shane et al, 1994; Beebe et al, 1992).

g) SUBLINGUAL:

1) 0.3 to 0.5 mg/kg sublingually prior to procedure (Layangool et al, 2008; Kogan et al, 2002; Karl et al, 1993).

h) SEDATION FOR MECHANICALLY VENTILATED PATIENT:

1) 0.05 to 0.2 mg/kg IV loading dose, followed by initial continuous infusion at a rate of 0.06 to 0.12 mg/kg/hour (1 to 2 mcg/kg/min); infusion should be titrated to maintain desired effect (generally by 25% increments) (Prod Info midazolam hcl IV injection, 2004; de Wildt et al, 2003; Rosen & Rosen, 1991; Notterman, 1997; Sheridan et al, 1994; Hartwig et al, 1991; Lloyd-Thomas & Booker, 1986; Booker et al, 1986).

i) STATUS EPILEPTICUS, REFRACTORY:

1) Loading dose: 0.2 mg/kg IV (Abend & Dlugos, 2008; Hayashi et al, 2007; Morrison et al, 2006; Brevoord et al, 2005; Ozdemir et al, 2005; Koul et al, 2002; Singhi et al, 2002; Rivera et al, 1993)
2) Maintenance infusion: 0.06 to 0.12 mg/kg/hour (1 to 2 mcg/kg/minute), titrated as needed for seizure control (Abend & Dlugos, 2008; Hayashi et al, 2007; Ozdemir et al, 2005; Koul et al, 2002; Singhi et al, 2002; Parent & Lowenstein, 1994; Rivera et al, 1993).

11) OXAZEPAM

a) Safety and efficacy in pediatric patients have not been established (Prod Info oxazepam oral capsule, 2007).

12) QUAZEPAM

a) Safety and efficacy in pediatric patients have not been established (Prod Info DORAL(R) oral tablets, 2013)

13) TEMAZEPAM

a) Safety and efficacy in pediatric patients have not been established (Prod Info RESTORIL(TM) oral capsules, 2008a).

14) TRIAZOLAM

a) Safety and efficacy in pediatric patients have not been established (Prod Info HALCION(R) oral tablets, 2008a).

Minimum Lethal Exposure

1) GENERAL: Few fatalities have been documented as being solely due to oral ingestion of one of these agents.
2) TRIAZOLAM

a) Several cases of fatality due to triazolam overdose have been described.
b) One case series reported three elderly patients (59, 75, and 76 years of age). Two patients had severe underlying illness and one consumed alcohol along with the triazolam (Sunter et al, 1988).
c) Two patients with multiple severe medical problems expired following ingestion of twenty-five (25) 0.5-mg triazolam tablets (Litovitz, 1987).

3) FLUNITRAZEPAM

a) One fatality due to ingestion of seven (7) flunitrazepam 4-mg tablets (28 mg total) in an adult has been reported (Heyndricks, 1987).
b) INTRAVENOUS use of benzodiazepines have resulted in respiratory depression and death.

Maximum Tolerated Exposure

1) ALPRAZOLAM

a) Two cases of alprazolam ingestion of 20 to 60 mg presented with mild lethargy and combativeness (McCormick et al, 1985).

2) CHLORDIAZEPOXIDE

a) Following overdosage situations, concomitant ethanol and chlordiazepoxide (levels of 2 to 25 mg/L) ingestion produce more CNS depression than chlordiazepoxide (levels of 2 to 15 mg/L) alone (Bailey, 1984).

3) DIAZEPAM

a) Ingestion of 500 to 2000 mg of diazepam have been reported with only minor toxicity (Greenblatt & Shader, 1978).

4) ESTAZOLAM

a) Recovery from overdose, as high as 40 mg of estazolam has been reported (Prod Info ProSom(TM), estazolam, 1990).

5) FLUBROMAZOLAM

a) A 27-year-old man developed a deep coma, tachycardia, hypotension, and respiratory failure following ingestion of 5 mg of flubromazolam, a designer benzodiazepine. Following antidotal treatment with flumazenil and supportive therapy, including IV fluids and vasopressor administration, the patient gradually recovered (Lukasik-Glebocka et al, 2016).

6) FLUNITRAZEPAM

a) A 21-month-old, 11.5-kg child developed coma, hypotension, bradycardia, shallow respiration, and muscular hypotonia 4 hours after an estimated ingestion of flunitrazepam 40 mg (Roald & Dahl, 1989).

7) FLURAZEPAM

a) Prolonged coma of 13 days with respiratory depression was reported in a 48-year-old woman after a mixed ingestion that included flurazepam 2.4 g and chlordiazepoxide 1.5 g (Ruff et al, 1981).

8) LORAZEPAM

a) Three children (aged 4 to 9) ingesting between 2.5 and 25 mg of lorazepam developed minor symptoms (ataxia, lethargy & hallucinations) (Vlachos et al, 1978).

9) OXAZEPAM

a) A 16-year-old boy developed grade I coma with absent deep tendon reflexes after ingestion of 900 mg oxazepam (Granguli, 1970).

10) TRIAZOLAM

a) Ingestions of 2 to 20 mg of triazolam have resulted in coma and lethargy (Olson et al, 1985). A case report described an 83-year-old woman who developed coma and respiratory depression following triazolam use. The patient was receiving erythromycin ethylsuccinate 400 mg 4 times daily and was administered a single 0.5-mg dose of triazolam. She developed coma and respiratory depression requiring 36 hours of ventilatory support. No serum levels of toxicology screen results were reported (Sullivan, 1989).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) FLUNITRAZEPAM

1) In an adult, 10 nanomoles/L is the minimal sedative concentration (Amrein et al, 1979).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) BROMAZEPAM: A serum bromazepam concentration of 7.7 mg/L was detected in a 42-year-old female following ingestion of 420 mg bromazepam in an apparent suicide attempt (Michaud et al, 2001).
b) CLORAZEPATE

1) Authors measured serum nordiazepam concentrations between 0.7 and 5.1 mcg/mL in 5 cases of clorazepate related (dose up to 300 mg) mixed drug overdoses (Jatlow et al, 1979).

c) CHLORDIAZEPOXIDE

1) There is a single case report suggesting a possible correlation between respiratory depression resulting from chlordiazepoxide intoxication and the concentration of demoxepam, the second metabolite. A 45-year-old female developed spontaneous respirations, leading to extubation, that coincided with a demoxepam concentration dropping below 10 mcg/mL (Minder, 1989).

d) DIAZEPAM

1) POSTMORTEM CONCENTRATIONS: Diazepam concentrations ranged from 0.004 to 64 mcg/mL and N-desmethyldiazepam concentrations ranged from 0.1 to 13.4 mcg/mL in a survey of 731 diazepam-related deaths in mixed drug overdoses (Finkle et al, 1979).
2) OVERDOSE CONCENTRATIONS: Serum diazepam concentrations were measured in 93 cases of diazepam and mixed drug overdoses. Total benzodiazepine concentrations ranged from 1 to 22 mcg/mL with a diazepam to nordiazepam ratio of 3:1 (Jatlow et al, 1979).

e) FLURAZEPAM: Postmortem blood concentrations of flurazepam and its metabolite, N-1-desalkylflurazepam, were 5.5 mg/L and 0.73 mg/L, respectively, in a 52-year-old female following an overdose ingestion of approximately 2.1 g (McIntyre et al, 1994).
f) FLUNITRAZEPAM

1) FLUNITRAZEPAM: In children, the estimated toxic dose of flunitrazepam is 0.1 mg/kg (Jager et al, 1984).
2) A flunitrazepam plasma concentration of 650 nanomoles/L produced coma, muscular hypotonia, hypotension (blood pressure, 60/30 mmHg), bradycardia (heart rate, 40 to 50 beats/minute), and shallow respiration in a 21-month-old, 11.5-kg child 4 hours after an estimated ingestion of flunitrazepam 40 mg (Roald & Dahl, 1989).
3) POSTMORTEM: Levels of flunitrazepam found after a fatal overdose in an adult included: kidney, 0.05 mg percent; stomach content 0.5 mg percent; and an intestinal content of 0.1 mg percent. Serum or blood values were not reported (Heyndrickx, 1987).
4) Postmortem levels were reported in 8 fatalities in which flunitrazepam ingestion may have been a factor. Range of levels: flunitrazepam 0 to 0.07 mg/L and 7-aminoflunitrazepam 0.12 to 0.77 mg/L (Drummer et al, 1993).

g) MIDAZOLAM: Postmortem blood concentration of midazolam in a 63-year-old male, who died after receiving 10 mg intravenously, was 2.4 mcg/ mL (Michalodimitrakis et al, 1999).
h) TEMAZEPAM

1) Postmortem blood concentrations of temazepam in overdose related deaths ranged from 885 to 14,000 mcg/L. Other drugs were also detected in amounts less than thought to be fatal.
2) In two cases where the only other ingestant detected was ethanol had blood concentrations of temazepam of 8200 and 14,000 mcg/L.
3) The highest reported blood concentration following therapeutic doses was 750 mcg/L (Forrest et al, 1986).

i) TRIAZOLAM

1) Postmortem blood levels of 47, 58, and 76 nanomoles/L were found in 3 patients who overdosed on triazolam (Sunter et al, 1988).
2) An ingestion of triazolam 5 mg resulted in coma. The serum levels upon admission were 30.7 nanogram (ng)/mL and 7.93 ng/mL 6 hours later (Olson et al, 1985).
3) Postmortem heart blood and peripheral blood triazolam levels of 0.12 mg/L and 0.091 mg/L, respectively, were detected in a 77-year-old female, who was found dead in her bathtub following ingestion of an unknown amount of triazolam. Alpha-hydroxytriazolam, an active metabolite of triazolam, was not detected in either postmortem blood sample, but was detected in the kidney, liver, and urine, at levels of 0.22 mg/L, 0.043 mg/L, and 1.37 mg/L, respectively (Levine et al, 2002).

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BENZODIAZEPINES

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Acid-Base

Dermatologic

Musculoskeletal

Endocrine

Immunologic

Reproductive

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

General Bibliography