AMPHETAMINES AND RELATED DRUGS

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Amphetamine Phosphate (synonym)
2) Amphetamine Sulfate (synonym)
3) Amfetamine
4) Benzphetamine (synonym)
5) Chlorphentermine (synonym)
6) Clobenzorex Hydrochloride (synonym)
7) Dextroamphetamine Sulfate (synonym)
8) Dextroamphetamine Tannate (synonym)
9) Dexamfetamine
10) Diethylpropion (synonym)
11) Lisdexamfetamine Dimesylate (synonym)
12) Mazindol (synonym)
13) 4-Methylthioamphetamine (synonym)
14) 4-MTA (synonym)
15) para-Methylthioamphetamine (synonym)
16) p-MTA (synonym)
17) Phendimetrazine (synonym)
18) Phenmetrazine (synonym)
19) Phentermine (synonym)

1.2.1) MOLECULAR FORMULA
1) AMPHETAMINE: C9H13N
2) AMPHETAMINE SULFATE: C18H28N2SO4
3) BENZPHETAMINE: C17H21N
4) DIETHYLPROPION: C13H19NO
5) MAZINDOL: C16H13ClN2O
6) METHAMPHETAMINE: C10H15NClH
7) PHENDIMETRAZINE: C12H17NO
8) PHENDIMETRAZINE TARTRATE: C12H17NO.C4H6O6
9) PHENMETRAZINE: C11H15NO
10) PHENTERMINE: C10H15N
11) PHENTERMINE HYDROCHLORIDE: C10H15N.HCl

Available Forms Sources

1) PHARMACEUTICAL PREPARATIONS

a) AMPHETAMINE COMPLEX: Biphetamine(R) is a resin complex of amphetamine and dextroamphetamine, containing equal parts. Capsules contain 12.5 or 20 mg of resin complex.
b) ADZENYS XR-ODT(TM): Amphetamine extended-release orally disintegrating tablets available in 3.1 mg, 6.3 mg, 9.4 mg, 15.7 mg, and 18.8 mg (Prod Info ADZENYS XR-ODT(R) oral extended-release disintegrating tablets, 2016).

1) The tablet is placed on the tongue and disintegrates without chewing to be swallowed with saliva. The tablet contains 50% immediate release and 50% delayed release amphetamine to be administered as once-daily dosing (Prod Info ADZENYS XR-ODT(R) oral extended-release disintegrating tablets, 2016).

c) BENZPHETAMINE: Available in 25 and 50 mg tablets (Didrex(R)).
d) DEXTROAMPHETAMINE:

1) Tablets: Available in 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg and 30 mg tablets (Prod Info Adderall (R) CII, 2005)
2) Extended-Release Capsules: Available in 5 mg, 10 mg, 15 mg, 20 mg, 25 mg and 30 mg capsules (Prod Info ADDERALL XR(R) CAPSULES, 2004)

e) CLOBENZOREX HYDROCHLORIDE: is an amphetamine-like agent used as an anorectic. Although weaker than (+)amphetamines, its active N-substituted derivative of (+)amphetamine has been identified in illicit drug use (Young et al, 1997).
f) DIETHYLPROPION: Available as 25 mg tablets and 75 mg sustained-release tablets (Tenuate(R)).
g) LISDEXAMFETAMINE DIMESYLATE: Available as 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg capsules (Prod Info VYVANSE(R) oral capsules, 2008).
h) MAZINDOL: Available in 1 mg and 2 mg tablets
i) PHENDIMETRAZINE TARTRATE: Available as 35 mg tablet and 105 mg sustained-release capsule (Bontril PDM(R), Phenzine(R), Statobex(R), Prelu-2(R), etc).
j) PHENMETRAZINE: Available as 25 mg tablet and 75 mg sustained-release tablet (Preludin(R)).
k) PHENTERMINE: Available as the hydrochloride salt (8 mg equals 6.4 mg base) or timed-release resin complex (30 mg equals 24 mg base). Trade names include Fastin(R), Adipex-P(R), Ionamin(R), Termene(R), Phentrol(R), Obermine(R), etc. NOTE: Phentermine was not affected by the FDA voluntary withdrawal of weight loss medications because no heart disease had been directly associated with it (Department of Health and Human Services, 1997).

2) ADULTERANTS

a) Most illicitly sold drugs alleged to be amphetamines are often found to contain caffeine, ephedrine, or phenylpropanolamine (Renfroe & Messinger, 1985). Local anesthetics (eg, benzocaine, lidocaine, procaine, tetracaine), quinine, phencyclidine, pseudoephedrine, and strychnine may also be misrepresented as amphetamine.
b) Agents used to dilute ("cut") the amount of true drug in a given sample include detergents, talc, and sugars such as lactose, sucrose, mannitol, and sorbitol (Newburn, 1981; Jordan, 1981; Pharm Chem, 1984).
c) SMOKING: Methamphetamine has also been abused via smoking mixed with tobacco (Sekine & Nakahara, 1987).
d) "ICE"

1) ICE is a form of methamphetamine and so named for its clear crystalline appearance. It can be smoked, insufflated or injected, and produces an almost instantaneous "rush" similar to intravenous methamphetamine. Its effects reportedly last from 8 to 24 hours, and severe psychoses have been reported with use (Hall, 1989; Derlet & Heischober, 1990). It has also been referred to as "crystal" or "crank" (Catanzarite & Stein, 1995).
2) Use of "ice" is associated with unique neuropsychiatric toxicity. Auditory hallucinations, severe paranoia, and violent behavior have been reported (Anon, 1989).

e) p-METHYL AMPHETAMINE and N,p-dimethyl amphetamine have been isolated in some illicit amphetamine preparations. The use of this combination resulted in hypertensive crisis, hyperglycemia, leukocytosis, and severe persistent anxiety in one case (Bal et al, 1989).
f) "Jeff" is 2-methylamino-1-phenyl-propan-1-one. It is also called ephedrone and is an oxidation product of ephedrine. This agent has been responsible for numerous overdoses and deaths in the Soviet Union (Zhingel et al, 1991).
g) 4-MTA: An herbal stimulant ('S-5 tablets') marketed in the Netherlands was found to contain PARA-METHYLTHIOAMPHETAMINE (p-MTA or 4-methylthioamphetamine {4-MTA}). It appears to be a potent selective serotonin releaser without serotonin neurotoxic effects. At least one fatality has been associated with 4-MTA ingestion (Elliott, 2000). 4-MTA has a street name of "flatliners" and the tablets resemble 'Ecstasy' with each tablet containing 100 milligrams of 4-MTA with few impurities reported (Elliott, 2000)

3) ROUTE OF EXPOSURE

a) As a drug of abuse, amphetamines are most often injected, smoked, ingested, or insufflated. Rectal administration has also been described ("booty bumping", "keistering", "butt whacking") (Cantrell et al, 2006).

1) POSTMARKETING SURVEILLANCE/DRUG WITHDRAWAL

a) PEMOLINE

1) As of October, 2005, pemoline has been voluntarily withdrawn from the United States market due its overall risk of hepatic toxicity. Although the FDA reported only 13 cases of liver failure resulting in liver transplant or death, it is believed that the risk of liver toxicity following pemoline therapy outweighs any potential benefits (Anon, 2005).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Amphetamines and related agents are CNS stimulants. They are sold as commercial pharmaceutical agents to treat medical conditions (eg, attention deficit disorder, narcolepsy, and obesity). Illicit amphetamines, such as hallucinogenic amphetamines, methamphetamine, and methylphenidate, are covered in separate managements.
B) PHARMACOLOGY: Amphetamines are sympathomimetic agents structurally related to norepinephrine. They have greater stimulant effects than other catecholamines. Peripherally, amphetamines promote the release of norepinephrine from stores in adrenergic nerve terminals and directly stimulate alpha- and beta-adrenergic receptors. They also inhibit catecholamine metabolism by inhibiting monoamine oxidase enzymes. Centrally, amphetamines stimulate the cerebral cortex, medullary respiratory center, and reticular activating system.
C) TOXICOLOGY: Overdose or chronic excessive use causes a sympathomimetic toxidrome (eg, tachycardia, hypertension, agitation, and, in severe cases, psychosis).
D) EPIDEMIOLOGY: Exposures are common. Severe effects are rare but may be seen in large overdoses and chronic exposures. Diversion and abuse of pharmaceutical amphetamines is common.
E) WITH THERAPEUTIC USE

1) Tachycardia, hypertension, agitation, dyskinesias, psychosis, and seizures. Dose response may be unpredictable. Chronic amphetamine abuse may result in cardiomyopathy, heart failure, malnutrition, weight loss, cerebral vasculitis, permanent psychiatric illness including depression and paranoid psychoses, bruxism, and infection. Amphetamine exposure to the fetus may cause neonatal withdrawal symptoms. An adult withdrawal syndrome has been described in chronic abusers, including severe depression.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE POISONING: Hyperactivity, diaphoresis, flushing, mydriasis, nausea, vomiting, abdominal pain, hypertension, palpitations, tachycardia, chest pain, headache, hyperventilation, and confusion.
2) SEVERE POISONING: Generally only seen after illicit use (usually by injection, insufflations, or smoking) of high doses. May cause hyperthermia (greater than 40 degrees C can be life-threatening), dehydration, severe hypertension, tachydysrhythmia, myocardial infarction, vasospasm, aortic dissection, cerebral vascular accidents, sudden cardiac death, pneumothorax, psychosis, seizures, ischemic colitis, rhabdomyolysis, renal failure, hepatic failure, serotonin syndrome, delirium, paranoia, and coma. Rarely, severe acidosis, multiorgan failure, and death occur.

0.2.20)

A) Benzphetamine, phendimetrazine, and phentermine (as monotherapy or in combination with topiramate) are classified as FDA pregnancy category X. Amphetamines/dextroamphetamines, amphetamine sulfate, dextroamphetamine, methamphetamines, and lisdexamfetamine are classified as FDA pregnancy category C. Diethylpropion is classified by the manufacturer as FDA pregnancy category B. Amphetamine use during pregnancy has been associated with congenital anomalies (ie, biliary atresia and cleft palate), aggressive behavior, withdrawal symptoms, low birth weights, premature births, fetal distress, and, in some cases, death. Methamphetamines have been shown to cross the placenta.
B) Amphetamines have been measured in breast milk in several case reports.

0.2.21)

A) AMPHETAMINE SULFATE

1) At the time of this review, the manufacturer does not report any carcinogenic potential of amphetamine sulfate in humans (Prod Info EVEKEO(TM) oral tablets, 2015).

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Most amphetamine related toxicity may be safely managed with supportive care that includes monitoring airway, breathing, and circulation, and control of agitation with benzodiazepines. Intravenous fluids may be needed for mild dehydration, and sedation for agitation. Charcoal may be indicated if recent ingestion, airway controlled, and low seizure risk.

B) MANAGEMENT OF SEVERE TOXICITY

1) Severe agitation requires aggressive treatment to avoid malignant hypertension, rhabdomyolysis, hyperthermia, and seizures. Large doses of benzodiazepines may be needed. Severe cases may require neuromuscular paralysis, intubation, and active cooling measures. For tachycardia, treat with intravenous fluids, sedation. For severe hypertension unresponsive to sedation, consider IV nitroprusside. Rhabdomyolysis is best treated with adequate 0.9% normal saline; monitor CK, electrolytes, and creatinine. Diuretics and urinary alkalinization are not recommended. Ventricular dysrhythmias should be treated with standard ACLS protocols.

C) DECONTAMINATION

1) PREHOSPITAL: Not recommended because of potential for agitation, seizures.
2) HOSPITAL: Activated charcoal binds amphetamines. For oral exposures, consider charcoal administration if patient is able to drink safely, low risk for seizures.

D) AIRWAY MANAGEMENT

1) Intubate if unable to protect airway, to control agitation, hyperthermia, and status epilepticus.

E) ANTIDOTE

1) None

F) PSYCHOMOTOR AGITATION

1) Sedate patient with benzodiazepines as necessary; large doses may be required.

G) HYPERTENSIVE EPISODE

1) Consider IV nitroprusside for severe hypertension unresponsive to sedation. DOSE: Start at 0.5 to 1 mcg/kg/min and titrate as needed.

H) ENHANCED ELIMINATION

1) Hemodialysis and hemoperfusion are not useful because of the large volume of distribution.

I) PATIENT DISPOSITION

1) HOME CRITERIA: Inadvertent ingestions in asymptomatic patients, and pediatric exposures of commercial pharmaceutical agents within published pediatric therapeutic dose, who have no synergistic co-ingestions, may be monitored at home.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions, synergistic co-ingestions, unclear history, symptomatic or intoxicated patients, exposure to doses outside published therapeutic ranges, or those in unstable social situations should be sent to a healthcare facility for observation.
3) ADMISSION CRITERIA: Patients with persistent or worsening vital sign abnormalities, continued or difficult to control agitation or psychosis, multiple seizures, cardiac ischemia, or dysrhythmias should be admitted. Intensive care unit is indicated for aggressive airway or cardiac monitoring.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (ie, progressive agitation, psychosis, dysrhythmias, malignant hypertension, hyperthermia), concerns about decontamination, or in whom the diagnosis is unclear.

J) PITFALLS

1) Drug effect may be prolonged, requiring extended observation times or admission until symptoms resolve. Prolonged toxicity may develop after ingestion of sustained-release formulations. Other complications of drug abuse may be present (eg, trauma, infection).

K) PHARMACOKINETICS

1) Most amphetamines are well absorbed from the gastrointestinal tract. Peak plasma levels occur in about 2 to 3 hours after oral amphetamine exposure. Amphetamine protein binding is approximately 16%. Volume of distribution for amphetamine is 3.2 to 5.6 L/kg. Amphetamine is hepatically metabolized by hydroxylation and n-dealkylation pathways. P-hydroxyamphetamine, a potent hallucinogen, is a major metabolite of amphetamine. Non-metabolized amphetamine is excreted in the urine. Duration of effect varies depending on agent and urine pH. Excretion is enhanced in more acidic urine. Half-life is 7 to 34 hours and is, in part, dependent on urine pH (half-life is longer with alkaline urine).

L) DIFFERENTIAL DIAGNOSIS

1) Cocaine intoxication, phencyclidine (PCP) toxicity, anticholinergic poisoning, sepsis, encephalitis, trauma. In pediatric population, also consider scorpion envenomation, intussusception, meningitis, and sepsis.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.3)

A) FEVER: AMPHETAMINE/METHAMPHETAMINE: Severe hyperthermia may develop after amphetamine or methamphetamine use (Kolecki, 1998; Chan et al, 1994; Katsumata et al, 1993; Ginsberg et al, 1970). Hyperthermia may result from hypothalamic dysfunction, metabolic and muscle hyperactivity or prolonged seizures.

1) Severe hyperthermia (greater than 41 degrees C) is associated with a high fatality rate and requires aggressive sedation and cooling (Lan et al, 1998).

B) LISDEXAMFETAMINE: According to a retrospective review of 5 poison center databases, involving lisdexamfetamine therapy following the first 10 months of postmarketing use, fever was reported in 2 of 28 patients (7%) (Spiller et al, 2008).

3.3.4)

A) HYPERTENSION: Systolic and diastolic hypertension are common and may be postural.

3.3.5)

A) TACHYCARDIA/BRADYCARDIA: Tachycardia is common (Anon, 1989; Lan et al, 1998); reflex bradycardia secondary to hypertension may be observed.

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) MYDRIASIS: Pupils are usually mydriatic and often sluggishly reactive to light following exposure (Chan et al, 1994).

Cardiovascular

3.5.2)

A) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

1) In the same study, conduction disturbances were reported in 17 patients, 12 patients, and 32 patients following acute ingestions of lisdexamfetamine, dextroamphetamine/amphetamine extended release, and dextroamphetamine/amphetamine immediate release, respectively (Kaland & Klein-Schwartz, 2015).

2) It appears that the l-isomer of amphetamine affects the cardiovascular system to a greater extent than the d-isomer (Morgan, 1992).

B) TACHYARRHYTHMIA

1) WITH THERAPEUTIC USE

a) LISDEXAMFETAMINE: In a retrospective review of poison center cases involving therapeutic use of lisdexamfetamine following the first 10 months of postmarketing use, tachycardia was reported in 39% of patients (n=28) (Spiller et al, 2008).
b) According to a retrospective observational case series of single-substance exposures to amphetamine-related agents reported to the American Association of Poison Control Centers (AAPCC) and National Poison Data System (NPDS) from January 2007 to December 2012, tachycardia was reported in 19.2%, 22.8%, and 23.9% of patients following exposures to lisdexamfetamine (n=7113), dextroamphetamine/amphetamine extended release (n=6245), and dextroamphetamine/amphetamine immediate release (n=10,195), respectively (Kaland & Klein-Schwartz, 2015).

C) TORSADES DE POINTES

1) WITH POISONING/EXPOSURE

a) CASE REPORT/PHENTERMINE: A 23-year-old woman presented with lethargy, syncope, tachycardia, abdominal tenderness, and diminished bowel sounds. An ECG demonstrated QT interval prolongation and polymorphic ventricular tachycardia. A review of her medication history revealed that, for 3 days prior to presentation, the patient had been taking an illegally imported weight-reducing drug, 1 capsule per day. A urine tox screen was positive for phentermine and chlorpheniramine. With supportive therapy, the patient's symptoms resolved. A follow-up ECG showed normal sinus rhythm and no QT interval prolongation (Hung & Chang, 2006).

D) CARDIOMYOPATHY

1) CASE REPORTS

a) AMPHETAMINE: Acute cardiomyopathy with left ventricular dysfunction, pulmonary edema, and hypotension occurred in an adult woman 10 hours after IV amphetamine use. Evidence of mild myocardial necrosis (elevated MB fraction of 6%) was found. The myocardial effects may have been caused by unknown "cutting" agents used to prepare the drug (Call et al, 1982).

1) Cardiomyopathy was also described after intravenous injection of 20 to 60 mg of amphetamine in a 24-year-old man (O'Neill et al, 1983).

b) CLOBENZOREX: Congestive cardiomyopathy occurred in a 29-year-old woman addicted to clobenzorex. The patient had been taking 5 to 7 capsules/day for 5 years. Long-term digitalis therapy (up to 1 year later) was required for residual myocardial injury (Cornaert et al, 1986).

E) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) According to a retrospective observational case series of single-substance exposures to amphetamine-related agents reported to the American Association of Poison Control Centers (AAPCC) and National Poison Data System (NPDS) from January 2007 to December 2012, bradycardia was reported in 2 of 7113 patients, 6 of 6245 patients, and 11 of 10,195 patients following acute ingestions of lisdexamfetamine, dextroamphetamine/amphetamine extended release, and dextroamphetamine/amphetamine immediate release, respectively (Kaland & Klein-Schwartz, 2015).
b) A patient presented with agitation, disorientation, diaphoresis, and hypertension, with subsequent development of a severe headache, bradycardia, and respiratory arrest after ingesting 104 20-mg dextroamphetamine/amphetamine capsules. A dissected aneurysm at the base of his skull was detected upon imaging. There was no improvement neurologically and the patient died several days later (Kaland & Klein-Schwartz, 2015).

F) CHEST PAIN

1) WITH THERAPEUTIC USE

a) LISDEXAMFETAMINE: In a retrospective review of poison center cases involving therapeutic use of lisdexamfetamine following the first 10 months of postmarketing use, chest pain was reported in 4 of 28 patients (14%) (Spiller et al, 2008).

G) MYOCARDIAL INFARCTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 15-year-old boy, with no history of cardiac abnormalities nor any reported underlying risk factors, presented to the emergency department with a 1-day history of acute left-sided chest pain. Four days prior to presentation, he had started taking Adderall XR(R) 5 mg daily. An initial ECG revealed ST segment elevation in the inferior leads and V2 through V4 (which may have been early repolarization), and laboratory data revealed elevated cardiac enzyme concentrations (CPK 508 [normal range 55 to 170]; CK-MB 7.3 [normal range 0.6 to 6.3]; troponin I 0.65 [normal range 0.01 to 0.10]). Serial troponin concentrations increased to a maximum concentration of 2.25. Following transfer to a tertiary care center, cardiac catheterization was performed and was normal, and the patient recovered with normalization of cardiac enzyme concentrations approximately 6 days post-presentation. It is believed that the patient experienced an acute myocardial infarction secondary to Adderall XR (R) therapy (Sylvester & Agarwala, 2011).

2) WITH POISONING/EXPOSURE

a) AMPHETAMINE: Myocardial infarction (Hong et al, 1991; Furst et al, 1990; Carson et al, 1987), ischemia, and ventricular dysfunction may occur. In addition, exertional angina may occur after acute or chronic ingestion.

1) CASE REPORT: A 27-year-old man developed an acute myocardial infarction after amphetamine injection. Coronary arteriography was normal (Packe et al, 1990).
2) CASE REPORT: A 26-year-old man with a long history of cocaine and amphetamine abuse developed severe chest pain after amphetamine use. An initial ECG showed ST-segment elevation consistent with an anterior myocardial infarction. Alteplase and heparin were given and symptoms stabilized over 48 hours with no permanent sequelae (Guharoy et al, 1999).
3) CASE REPORT: A 31-year-old man, with no symptoms suggestive of an ischemic cardiac event, experienced a non-Q-wave anterior wall myocardial infarction after injecting 4 doses of amphetamine and methamphetamine ("crank") over a 48-hour period. An initial ECG revealed inverted T waves in leads II, III, aVF, and V1 through V5. A second ECG showed a new left bundle branch block. Transthoracic echocardiography showed reduced anterior wall motion with an estimated shortening fraction of 25% (Waksman et al, 2001).
4) CASE REPORT: After ingesting approximately 20 Adderall(R) (amphetamine/dextroamphetamine) 5-mg and 10-mg tablets, a 13-year-old girl developed hypertension, bigeminy, pulmonary edema and a myocardial infarction with an elevated CK MB fraction. An initial ECG revealed sinus tachycardia with ventricular bigeminy at 149 beats/min and ST-segment depression, most pronounced in the inferior and lateral leads. A chest x-ray showed bilateral interstitial edema and increased pulmonary vasculature. An ECG approximately 3 days postingestion revealed sinus rhythm with a ventricular rate of 101 beats/min, resolution of the bigeminy, and improvement of ST-segment depression. No Q waves were noted and QT prolongations (QTc 456 msec) persisted. Following supportive care, the patient recovered without further sequelae (Sztajnkrycer et al, 2002).

H) VASOSPASM

1) WITH POISONING/EXPOSURE

a) PHENTERMINE: Vasospasm resulting in distal ischemia was reported after inadvertent intra-arterial injection of phentermine (Hamer & Phelps, 1981).

I) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension in the setting of amphetamine intoxication is associated with a high fatality rate (Lan et al, 1998).
b) According to a retrospective observational case series of single-substance exposures to amphetamine-related agents reported to the American Association of Poison Control Centers (AAPCC) and National Poison Data System (NPDS) from January 2007 to December 2012, hypotension was reported in 4 of 7113 patients, 8 of 6245 patients, and 27 of 10,195 patients following acute ingestions of lisdexamfetamine, dextroamphetamine/amphetamine extended release, and dextroamphetamine/amphetamine immediate release, respectively (Kaland & Klein-Schwartz, 2015).

J) DISSECTION OF AORTA

1) WITH POISONING/EXPOSURE

a) CASE REPORTS

1) AMPHETAMINE: A 27-year-old man with a history of IV amphetamine use, presented with a complete aortic dissection requiring urgent surgical repair. Despite surgical intervention, the patient died 32 days later of septicemia and multiorgan failure. Amphetamine concentration at admission was 0.14 mg/L. It is unknown whether the amphetamines taken by this patient may have been contaminated with other drugs producing an additive effect (Dihmis et al, 1997).

K) RUPTURED ANEURYSM

1) WITH THERAPEUTIC USE

a) PHENTERMINE: A ruptured retroperitoneal aneurysm was reported in a 70-year-old woman following the therapeutic use of phentermine hydrochloride (30 mg/day) for approximately 1 month for appetite suppression. Chronic medications included fluoxetine and amitriptyline with no over-the-counter drug use reported. Following surgical repair and evacuation of a large retroperitoneal hematoma, the patient recovered. Although a direct association could not be determined, it was suggested that the risk of rupture increased with phentermine use (Sobel, 1999).

L) HYPERTENSIVE DISORDER

1) WITH POISONING/EXPOSURE

a) According to a retrospective observational case series of single-substance exposures to amphetamine-related agents reported to the American Association of Poison Control Centers (AAPCC) and National Poison Data System (NPDS) from January 2007 to December 2012, hypertension was reported in 7.2%, 9.6%, and 9.1% of patients following exposures to lisdexamfetamine (n=7113), dextroamphetamine/amphetamine extended release (n=6245), and dextroamphetamine/amphetamine immediate release (n=10,195), respectively (Kaland & Klein-Schwartz, 2015).
b) A patient presented with agitation, disorientation, diaphoresis, and hypertension, with subsequent development of a severe headache, bradycardia, and respiratory arrest after ingesting 104 20-mg dextroamphetamine/amphetamine capsules. A dissected aneurysm at the base of his skull was detected upon imaging. There was no improvement neurologically and the patient died several days later (Kaland & Klein-Schwartz, 2015).

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) PHENMETRAZINE: Noncardiogenic pulmonary edema was reported in a 23-year-old phenmetrazine abuser (Kendrick et al, 1977).

B) DECREASED RESPIRATORY FUNCTION

1) WITH POISONING/EXPOSURE

C) RESPIRATORY ARREST

1) WITH POISONING/EXPOSURE

a) According to a retrospective observational case series of single-substance exposures to amphetamine-related agents reported to the American Association of Poison Control Centers (AAPCC) and National Poison Data System (NPDS) from January 2007 to December 2012, respiratory arrest was reported in 1 of 7113 patients, 2 of 6245 patients, and 2 of 10,195 patients following acute ingestions of lisdexamfetamine, dextroamphetamine/amphetamine extended release, and dextroamphetamine/amphetamine immediate release, respectively (Kaland & Klein-Schwartz, 2015).
b) A patient developed a severe headache, bradycardia, and respiratory arrest after ingesting 104 20-mg dextroamphetamine/amphetamine capsules. A dissected aneurysm at the base of his skull was detected upon imaging. There was no improvement neurologically and the patient died several days later (Kaland & Klein-Schwartz, 2015).

Neurologic

3.7.2)

A) CENTRAL STIMULANT ADVERSE REACTION

1) WITH POISONING/EXPOSURE

a) CNS manifestations can include agitation, confusion, delirium, hallucinations, dizziness, dyskinesias, hyperactivity, muscle fasciculations and rigidity, rigors, tics, tremors, seizures, and coma.
b) Methamphetamine has a greater CNS penetration and efficacy than amphetamine (Derlet & Heischober, 1990).
c) The d-isomer of amphetamine is 3 to 4 times as potent as the l-isomer at producing CNS stimulation (Morgan, 1992).

B) CEREBROVASCULAR DISEASE

1) SUMMARY

a) CEREBROVASCULAR ACCIDENTS: Hemorrhagic or vasospastic cerebrovascular accidents, cerebral vasculitis, and ischemic cerebrovascular disease have been reported following the use of amphetamine, methamphetamine, phentermine, and possibly phendimetrazine.
b) RELATIVE RISK: Abuse of amphetamine, cocaine, and related drugs can increase the risk for cerebrovascular incidents in young adults (Chaudhuri & Salahudeen, 1999). In a retrospective review of 214 consecutive young patients admitted for ischemic or hemorrhagic stroke, the estimated relative risk for stroke among drug users compared with that among nonusers was 6.5 (Kaku & Lowenstein, 1990).
c) In a small study of 10 young adults with a diagnosis of drug-related (eg, amphetamine, cocaine, and ecstasy) intracerebral hemorrhage (ICH), intracranial aneurysms were found in 6 patients and arteriovenous malformations in 3 other patients; only 1 patient had a normal cerebral angiogram. Three other patients that were part of the study died prior to cerebral angiography. At autopsy 1 patient had a middle cerebral artery aneurysm. The authors concluded that contrary to previous opinion, drug-related ICH is frequently related to an underlying vascular malformation and arteriography is recommended for any young patient with a nontraumatic ICH with suspected amphetamine use (McEvoy et al, 2000).

2) AMPHETAMINE

a) Hemorrhagic or vasospastic cerebrovascular accidents and cerebral vasculitis have been seen after oral or intravenous use of amphetamine (Weiss et al, 1970; Salanova & Taubner, 1984; Delaney & Estes, 1980).

3) PHENTERMINE: Two cases of ischemic cerebrovascular disease involving a cerebral infarct, vasculitis, headache, and hemisensory disturbances (numbness) have been associated with the use of phentermine and possibly phendimetrazine (Kokkinos & Levine, 1993).

C) SEIZURE

1) WITH THERAPEUTIC USE

a) LISDEXAMFETAMINE: In a retrospective review of poison center cases involving therapeutic use of lisdexamfetamine following the first 10 months of postmarketing use, seizures were reported in 1 of 28 patients (Spiller et al, 2008).

2) WITH POISONING/EXPOSURE

D) ALTERED MENTAL STATUS

1) WITH THERAPEUTIC USE

a) LISDEXAMFETAMINE: In a retrospective review of poison center cases involving therapeutic use of lisdexamfetamine following the first 10 months of postmarketing use, agitation (43%), hallucinations (11%), and new onset of jitters (11%) were reported (n=28) (Spiller et al, 2008).

2) WITH POISONING/EXPOSURE

a) Patients may be confused, agitated, combative, or hallucinating. CNS depression and coma may develop in severe poisoning (Chan et al, 1994).
b) Amphetamines and methamphetamines can induce spontaneous recurrences of paranoid hallucinatory states known as flashbacks. One study found an increase in peripheral noradrenergic activity in patients during flashbacks compared to nonflashback-experiencing users (Yui et al, 1997).
c) According to a retrospective observational case series of single-substance exposures to amphetamine-related agents reported to the American Association of Poison Control Centers (AAPCC) and National Poison Data System (NPDS) from January 2007 to December 2012, agitation was reported in 19.8%, 21.7%, and 25.1% of patients following exposures to lisdexamfetamine (n=7113), dextroamphetamine/amphetamine extended release (n=6245), and dextroamphetamine/amphetamine immediate release (n=10,195), respectively (Kaland & Klein-Schwartz, 2015).
d) A patient presented with agitation, disorientation, diaphoresis, and hypertension, with subsequent development of a severe headache, bradycardia, and respiratory arrest after ingesting 104 20-mg dextroamphetamine/amphetamine capsules. A dissected aneurysm at the base of his skull was detected upon imaging. There was no improvement neurologically and the patient died several days later (Kaland & Klein-Schwartz, 2015).

E) DEPRESSIVE DISORDER

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 15-year-old man with ADHD was inhaling Ritalin(R) (3 crushed 20-mg methylphenidate tablets per dose) over a 2-week period for its euphoric effects and developed symptoms of clinical depression with drug withdrawal (Garland, 1998).

F) CHOREOATHETOSIS

1) WITH THERAPEUTIC USE

a) DEXAMPHETAMINE: A 68-year-old man developed choreoathetoid movements, oro-facio-mandibular movements, and involuntary movements of his hands, including pill rolling, following a 25-year history of high-dose dexamphetamine therapy for treatment of narcolepsy. Following cessation of therapy, the patient's involuntary movements improved with a decrease in his Abnormal Involuntary Movement Scale (AIMS) from a baseline of 52 to less than 10 in approximately 6 weeks (Garg et al, 2011).

2) WITH POISONING/EXPOSURE

a) AMPHETAMINE: Chronic amphetamine abuse has been associated with choreiform movements, which usually resolve in several days but may persist for years after abstinence (Lundh & Tunving, 1981).

1) Acute intravenous or oral administration of amphetamine compounds was reported to result in choreiform movements in 5 patients. Symptoms rapidly resolved in these cases over a few hours. Haloperidol was used in 2 patients with psychotic behavior (Mattson & Calverley, 1968; Rhee et al, 1988).

G) DYSKINESIA

1) WITH THERAPEUTIC USE

a) In a retrospective cross-sectional analysis, 9% of children (12 cases) with ADHD treated with stimulants had tics and dyskinesias (T/D). Of the 12 cases that developed T/D, 9 occurred during treatment with methylphenidate and 3 with dextroamphetamine (Lipkin et al, 1994).

1) The occurrence of T/D did not appear dose-dependent, or based on a family history of tics, or related to the age of the child. The authors speculated that dopaminergic pathways may be linked to the development of T/D (Lipkin et al, 1994).

b) LISDEXAMFETAMINE: In a retrospective review of poison center cases involving therapeutic use of lisdexamfetamine following the first 10 months of postmarketing use, dystonia was reported in 29% of patients (n=28) (Spiller et al, 2008).

H) COMA

1) WITH POISONING/EXPOSURE

a) Coma in the setting of amphetamine overdose is associated with a high mortality rate (Lan et al, 1998).

I) INSOMNIA

1) WITH THERAPEUTIC USE

a) LISDEXAMFETAMINE: According to a retrospective review of 5 poison center databases, involving lisdexamfetamine therapy following the first 10 months of postmarketing use, insomnia was reported in 29% of patients (n=28) (Spiller et al, 2008).

2) WITH POISONING/EXPOSURE

a) Insomnia, irritability, and anxiety are often observed. These symptoms may be severe with "ICE" intoxication (Anon, 1989).

J) INTRACRANIAL HEMORRHAGE

1) WITH THERAPEUTIC USE

a) PHENTERMINE/CASE REPORT: A 35-year-old woman, who had been taking phentermine for weight loss for several years, presented to the emergency department with altered mental status and 2 episodes of generalized seizures that were witnessed. Vital signs showed hypertension (198/111 mmHg). A CT scan of the head revealed large parietooccipital hemorrhages bilaterally and an MRI T2 fluid-attenuated inversion recovery (FLAIR) sequence showed diffuse cortical and subcortical foci indicative of vasogenic edema. The imaging findings in combination with the patient's acute hypertension are consistent with a diagnosis of posterior reversible encephalopathy syndrome, believed to be secondary to chronic phentermine use. The patient gradually recovered with supportive care and cessation of phentermine therapy (Wong et al, 2011).

K) SEROTONIN SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT (CHILD): A 6-year-old girl presented to the emergency department with anxiety, hyperactivity and combativeness after a suspected unintentional ingestion of an unknown amount of lisdexamfetamine. At admission, she experienced visual and auditory hallucinations, diaphoresis, myoclonus and hyperreflexia of her lower extremities, tachycardia (142 bpm), and tachypnea (34 breaths per min), indicative of serotonin syndrome. Despite administration of benzodiazepines, the patient's agitation worsened with an increase in blood pressure and heart rate. Toxicologic urinalysis was positive for amphetamines (greater than 1000 ng/mL) and laboratory analysis indicated elevated serum myoglobin and serum creatine kinase levels (565 mcg/L [normal 14 to 106 mcg/L] and 689 units/L [normal 20 to 200 units/L], respectively). Dexmedetomidine was then administered, resulting in a significant reduction in her agitation, as well as decreases in her blood pressure, heart rate, and respiratory rate (Akingbola & Singh, 2012).

L) ANEURYSM

1) WITH POISONING/EXPOSURE

a) A patient presented with agitation, disorientation, diaphoresis, and hypertension, with subsequent development of a severe headache, bradycardia, and respiratory arrest after ingesting 104 20-mg dextroamphetamine/amphetamine capsules. A dissected aneurysm at the base of his skull was detected upon imaging. There was no improvement neurologically and the patient died several days later (Kaland & Klein-Schwartz, 2015).

Gastrointestinal

3.8.2)

A) VOMITING

1) WITH THERAPEUTIC USE

a) LISDEXAMFETAMINE: In a retrospective review of poison center cases involving therapeutic use of lisdexamfetamine following the first 10 months of postmarketing use, vomiting was reported in 18% of patients (n=28) (Spiller et al, 2008).

2) WITH POISONING/EXPOSURE

a) Nausea, vomiting, diarrhea, and abdominal cramps are common following exposure.

B) HEMATEMESIS

1) WITH POISONING/EXPOSURE

a) Epigastric pain and hematemesis have been described after IV amphetamine use (Derlet et al, 1989).

C) COLITIS

1) WITH THERAPEUTIC USE

a) CASE REPORTS

1) DEXTROAMPHETAMINE: A 47-year-old narcoleptic taking 15 mg of dextroamphetamine daily developed ischemic colitis. Symptoms included abdominal pain and rectal bleeding which resolved within 7 days of drug cessation (Beyer et al, 1991).
2) FENFLURAMINE AND PHENTERMINE: Ischemic colitis occurred in a 36-year-old woman who was taking fenfluramine (20 mg 3 times daily) and phentermine (30 mg daily) for approximately 3 months for weight loss; no other medications were taken. Biopsy findings were normal 2 weeks after drug cessation (Schembre & Boynton, 1997).

Hepatic

3.9.2)

A) LIVER DAMAGE

1) WITH THERAPEUTIC USE

a) AMPHETAMINE

1) Hepatic injury is common in patients who develop hyperthermia associated with amphetamine abuse. Vasospasm may also contribute to hepatic injury.

b) PEMOLINE

1) As of October 2005, pemoline has been voluntarily withdrawn from the United States market due its overall risk of hepatic toxicity. Although the US Food and Drug Administration reported only 13 cases of liver failure resulting in liver transplant or death, it is believed that the risk of liver toxicity following pemoline therapy outweighs any potential benefits (Anon, 2005).
2) Case reports of hepatotoxicity resulting in hepatocellular injury has been reported in children receiving pemoline (Marotta & Roberts, 1998; Adcock et al, 1998).

B) HEPATIC FAILURE

1) WITH THERAPEUTIC USE

a) PEMOLINE

1) WITHDRAWAL FROM MARKET: As of October 2005, pemoline has been voluntarily withdrawn from the United States (US) market due its overall risk of hepatic toxicity. Although the US Food and Drug Administration reported only 13 cases of liver failure resulting in liver transplant or death, it is believed that the risk of liver toxicity following pemoline therapy outweighs any potential benefits (Anon, 2005).
2) In postmarketing experience in the US, 15 cases of acute hepatic failure have occurred in children receiving pemoline; 12 cases resulted in death or liver transplantation within 4 weeks of hepatic injury symptoms ((Anon, 1999)).

Genitourinary

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Renal failure may develop secondary to dehydration or rhabdomyolysis in patients with severe amphetamine or methamphetamine poisoning (Chan et al, 1994). Oliguric renal failure in the setting of amphetamine overdose is also associated with a high mortality (Lan et al, 1998).
b) CASE REPORT: Rhabdomyolysis and myoglobinuric renal failure were described in a 30-year-old man who ingested 50 amphetamine sulfate tablets (estimated dose 250 to 500 mg) (Scandling & Spital, 1982).
c) CASE REPORT: Acute interstitial nephritis without coexisting rhabdomyolysis, hyperpyrexia, and angitis was reported in a 32-year-old man who reported chronic amphetamine use (Foley et al, 1984).
d) CASE REPORT/PHENTERMINE: A 32-year-old man developed acute renal failure secondary to rhabdomyolysis after taking phentermine as an appetite suppressant at a dose of 37.5 mg twice daily (double the recommended dose) for approximately 1 week. The patient recovered with supportive therapy and discontinuation of phentermine (Steidl et al, 2010).

B) DYSURIA

1) WITH POISONING/EXPOSURE

a) Increased bladder sphincter tone may cause dysuria, hesitancy, and acute urinary retention following intravenous amphetamine use. The effect may be a direct result of peripheral alpha-agonist activity (Worsey et al, 1989).

Acid-Base

3.11.2)

A) METABOLIC ACIDOSIS

1) Metabolic acidosis occurs with severe poisoning (Lan et al, 1998).

Hematologic

3.13.2)

A) THROMBOCYTOPENIC DISORDER

1) Idiopathic thrombocytopenic purpura may occur but is not a common effect (Gynn et al, 1972).

Dermatologic

3.14.2)

A) EXCESSIVE SWEATING

1) WITH POISONING/EXPOSURE

a) The skin is usually flushed and diaphoretic following amphetamine exposure.

B) VITAMIN DEFICIENCY

1) CHRONIC TOXICITY

a) Poor dietary habits may lead to vitamin deficiency which can result in dermatologic signs such as cheilosis or purpura. Intravenous amphetamine use can produce skin lesions, such as tracks, abscesses, ulcers, cellulitis, or necrotizing angitis.

C) ALOPECIA

1) Diffuse hair loss has been associated with the use of amphetamines (Eckert et al, 1967; Alexander, 1965).

D) LOCAL INFECTION OF WOUND

1) WITH POISONING/EXPOSURE

a) In a review of 461 parenteral methamphetamine exposures, 21 cases of skin abscess and 7 cases of cellulitis were reported. All patients with abscesses required incision and drainage; 9 required an operative procedure (Richards et al, 1999).

Musculoskeletal

3.15.2)

A) SPASMODIC MOVEMENT

1) WITH POISONING/EXPOSURE

a) Muscle rigidity and fasciculations may occur.

B) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Rhabdomyolysis may develop in patients with severe agitation, muscular hyperactivity, hyperthermia, or seizures (Suchard & Saba, 1999; Lan et al, 1998; Chan et al, 1994; Briscoe et al, 1988; Scandling & Spital, 1982; Kendrick et al, 1977; Grossman et al, 1974; Ginsberg et al, 1970).
b) CASE REPORT/PHENTERMINE: A 32-year-old man presented to the emergency department with upper extremity weakness. Prior to presentation, the patient experienced lethargy, severe pain and a rash on his left shoulder, and swelling of the left parotid gland. Laboratory data revealed a troponin I concentration of 17.46 ng/mL (normal, less than 0.1 ng/mL), a creatine kinase (CK) concentration of 114,383 units/L (normal, 20 to 200 units/L), a CK-MB concentration of 745.5 ng/mL (normal, less than 6.70 ng/mL) and abnormal renal function tests (BUN of 34 mg/dL and a serum creatinine of 2.8 mg/dL). In addition, he was initially oliguric that progressed to anuria on hospital day 2. A whole body bone scan revealed evidence of rhabdomyolysis in his left deltoid muscle and shoulder, his posterior scapula, and in his upper thorax. Interview of the patient revealed that he had started taking phentermine as an appetite suppressant at a dose of 37.5 mg twice daily (double the recommended dose) approximately 1 week prior to onset of symptoms. With supportive therapy and discontinuation of phentermine, the patient recovered and was discharged on hospital day 6 (Steidl et al, 2010).

Endocrine

3.16.2)

A) INCREASED THYROXINE LEVEL

1) WITH POISONING/EXPOSURE

a) Transient hyperthyroxinemia may result from excessive exposure (Morley et al, 1980).
b) THYROTOXICOSIS MASKED BY AMPHETAMINE ABUSE

1) CASE REPORT: A 17-year-old man with known amphetamine, alcohol, and cocaine abuse was admitted with Graves disease and severe hyperadrenergic symptomatology that was initially misdiagnosed as sympathomimetic drug abuse (Jacobson et al, 1994).

Reproductive

3.20.1)

3.20.2)

A) LACK OF INFORMATION

1) LISDEXAMFETAMINE

a) At the time of this review, reproduction studies had not been conducted in humans (Prod Info VYVANSE(R) oral capsules, 2012).

2) PHENTERMINE HYDROCHLORIDE MONOTHERAPY

a) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info Suprenza(TM) oral disintegrating tablets, 2011).

B) CONGENITAL ANOMALY

1) DEXTROAMPHETAMINE: There has been one report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (vater association) in a baby born following maternal exposure to dextroamphetamine with lovastatin during the first trimester of pregnancy (Prod Info ADDERALL XR(R) oral capsules, 2014).

C) BILIARY ATRESIA

1) AMPHETAMINES: Eleven infants were born with biliary atresia to mothers who had taken amphetamines in various doses during the second and third trimesters (time of development of a biliary tree). In a controlled group of 50 normal infants, it was noted that 3 of 50 mothers had taken amphetamines (Levin, 1971).

D) ORAL CLEFT

1) AMPHETAMINES, PHENMETRAZINE: A large prospective, observational study of pregnancy and child development was undertaken related to anorectic drugs (amphetamines and phenmetrazine) prescribed to gravid women during different stages of pregnancy and evaluated for their teratogenicity. There was an excess of oral clefts in the infants of mothers who had amphetamines prescribed in the first 55 days from the last menstrual period (Milkovich & Van Den Berg, 1977).

E) LACK OF EFFECT

1) AMPHETAMINES/PHENMETRAZINE

a) A large prospective, observational study of pregnancy and child development was undertaken related to anorectic drugs (amphetamines and phenmetrazine) prescribed to gravid women during different stages of pregnancy and evaluated for their teratogenicity. The severe congenital anomaly rate (SCA) per 100 live-born children at age 5 years did not differ from the SCA rate of the group of children whose mothers did not use these drugs (Milkovich & Van Den Berg, 1977).

2) LISDEXAMFETAMINE

a) Reproduction studies with lisdexamfetamine (prodrug of dextroamphetamine) have not been conducted in humans. Vasoconstriction and thereby decreased placental perfusion may occur in pregnant women who receive amphetamines, such as lisdexamfetamine. There is an increased risk of premature delivery and low birth weight in infants born to mothers dependent on amphetamine. Additionally, withdrawal symptoms, such as feeding difficulties, irritability, agitation, and excessive drowsiness, may be present in such infants. An increase in congenital abnormalities was not observed during 2 case studies of more than 1000 patients exposed to amphetamines at varying gestational ages (Prod Info VYVANSE(R) oral capsules, 2012).

F) ANIMAL STUDIES

1) AMPHETAMINE

a) No effects on embryofetal morphological development or survival were reported with oral administration of amphetamine during organogenesis at doses up to 8 times the maximum recommended human dose (MRHD). With parenteral administration, both fetal malformations and death were reported at doses approximately 6 times the MRHD (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015).

2) AMPHETAMINES/DEXTROAMPHETAMINES

a) RATS: Amphetamine, in the enantiomer ratio present in Adderall XR (d- to I- ratio of 3:1), was given to pregnant rats from gestation day 6 to lactation day 20 in doses of 2, 6, and 10 mg/kg/day (approximately 0.8, 2, and 4 times the maximum recommended human dose (MRHD) for adolescents of 20 mg/day, on a mg/m(2) basis). All doses caused hyperactivity and a decrease in weight gain in the mother rats, as well as a decrease in pup survival. Doses of 6 and 10 mg/kg showed a decrease in pup body weight, correlating with delays in developmental landmarks. Doses of 10 mg/kg caused an increase in pup locomotor activity on day 22 postpartum but not at 5 weeks postweaning. When the pups matured and were tested for reproductive performance, the pups whose mothers had been given 10 mg/kg showed decreases in gestational weight gain, number of implantations, and number of delivered pups (Prod Info ADDERALL XR(R) oral capsules, 2014).
b) RATS, RABBITS: There was no evidence of adverse effects on embryofetal morphological development or survival when a combination amphetamine/dextroamphetamine product (amphetamine d- to l-enantiomer ratio of 3:1) was orally administered to pregnant rats and rabbits at doses of up to 6 mg/kg/day (1.5 times the maximum recommended human dose (MRHD) of 30 mg/day on a body surface area basis) and 16 mg/kg/day (8 times the MRHD), respectively, throughout the period of organogenesis (Prod Info ADDERALL XR(R) oral capsules, 2014).
c) MICE: Fetal malformations and death and severe maternal toxicity have been reported in mice following parenteral administration of d-amphetamine doses of 50 mg/kg/day (approximately 6 times the MRHD) or greater (Prod Info ADDERALL XR(R) oral capsules, 2014).

3) LISDEXAMFETAMINE

a) RATS, RABBITS: In pregnant rats and rabbits, orally administered lisdexamfetamine dimesylate at doses up to 40 and 120 mg/kg/day, respectively, (approximately 4 and 27 times the maximum recommended human dose of 70 mg/day on a mg/m(2) basis, respectively) did not affect embryofetal development or survival. However, in several studies in rodents, prenatal or early postnatal exposure to clinically relevant amphetamine or dextroamphetamine doses led to long-term neurochemical and behavioral effects, such as learning and memory deficits, altered locomotor activity, and changes in sexual function (Prod Info VYVANSE(R) oral capsules, 2012).

4) PHENTERMINE HYDROCHLORIDE/TOPIRAMATE

a) RATS: Reduced maternal and fetal body weight occurred at the maximum dose of 3.75 mg/kg phentermine and 25 mg/kg topiramate (approximately 2 times the maximum recommended human dose (MRHD) based on AUC estimates for each component) administered during the period of organogenesis. Rabbits administered approximately 0.1 times the MRHD for phentermine and 1 times the MRHD for topiramate, based on AUC, no effects on embryo-fetal development were observed. Offspring toxicity, including increased limb and tail malformations and delayed growth, development, and sexual malformation without effects to learning, memory, or fertility and reproduction resulted from 11.25 mg/kg/day phentermine and 75 mg/kg/day topiramate (approximately 5 and 6 times the exposures at the MRHD, respectively, based on AUC) administered throughout organogenesis and lactation (Prod Info QSYMIA(R) oral extended-release capsules, 2014).

3.20.3)

A) LACK OF INFORMATION

1) PHENTERMINE HYDROCHLORIDE

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 Suprenza(TM) oral disintegrating tablets, 2011).

B) RISK SUMMARY

1) AMPHETAMINE

a) Due to the potential for fetal and/or neonatal adverse reactions, use during pregnancy only if the potential maternal benefit outweighs the potential fetal risk (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015).

C) CONTRAINDICATED

1) PHENDIMETRAZINE

a) Phendimetrazine use is contraindicated in pregnant women. Although there are no data on the use of phendimetrazine in pregnant women and animal studies have not been conducted, the use of weight-loss medications during pregnancy is not recommended. A minimum weight gain is recommended for all pregnant women, even those who are overweight or obese (Prod Info phendimetrazine tartrate oral extended-release capsules, 2011). The use of weight loss medications during pregnancy may interfere with adequate nutrition for both the woman and her fetus (Conover, 2002). If phendimetrazine is used during pregnancy or if a patient becomes pregnant while receiving therapy, apprise the patient of the potential hazard to the fetus (Prod Info phendimetrazine tartrate oral extended-release capsules, 2011).

2) PHENTERMINE HYDROCHLORIDE (MONOTHERAPY OR IN COMBINATION WITH TOPIRAMATE)

a) The use of phentermine hydrochloride is contraindicated in pregnancy. There are no adequate and well-controlled studies of phentermine use during pregnancy and there has not been sufficient experience to establish the safety of phentermine during pregnancy. The current recommendations for pregnant women are a minimum weight gain and no weight loss. The use of weight-loss medications during pregnancy provides no maternal benefit and may result in fetal harm. If phentermine is used during pregnancy, or if the patient becomes pregnant while receiving the drug, inform the patient of the potential risk to her and the fetus (Prod Info ADIPEX-P(R) oral tablets, oral capsules, 2012; Prod Info Suprenza(TM) oral disintegrating tablets, 2011; Prod Info QSYMIA(TM) extended-release oral capsules, 2012). If phentermine is used in women who may become pregnant, weigh the potential benefit against the potential risk to the mother and infant (Prod Info PHENTERMINE RESIN ER oral extended-release capsules, 2011). There are no conclusive data to suggest that phentermine is teratogenic. However, some reports have suggested an increased incidence of malformations associated with amphetamines (AMA, 1983; Milkovich & van den Berg, 1978).

D) EMBRYO/FETAL RISK

1) AMPHETAMINE SULFATE

a) Use during pregnancy only if the potential maternal benefit outweighs the potential fetal risk (Prod Info EVEKEO(TM) oral tablets, 2015).

E) PLACENTAL BARRIER

1) METHAMPHETAMINE has been shown to cross the placenta (Bost et al, 1989; Garriott & Spruill, 1973).

F) WITHDRAWAL SYNDROME

1) AMPHETAMINE: Infants exposed to amphetamine in utero may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015; Prod Info EVEKEO(TM) oral tablets, 2015; Prod Info ADDERALL XR(R) oral capsules, 2007). Neonatal withdrawal symptoms (seizures, hypoglycemia) were reported in an infant born to a woman that used intravenous amphetamine (Ramer, 1974).

G) BIRTH PREMATURE

1) AMPHETAMINE: The risk of premature delivery and low birth weight is increased in infants born to mothers dependent on amphetamines (Prod Info ADDERALL XR(R) oral capsules, 2007).
2) METHAMPHETAMINE: Infants who have been exposed to methamphetamine tend to have low birth weights and are prone to prematurity (Oro & Dixon, 1987; Little et al, 1988).

H) SMALL FOR GESTATIONAL AGE

1) METHAMPHETAMINE: In a study of 1618 mother-infant pairs, infants exposed to methamphetamine (determined by maternal history and/or meconium analysis) were 3.5 times more likely to be small for gestational age (SGA defined as <10th percentile for birth weight) than unexposed infants. The incidence of SGA for methamphetamine exposed infants was 19% compared with 8.5% in unexposed infants. Gestational age at birth was also lower in methamphetamine exposed compared with unexposed infants (mean 38.7 +/- 2.4 weeks compared with 39.2 +/- 1.9 weeks). In addition, 12.5% of methamphetamine exposed infants were born before 37 weeks gestation compared with 6.5% of unexposed infants (Smith LM et al, 2006).
2) A large prospective, observational study of pregnancy and child development was undertaken related to anorectic drugs (amphetamines and phenmetrazine) prescribed to gravid women during different stages of pregnancy and evaluated for their teratogenicity. A rough test of efficacy of anorectic drugs was made by comparing mean weight gain in 4-week periods before and after the prescription; it showed only short-term and limited reduction of weight gain (Milkovich & Van Den Berg, 1977).

I) AGGRESSIVE BEHAVIOR

1) A statistically significant correlation between aggressive behavior and amphetamine exposure during fetal life has been reported (Eriksson & Zetterstrom, 1994).

J) DEATH

1) CASE REPORT: Two cases of maternal death have been associated with "crystal," also known as "ice" methamphetamine. In both cases, the women were multiparous and presented in their third trimester having acutely abused "crystal." One woman died of amniotic fluid embolism due to methamphetamine abuse, and the other died of eclampsia and HELLP syndrome that may have been related to amphetamine abuse (Catanzarite & Stein, 1995).

K) PREGNANCY CATEGORY

1) Benzphetamine, phendimetrazine, and phentermine hydrochloride (as monotherapy or in combination with topiramate) are classified by their manufacturers as FDA pregnancy category X (Prod Info DIDREX(R) oral tablets, 2006; Prod Info phendimetrazine tartrate oral extended-release capsules, 2011; Prod Info Suprenza(TM) oral disintegrating tablets, 2011; Prod Info QSYMIA(TM) extended-release oral capsules, 2012).
2) Amphetamine sulfate, amphetamine/dextroamphetamine, dextroamphetamine, lisdexamfetamine, and methamphetamine are classified by their manufacturers as FDA pregnancy category C (Prod Info EVEKEO(TM) oral tablets, 2015; Prod Info VYVANSE(R) oral capsules, 2012a; Prod Info ADDERALL XR(R) oral capsules, 2014; Prod Info DEXEDRINE(R) sustained release oral capsules, 2008; Prod Info DESOXYN(R) oral tablets, 2007).
3) Diethylpropion is classified by the manufacturer as FDA pregnancy category B (Prod Info TENUATE(R) immediate release tablets, 2003).

L) ANIMAL STUDIES

1) AMPHETAMINES/DEXTROAMPHETAMINES

a) MICE: Severe maternal toxicity has been reported in mice following parenteral administration of d-amphetamine doses of 50 mg/kg/day (approximately 6 times the MRHD) or greater (Prod Info ADDERALL XR(R) oral capsules, 2014).
b) RODENTS: Long-term neurochemical and behavioral alterations (ie, learning and memory deficits, altered locomotor activity, and changes in sexual function) resulted from prenatal or early postnatal exposure to amphetamine (d- or d,l-) in rodents, at doses similar to those used clinically (Prod Info ADDERALL XR(R) oral capsules, 2014).

2) METHAMPHETAMINE

a) OVINE - Experiments using the ovine model demonstrate that methamphetamine does cross the placenta and is distributed in fetal tissue (Burchfield et al, 1991).

3) PHENTERMINE HYDROCHLORIDE/TOPIRAMATE

a) RATS: Reduced maternal and fetal body weight occurred at the maximum dose of 3.75 mg/kg phentermine and 25 mg/kg topiramate (approximately 2 times the maximum recommended human dose (MRHD) based on AUC estimates for each component) administered during the period of organogenesis. Rabbits administered approximately 0.1 times the MRHD for phentermine and 1 times the MRHD for topiramate, based on AUC, significantly lower maternal body weight gain was observed. Lower maternal body weight gain and offspring toxicity, including lower pup survival, reduced pup body weight and delayed growth, development, and sexual malformation resulted from 11.25 mg/kg/day phentermine and 75 mg/kg/day topiramate (approximately 5 and 6 times the exposures at the MRHD, respectively, based on AUC) administered throughout organogenesis and lactation (Prod Info QSYMIA(R) oral extended-release capsules, 2014).

3.20.4)

A) BREAST MILK

1) METHYLAMPHETAMINE/AMPHETAMINE: Two case reports described methylamphetamine and amphetamine exposure in 4- and 2-month-old nursing infants following recreational use of methylamphetamine by the 2 mothers ages 29 and 26 years, respectively, who were recruited from the intervention arm of the randomized, controlled HIT trial. The women self-injected a single methylamphetamine dose of unknown purity and quantity. Four hours following drug use, urine samples were collected. A 5- to 10-mL breast milk sample was collected just prior to drug use and then in 2 to 6 hour intervals for 24 hours following methylamphetamine use. Methylamphetamine and amphetamine were estimated using high-performance liquid chromatography. The primary compound detected in the urine and breast milk of both subjects was methylamphetamine with a small quantity of amphetamine present. The approximate methylamphetamine and amphetamine half-lives were 13.6 and 43 hours, respectively, in subject 1, and 7.4 and 14 hours, respectively, in subject 2. The average concentration (Cavg) of methylamphetamine in the breast milk was 111 and 281 mcg/L for subjects 1 and 2, respectively, resulting in an absolute infant dose of 16.7 and 42.2 mcg/kg/day. The Cavg of amphetamine in the breast milk was 4 and 15 mcg/L for subjects 1 and 2, respectively, resulting in an absolute infant dose of 0.8 and 2.5 mcg/kg/day (Bartu et al, 2009).
2) AMPHETAMINE: Since amphetamines are excreted in human breast milk, advise women taking amphetamines to refrain from nursing (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015; Prod Info EVEKEO(TM) oral tablets, 2015; Prod Info Adderall(R) oral tablets, 2013; Prod Info ADDERALL XR(R) oral capsules, 2014). Concentrations of amphetamine were 3 and 7 times higher in breast milk than maternal plasma on the 10th and 42nd days after delivery, respectively, following administration of amphetamine 20 mg daily to a nursing mother with narcolepsy. Amphetamine was found in measurable amounts in the urine of the infant (Steiner et al, 1984).

a) Amphetamine is present in human breast milk at relative doses of 2% to 13.8% of the maternal weight-adjusted dosage. Milk plasma ratios range between 1.9 and 7.5 (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015).

3) LISDEXAMFETAMINE: It is unknown what the long-term neurodevelopment effects on infants from amphetamine exposure are. However, as amphetamines are excreted in human milk, breastfeeding women receiving lisdexamfetamine should be advised to either discontinue breastfeeding or discontinue lisdexamfetamine treatment, taking into account the importance of the drug to the mother (Prod Info VYVANSE(R) oral capsules, 2012).
4) PHENDIMETRAZINE: No reports describing the use of phendimetrazine during human lactation are available and the effects on the nursing infant from exposure to the drug in milk are unknown. It is not known if phendimetrazine affects the quantity and composition of breast milk. Considering the caloric demands of the breastfeeding mother, the use of weight-loss medications during lactation is discouraged because they may interfere with adequate nutrition for both the woman and her infant (Schaefer, 2001). Because many drugs are excreted into human milk, the manufacturer recommends discontinuing nursing or discontinuing phendimetrazine therapy, taking into account the importance of the drug to the mother and the importance of breastfeeding to the infant (Prod Info phendimetrazine tartrate oral extended-release capsules, 2011).
5) PHENTERMINE: Lactation studies with phentermine hydrochloride have not been conducted in humans. It is not known whether phentermine is excreted into human breast milk. Because many drugs are excreted in human milk, there is the potential for adverse reactions in nursing infants. Therefore, the use of phentermine hydrochloride during lactation is contraindicated (Prod Info ADIPEX-P(R) oral tablets, oral capsules, 2012; Prod Info Suprenza(TM) oral disintegrating tablets, 2011). It is not known if phentermine affects the quantity or composition of breast milk (Schaefer, 2001).

B) CONTRAINDICATED

1) PHENTERMINE HYDROCHLORIDE MONOTHERAPY

a) Lactation studies with phentermine hydrochloride have not been conducted in humans. It is not known whether phentermine is excreted into human breast milk. Because many drugs are excreted in human milk, there is the potential for adverse reactions in nursing infants. Therefore, the use of phentermine hydrochloride during nursing is contraindicated (Prod Info ADIPEX-P(R) oral tablets, oral capsules, 2012; Prod Info Suprenza(TM) oral disintegrating tablets, 2011). It is not known if phentermine affects the quantity or composition of breast milk (Schaefer, 2001).

3.20.5)

A) ANIMAL STUDIES

1) Neither fertility nor early embryonic development were adversely effected when rats were given amphetamine/dextroamphetamine doses of up to 20 mg/kg/day (approximately 5 times the maximum recommended human dose of 30 mg/day on a mg/m(2) body surface area basis) (Prod Info ADDERALL XR(R) oral capsules, 2014).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS300-62-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

B) IARC Carcinogenicity Ratings for CAS139-10-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

C) IARC Carcinogenicity Ratings for CAS156-08-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

D) IARC Carcinogenicity Ratings for CAS5411-22-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

E) IARC Carcinogenicity Ratings for CAS51-63-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

F) IARC Carcinogenicity Ratings for CAS90-84-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

G) IARC Carcinogenicity Ratings for CAS22232-71-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

H) IARC Carcinogenicity Ratings for CAS2152-34-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

I) IARC Carcinogenicity Ratings for CAS122-09-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) AMPHETAMINE SULFATE

1) At the time of this review, the manufacturer does not report any carcinogenic potential of amphetamine sulfate in humans (Prod Info EVEKEO(TM) oral tablets, 2015).

3.21.4)

A) LACK OF EFFECT

1) AMPHETAMINE

a) There was no evidence of carcinogenicity with administration of amphetamine in animals for 2 years at doses up to 2.4 times the maximum recommended human dose (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015).

Genotoxicity

1) There was no evidence of mutagenicity in the in vivo mouse bone marrow micronucleus test or the E. coli component of the in vitro Ames test. The d, l-amphetamine enantiomer produced a positive response in the mouse bone marrow micronucleus test and Ames test and a negative response in the in vitro sister chromatid exchange and chromosomal aberration assay (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs (including core temperature) and mental status.
B) Serum concentrations of amphetamine and related agents are not readily available or clinically useful.
C) Urine toxicology screens may detect amphetamines as a class, but do not distinguish between pharmaceutical and illicit forms. False positive amphetamine results may occur after exposure to over-the-counter cold preparations containing ephedrine or pseudoephedrine.
D) No specific lab work is needed in patients with mild clinical signs and symptoms.
E) In patients with severe toxicity, monitor serum electrolytes, CK, renal function, and troponin.
F) Obtain an ECG and institute continuous cardiac monitoring.
G) Consider chest radiograph or CT to exclude pneumothorax or aortic dissection as clinically indicated.
H) Consider a brain CT to exclude traumatic injury or cerebrovascular accident as clinically indicated.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) No specific lab work is needed in patients with mild clinical signs and symptoms.
2) In patients with severe toxicity, monitor serum electrolytes, CK, renal function, and troponin.
3) Serum concentrations of amphetamine and related agents are not readily available or clinically useful.
4) Additional laboratory studies may include a CBC and coagulation profile as indicated in symptomatic patients.

4.1.3)

A) Most members of the amphetamine family and related diet pill constituents are readily detectable in the urine. They are difficult to detect in the plasma unless very large amounts have been ingested, as in chronic abusers.
B) Amphetamine immunoassays have limited ability to detect MDMA. High concentrations of MDMA (3,4-methylenedioxymethamphetamine) in the urine are needed to elicit a response on screenings for amphetamines and methamphetamines. For common monoclonal amphetamine immunoassays (eg, EMIT, FPIA, RIA) the sensitivity for MDMA is approximately 50% less than for amphetamines and methamphetamines (Moeller et al, 2008).
C) FALSE POSITIVE RESULTS

1) CASE REPORT: A 7-year-old boy, who presented with hallucinations approximately 24 hours after reportedly receiving 5 mL of a cough and cold medicine containing pseudoephedrine, tested positive for amphetamines following a urine dipstick test. Subsequent testing of the urine sample, using gas chromatography, showed no evidence of amphetamines but did indicate a high ephedrine level (Boroda & Akhter, 2008).
2) CASE REPORTS: Two children presented with lethargy and ataxia after suspected ingestion of aripiprazole (as the sole ingestant in a 2-year-old child and as a combination ingestion with other medications, including alprazolam, fluvoxamine, clonazepam, and buspirone, in a 20-month-old child). In-house urine drug screening, using qualitative immunoassay techniques, was conducted with both patients, which revealed positive amphetamine results, although there was no evidence of amphetamine ingestion with either child. Blood and urine samples were then sent to an outside laboratory for quantitative confirmatory testing, which yielded negative results, suggesting that in-house amphetamine results were false-positive (Kaplan et al, 2015).

4.1.4)

A) OTHER

1) MONITORING

a) Monitor vital signs (including core temperature) and mental status.

2) CARDIAC MONITORING

a) Obtain a baseline ECG in all patients and repeat as necessary. Continuous cardiac monitoring is indicated.

3) FORENSIC EVALUATION

a) For children removed from suspected clandestine methamphetamine laboratories the following procedure is recommended to document exposure and aid prosecution:

1) Collect urine from any child that may have been exposed to methamphetamine in the past 72 hours. Place specimen cup in a biohazard bag and seal with security tape. Complete the chain of evidence form and release to the appropriate law enforcement personnel (Mecham & Melini, 2002).
2) Hair analysis may provide documentation of methamphetamine or other drug exposure for several months or longer. The condition of the hair (wet, dry, dirty, permed or dyed) does not affect results.
3) To obtain hair samples, a new disposable scissors should be used to cut a very small amount of hair (100 mg total, about the width of a pencil) from about 10 places. Obtain the hair as close to the scalp as possible (Mecham & Melini, 2002).
4) Place the specimen in an evidence envelope or plastic bag and seal with security tape. Complete the chain of evidence form and release to the appropriate law enforcement personnel.

Radiographic Studies

1) Severe headache following the use of amphetamines may be a symptom of intracerebral hemorrhage; a cerebral CT is recommended in symptomatic patients (McEvoy et al, 2000).
2) Consider chest radiograph or CT to exclude pneumothorax or aortic dissection as clinically indicated.

Methods

1) A SEMIQUANTITATIVE EMIT(R) HOMOGENEOUS ENZYME IMMUNOASSAY is available for measurement of the class of commonly abused amphetamines in urine. The detection limit (sensitivity) is 0.3 mcg/mL for amphetamine or methamphetamine.

a) The assay also detects other phenylethylamines at higher levels, and confirmatory testing is recommended (Prod Info EMIT(R) d.a.u.(TM) Amphetamine Assay, 1984). CDC proficiency testing shows the method to be at least as accurate as GC and TLC.
b) A confirmatory test is available to eliminate interference from OTC cold medications containing ephedrine, pseudoephedrine, or phenylpropanolamine.

2) Also available is a qualitative EMIT urine assay, which detects as little as 0.7 mcg/ml of amphetamine; this method correlated well with GLC, TLC, HPLC, and RIA in clinical studies.
3) FALSE POSITIVE RESULTS

a) THE EMIT MONOCLONAL AMPHETAMINE ASSAY: The Syva EMIT monoclonal amphetamine assay has produced FALSE POSITIVE results in patients taking: brompheniramine, chlorpromazine, fenfluramine, fluspirilene, isometheptene, isoxsuprine, labetalol, mephentermine, methylenedioxyethylamphetamine, nylidrin, phenylpropanolamine, phenethylamine, phenmetrazine, phentermine, pipothiazine, propylhexedrine, pseudoephedrine, ranitidine, ritodrine and tyramine (Crane et al, 1993; Olsen et al, 1992; Grinstead, 1989; Nice & Maturen, 1989). A confirmatory test should be done for positive samples done by this method.
b) Bupropion and its metabolites may cause false-positive results for amphetamines in certain urine toxicology screens (EMIT U AMP method on the Dade-Behring aca(R)- discrete clinical analyzer, Syva Emit II monoclonal immunoassay) (Casey et al, 2011; Weintraub & Linder, 2000; Nixon et al, 1995).
c) Ingestion of famprofazone, an analgesic and antipyretic agent available in Europe and known to metabolize to amphetamine and methamphetamine, has resulted in urine specimens testing positive for the presence of amphetamine and methamphetamine (Tseng et al, 2007).
d) The EMIT polyclonal amphetamine assay has NOT been associated with false positives in patients taking chlorpromazine, fluspirilene, or pipothiazine (Crane et al, 1993).
e) CASE REPORTS: Two children presented with lethargy and ataxia after suspected ingestion of aripiprazole (as the sole ingestant in a 2-year-old child and as a combination ingestion with other medications, including alprazolam, fluvoxamine, clonazepam, and buspirone, in a 20-month-old child). In-house urine drug screening, using qualitative immunoassay techniques, was conducted with both patients, which revealed positive amphetamine results, although there was no evidence of amphetamine ingestion with either child. Blood and urine samples were then sent to an outside laboratory for quantitative confirmatory testing, which yielded negative results, suggesting that in-house amphetamine results were false-positive (Kaplan et al, 2015).

4) FALSE NEGATIVE RESULTS

a) Mefenamic acid interferes with the ability to detect amphetamines using the EMIT(TM) polyclonal assay (Crane et al, 1993).
b) Cross-reactivity of methamphetamine and chlorpromazine metabolites, including nor-2-chlropromazine sulfoxide, was responsible for the false negative results in detecting the presence of methamphetamine and amphetamine when using the Triage(R) Drug of Abuse panel (Hikiji et al, 2009).

5) VARIOUS METHODS

a) The monoclonal test showed less cross-sensitivity than the polyclonal EMIT test when evaluated in 500 patients (Poklis et al, 1990).
b) The Abuscreen ONLINE assay was associated with fewer false positive results for amphetamines than the Syva EMIT assay in one study (Baker et al, 1995).
c) Other methods that have been described for the detection of amphetamine and methamphetamine include fluorescence polarization immunoassay and radioimmunoassay (Poklis & Moore, 1995; Ward et al, 1994).

1) A specific, sensitive and reliable gas chromatography-mass spectrometry (GC/MS) technique for the detection of sympathomimetic amines has been described which includes: amphetamines, phentermine, mephenorex, benzphetamine, and clobenzorex (Waksman et al, 2001; Franceschini et al, 1991). It has also been used to differentiate amphetamine and methamphetamine from 7 common sympathomimetic amines and MDA and MDMA (Thurman et al, 1992).
2) HYDROYCLOBENZOREX: The use of GC-MS method to detect hydroxyclobenzorex has been studied and was reportedly able to detect the drug for at least as long after ingestion as amphetamines (Maurer et al, 1997).
3) FALSE POSITIVE RESULTS: Exposure to prescription diet drugs that are metabolized to amphetamine and/or methamphetamine can result in a positive urine test for amphetamine. In one patient taking clobenzorex, GC/MS urine testing was positive for amphetamine (Wallace et al, 2000).

1) PHENYL-2-PROPANONE (P2P) is used in the illicit synthesis of amphetamine and methamphetamine. It can be identified by either nuclear magnetic resonance or gas chromatography in combination with vapor-phase Fourier transform infrared spectroscopy and electron impact mass spectroscopy detection (Allen et al, 1992).
2) TEST COMPARISONS: several references have evaluated the various amphetamine tests for effectiveness and cross-reactivity (Smith & Kidwell, 1991; Przekop et al, 1991; Thurman et al, 1992; Poklis et al, 1991; Cody, 1990).

1) Sectional hair analysis using stable-isotope dilution GC/MS correlated well with most histories of drug use/misuse (Nakahara, 1995; DuPont & Baumgartner, 1995; Nakahara et al, 1990). A GC/MS method also detected methamphetamine in hair samples using hepatafluorobutyric anhydride (HFBA) as the derivatizing reagent (Saito et al, 2000).
2) Immunoassay and HPLC methods for detecting amphetamines in hair have also been described (Nakahara, 1995; DuPont & Baumgartner, 1995).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with persistent or worsening vital sign abnormalities, continued or difficult to control agitation or psychosis, multiple seizures, cardiac ischemia, or dysrhythmias should be admitted. Intensive care unit is indicated for aggressive airway or cardiac monitoring.

6.3.1.2) HOME CRITERIA/ORAL

A) Inadvertent ingestions in asymptomatic patients, and pediatric exposures of commercial pharmaceutical agents within published pediatric therapeutic dose, who have no synergistic coingestions, may be monitored at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (ie, progressive agitation, psychosis, dysrhythmias, malignant hypertension, hyperthermia), concerns about decontamination, or in whom the diagnosis is unclear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate ingestions, synergistic coingestions, unclear history, symptomatic or intoxicated patients, exposure to doses outside published therapeutic ranges, or those in unstable social situations should be sent to a healthcare facility for observation.

Monitoring

Oral Exposure

6.5.1)

A) ACTIVATED CHARCOAL

1) Activated charcoal binds amphetamines. For oral exposures, consider charcoal administration if patient is able to drink safely, low risk for seizures.
2) 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).

3) 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) EFFICACY: Activated charcoal binds amphetamine (Decker et al, 1968).

a) In a controlled animal study, CD-1 mice given 1 gram/kilogram activated charcoal or an equivalent volume of water following 100 milligrams/kilogram methamphetamine (LD for fasting mice) were found to have delayed onset of toxicity and delayed early mortality following charcoal administration; overall mortality was not affected (McKinney et al, 1994).

1) BODY PACKERS/BODY STUFFERS: Please refer to the appropriate management if body packing or body stuffing is known/suspected.

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs (including core temperature) and mental status.
2) Serum concentrations of amphetamine and related agents are not readily available or clinically useful.
3) Urine toxicology screens may detect amphetamines as a class, but do not distinguish between pharmaceutical and illicit forms. False positive amphetamine results may occur after exposure to over-the-counter cold preparations containing ephedrine or pseudoephedrine.
4) No specific lab work is needed in patients with mild clinical signs and symptoms.
5) In patients with severe toxicity, monitor serum electrolytes, CK, renal function, and troponin.
6) Obtain an ECG and institute continuous cardiac monitoring.
7) Consider chest radiograph or CT to exclude pneumothorax or aortic dissection as clinically indicated.
8) Consider a brain CT to exclude traumatic injury or cerebrovascular accident as clinically indicated.

B) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

7) RECURRING SEIZURES

a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:

1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)

b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

8) STUDIES

a) ANIMAL: Rats pretreated with diazepam (5 to 10 milligrams/kilogram given intraperitoneally 30 minutes BEFORE 75 milligrams/kilogram of amphetamine) had significantly reduced incidence of seizures but had no such protection against death (Derlet et al, 1990).

C) HYPERTENSIVE EPISODE

1) Hypertension is generally transient and frequently does not require pharmacologic treatment unless severe.
2) Sedation with intravenous benzodiazepines (diazepam 5 to 10 milligrams IV repeated every 5 to 10 minutes as needed in adults) is often effective in treating hypertension. A short acting, titratable agent such as sodium nitroprusside should be considered if severe hypertension is unresponsive to benzodiazepines.
3) SODIUM NITROPRUSSIDE/INDICATIONS

a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.

4) SODIUM NITROPRUSSIDE/DOSE

a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).

5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION

a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS

a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

D) ARTERIOSPASM

1) Heparinization and intravenous or intra-arterial nitroprusside appear to be effective.

E) PSYCHOMOTOR AGITATION

1) INDICATION

a) If patient is severely agitated, sedate with IV benzodiazepines.

2) DIAZEPAM DOSE

a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

3) LORAZEPAM DOSE

a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
b) CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

4) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
5) Extreme agitation and hallucinations may respond to intravenous droperidol (up to 0.1 milligram/kilogram) (Derlet & Duncan, 1996; Richards et al, 1997; Gary & Saidi, 1978).

a) CAUTION: DROPERIDOL: Based on cases of QT prolongation and/or torsades de pointes in patients receiving droperidol at doses at or below recommended dosing, it should be reserved for use in patients who fail to show an acceptable response to other agents ((Anon, 2001)).
b) A baseline ECG (repeat as indicated) and continuous cardiac monitoring for 3 hours are recommended for all patients receiving droperidol.

6) In a prospective study of droperidol vs lorazepam for the sedation of agitated methamphetamine intoxicated patients both agents were able to control agitation in patients. Droperidol provided more rapid and deeper sedation (Derlet & Duncan, 1996; Richards et al, 1997). It has been observed that the use of lorazepam may require more repeat dosing as compared to droperidol(Richards et al, 1997).
7) HALOPERIDOL has been advocated by some authors (Catravas et al, 1975; Derlet & Heischober, 1990). Since haloperidol lowers the seizure threshold and is associated with neuroleptic malignant syndrome most authors consider benzodiazepines to be the agent of choice.

a) A retrospective chart review was conducted, involving 18 pediatric patients, ranging in age from 4 months to 7.25 years, with methamphetamine poisoning and who presented with tachycardia and agitation. All patients received benzodiazepines and 12 patients also received haloperidol intravenously. There were no reports of adverse effects associated with the administration of these medications (Ruha & Yarema, 2006).

F) BODY TEMPERATURE ABOVE REFERENCE RANGE

1) Hyperthermia is a common cause of mortality in amphetamine overdose and should be treated aggressively with deep sedation and rapid reduction in body temperature. Temperature should be monitored by rectal probe in extreme cases.
2) Core temperature above 40 degrees may be life threatening and indicates the need for aggressive sedation and cooling.
3) Administer intravenous benzodiazepines (Diazepam: Adults: 5 to 10 milligrams IV repeat every 5 to 10 minutes as needed, Children: 0.1 to 0.3 milligrams/kilogram IV repeat every 5 to 10 minutes as required. Lorazepam: Adults 2 to 4 milligrams IV repeat every 5 to 10 minutes as needed; Children: 0.05 to 0.1 milligram/kilogram IV repeat every 5 to 10 minutes as needed).
4) Large doses may be required. Monitor respiratory adequacy and airway. Be prepared to intubate and ventilate if needed.
5) Accelerate evaporative heat loss by keeping patient's skin wet with cool water and placing fans in the room. Monitor temperature every 30 minutes until below 38 degrees centigrade.

G) RHABDOMYOLYSIS

1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

H) VENTRICULAR ARRHYTHMIA

1) VENTRICULAR DYSRHYTHMIAS SUMMARY

a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

2) LIDOCAINE

a) LIDOCAINE/INDICATIONS

1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).

b) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

c) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

d) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

3) AMIODARONE

a) AMIODARONE/INDICATIONS

1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).

b) AMIODARONE/ADULT DOSE

1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).

c) AMIODARONE/PEDIATRIC DOSE

1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).

d) ADVERSE EFFECTS

1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).

I) TACHYARRHYTHMIA

1) Sedation with benzodiazepines to control agitation is sufficient in the vast majority of cases. Administer oxygen and intravenous fluids and correct hyperthermia as clinically indicated. If severe tachycardia persists and is associated with hemodynamic compromise or myocardial ischemia, additional therapy may be required, but this is unusual. Small incremental doses of labetalol may be useful because of the combined alpha and beta blocking effects. A short acting agent such as esmolol may also be considered, however esmolol carries the risk of inducing hypertension due to unopposed alpha agonist effects of amphetamines in this setting.
2) LABETALOL

a) INTRAVENOUS INDICATIONS

1) Consider if severe hypertension is unresponsive to short acting titratable agents such as sodium nitroprusside. Although labetalol has mixed alpha and beta adrenergic effects (Pearce & Wallin, 1994), it should be used cautiously if sympathomimetic agents are involved in the poisoning, as worsening hypertension may develop from alpha adrenergic effects.

b) ADULT DOSE

1) INTRAVENOUS BOLUS: Initial dose of 20 mg by slow IV injection over 2 minutes. Repeat with 40 to 80 mg at 10 minute intervals. Maximum total dose: 300 mg. Maximum effects on blood pressure usually occur within 5 minutes (Prod Info Trandate(R) IV injection, 2010).
2) INTRAVENOUS INFUSION: Administer infusion after initial bolus, until desired blood pressure is reached. Administer IV at 2 mg/min of diluted labetalol solution (1 mg/mL or 2 mg/3 mL concentrations); adjust as indicated and continue until adequate response is achieved; usual effective IV dose range is 50 to 200 mg total dose; maximum dose: 300 mg. Prepare 1 mg/mL concentration by adding 200 mg labetalol (40 mL) to 160 mL of a compatible solution and administered at a rate of 2 mL/min (2 mg/min); also can be mixed as an approximate 2 mg/3 mL concentration by adding 200 mg labetalol (40 mL) to 250 mL of solution and administered at a rate of 3 mL/min (2 mg/min) (Prod Info Trandate(R) IV injection, 2010). Use of an infusion pump is recommended (Prod Info Trandate(R) IV injection, 2010).

c) PEDIATRIC DOSE

1) INTRAVENOUS: LOADING DOSE: 0.2 to 1 mg/kg, may repeat every 5 to 10 minutes (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Fivush et al, 1997; Bunchman et al, 1992). Maximum dose: 40 mg/dose (Hari & Sinha, 2011; Flynn & Tullus, 2009). CONTINUOUS INFUSION: 0.25 to 3 mg/kg/hour IV (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Miller, 1994; Deal et al, 1992; Bunchman et al, 1992).

d) ADVERSE REACTIONS

1) Common adverse events include postural hypotension, dizziness; fatigue; nausea; vomiting, sweating, and flushing (Pearce & Wallin, 1994).

e) PRECAUTIONS

1) Contraindicated in patients with bronchial asthma, congestive heart failure, greater than first degree heart block, cardiogenic shock, or severe bradycardia or other conditions associated with prolonged or severe hypotension. In patients with pheochromocytoma, labetalol should be used with caution because it has produced a paradoxical hypertensive response in some patients with this tumor (Prod Info Trandate(R) IV injection, 2010).
2) Use caution in hepatic disease or intermittent claudication; effects of halothane may be enhanced by labetalol (Prod Info Trandate(R) IV injection, 2010). Labetalol should be stopped if there is laboratory evidence of liver injury or jaundice (Prod Info Trandate(R) IV injection, 2010).

f) MONITORING PARAMETER

1) Monitor blood pressure frequently during initial dosing and infusion (Prod Info Trandate(R) IV injection, 2010).

3) TACHYCARDIA SUMMARY

a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
c) ESMOLOL/ADULT LOADING DOSE

1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010).

d) ESMOLOL/ADULT MAINTENANCE DOSE

1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010).
2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010).
3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).

e) CAUTION

1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010).

J) HYPOTENSIVE EPISODE

1) A late clinical effect; should be treated with fluids. Vasopressors should be reserved for refractory cases. Warning: there is an increase in sympathetic tone which masks hypovolemia and postural hypotension.
2) 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.

3) 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).

K) DRUG WITHDRAWAL

1) Rapid withdrawal is a relatively safe procedure, but suicidal depression may occur. Withdrawal of a chronic abuser may result in a state of sleepiness and apathy.

L) DRUG-INDUCED CHOREA

1) Diazepam intravenously (Briscoe et al, 1988) and chlorpromazine (Bonthala & West, 1983).
2) Symptoms resolved or were markedly lessened within 12 to 18 hours in treated patients and resolved spontaneously in 38 to 48 hours in untreated patients (Singh et al, 1983; Nausieda et al, 1981).

M) SEROTONIN SYNDROME

1) SUMMARY

a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).

2) HYPERTHERMIA

a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
c) Non-depolarizing paralytics may be used in severe cases.

3) CYPROHEPTADINE

a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).

4) HYPERTENSION

a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.

5) HYPOTENSION

a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
c) NOREPINEPHRINE

1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
2) INITIAL DOSE

a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.

3) MAINTENANCE DOSE

a) 0.5 to 1 mL (2 to 4 mcg)/minute.

6) SEIZURES

a) DIAZEPAM

1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.

b) LORAZEPAM

1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (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).

c) RECURRING SEIZURES

1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.

d) PHENOBARBITAL

1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.

7) CHLORPROMAZINE

a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.

8) NOT RECOMMENDED

a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

9) DEXMEDETOMIDINE: A 6-year-old girl presented to the emergency department with evidence of serotonin syndrome (agitation, hyperactivity, myoclonus, hyperreflexia, diaphoresis, tachycardia, tachypnea) after a suspected unintentional ingestion of an unknown amount of lisdexamfetamine. Despite administration of benzodiazepines, the patient's agitation worsened with increases in blood pressure, heart rate and respiratory rate. Following initiation of dexmedetomidine therapy, with a 1 mcg/kg IV bolus given over 10 minutes followed by a maintenance dose of 0.5 mcg/kg/hour, the patient's agitation was significantly decreased. Another 1 mcg/kg IV bolus of dexmedetomidine was then administered, followed by an increase in the infusion dose to 0.7 mcg/kg/hour, resulting in a decrease in the patient's blood pressure, heart rate, and respiratory rate. The infusion rate was gradually decreased by 0.1 mcg/kg/hour every 4 hours until it was discontinued, approximately 24 hours later (Akingbola & Singh, 2012).

N) EXPERIMENTAL THERAPY

1) ANIMAL STUDY: Mice given methamphetamine injections along with a neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI) produced hypothermic effects and protection against methamphetamine induced dopamine depletion (Callahan & Ricaurte, 1998). Agents which can reduce core body temperature may protect against methamphetamine neurotoxicity.

Enhanced Elimination

1) Hemodialysis and hemoperfusion are not useful because of the large volume of distribution.
2) The amount of amphetamine removed by extracorporeal procedures is small compared to normal metabolic pathways of elimination. These procedures may be warranted in patients who develop renal or hepatic failure or deteriorate despite aggressive supportive care (Zalis & Parmley, 1963).

1) Acidification enhances amphetamine excretion but may precipitate acute renal failure in patients with myoglobinuria and is CONTRAINDICATED (Albertson et al, 1999).

Abstracts

Case Reports

1) AMPHETAMINE: A 32-year-old man with a 16-year history of drug addiction, accidently injected approximately 20 mg of amphetamine intra-arterially and developed a swollen and blotchy hand with restricted movements. He was treated with papaverine, heparin, ampicillin, and a stellate ganglion block with bupivacaine. Gradual improvement was seen over 7 days, although some gangrenous patches on the hand occurred. One month later, gangrene disappeared and no functional disabilities were present (Birkhaen & Heifetz, 1973).
2) AMPHETAMINE: A 21-year-old man ingested 2.2 gm amphetamine orally in a suicide attempt. One hour after ingestion the patient became agitated, hyperkinetic, and incoherent. Rectal temperature reached 108.4 degrees F along with a blood pressure of 160/80 mmHg and a pulse of 168 beats/min (Ginsberg et al, 1970a).

a) Respirations were rapid and shallow at 48 breaths/min. Pupils were dilated bilaterally and reacted minimally to light. Blood count revealed leukocytosis with a normal differential. The urine was found to be 3 plus positive for protein.
b) Treatment with gastric lavage, chlorpromazine, pentobarbital, diuretics, and fluids were initiated. Following chlorpromazine therapy, the patient became hypotensive, somnolent, and obtunded. Subsequently, he developed a coagulopathy with intramuscular hemorrhages producing entrapment neuropathies and acute renal failure. Hemodialysis was initiated and the patient recovered (Ginsberg et al, 1970a).

3) PHENTERMINE: A 22-year-old woman with no history of psychiatric illness who took phentermine 30 mg/day for 9 months increased her dose to 90 mg/day. Three months later, she developed severe psychosis with paranoid delusions. She responded to trifluoperazine and withdrawal of phentermine, but symptoms recurred upon rechallenge 2 days later (Devan, 1990).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) AMPHETAMINE

1) ADDERALL(R)

a) ADHD: Usual dose is 20 mg daily (Prod Info ADDERALL XR(R) extended-release oral capsules, 2006).
b) NARCOLEPSY: Usual dose is 5 to 60 mg/day in divided doses (Prod Info Adderall (R) CII, 2005).

2) ADZENYS XR-ODT(TM)

a) ADHD: 12.5 mg orally once daily (Prod Info ADZENYS XR-ODT(R) oral extended-release disintegrating tablets, 2016)

3) DYANAVEL XR (TM)

a) INITIAL DOSE: 2.5 or 5 mg orally once daily in the morning (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015).
b) TITRATION: May increase by 2.5 to 10 mg/day every 4 to 7 days (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015).
c) MAXIMUM DOSE: 20 mg/day (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015)
d) SWITCHING FROM OTHER AMPHETAMINE PRODUCTS: Discontinue current amphetamine product and titrate Dyanavel(TM) using the above schedule. Do not substitute on a mg-per-mg basis due to differing amphetamine base compositions and pharmacokinetic profiles (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015).

B) AMPHETAMINE SULFATE

1) ADHD: 5 mg orally once or twice daily. Dose may be increased by 5 mg/day at weekly intervals until optimal response (Prod Info EVEKEO(TM) oral tablets, 2015).
2) EXOGENOUS OBESITY: Up to 30 mg daily, in divided doses of 5 to 10 mg administered 30 to 60 minutes before meals (Prod Info EVEKEO(TM) oral tablets, 2015).
3) NARCOLEPSY: Initial, 10 mg orally once daily. Dose may be increased by 10 mg/day at weekly intervals until optimal response (Prod Info EVEKEO(TM) oral tablets, 2015).

C) BENZPHETAMINE

1) Usual oral dose 25 to 50 mg tablets 1 to 3 times daily (Prod Info DIDREX(R) oral tablets, 2006)

D) DIETHYLPROPION

1) Usual oral dose is 25 mg as an immediate-release tablet 3 times daily; or 75 mg controlled-release tablet once daily (Prod Info diethylpropion hcl immediate-release oral tablets, controlled-release oral tablets, 2007)

E) LISDEXAMFETAMINE

1) ADHD: For adults starting treatment for the first time or switching from another medication, 30 mg once daily in the morning for the treatment of ADHD; may be increased up to a maximum dose of 70 mg once daily (Prod Info Vyvanse(R) oral capsules, 2011).

F) PHENDIMETRAZINE

1) OBESITY: Usual oral dose is 35 mg immediate-release tablets 2 or 3 times daily; or 105 mg sustained-release capsules once daily for the short-term therapy of obesity (Prod Info phendimetrazine tartrate oral tablets, 2006; Prod Info phendimetrazine tartrate oral extended-release capsules, 2011).

G) PHENTERMINE

1) Usual oral dose is 37.5 mg capsule or tablet once daily or 18.75 mg (half tablet) may be adequate for some patients (Prod Info phentermine hydrochloride oral tablets, 2009).

H) PHENTERMINE/TOPIRAMATE

1) OBESITY: Initial dose for obesity is phentermine 3.75 mg/topiramate 23 mg orally once daily for 14 days, titrate to an effective dose; phentermine 15 mg/topiramate 92 mg is the maximum daily dose (Prod Info QSYMIA(TM) extended-release oral capsules, 2012)

7.2.2)

A) AMPHETAMINE

1) ADDERALL(R)

a) ADHD (6 YEARS AND OLDER): Usual oral dose is 5 mg once or twice daily; adjust dose as indicated; rare for dose to exceed 40 mg per day for ADHD (Prod Info Adderall (R) CII, 2005) or 10 mg extended-release capsule once daily not to exceed 30 mg daily for ADHD (Prod Info ADDERALL XR(R) extended-release oral capsules, 2006).

2) ADZENYS XR-ODT(TM)

a) 6 YEARS OF AGE AND OLDER: The recommended starting dose is 6.3 mg orally once daily (Prod Info ADZENYS XR-ODT(R) oral extended-release disintegrating tablets, 2016).
b) 6 YEARS OF AGE AND OLDER: Titration, may increase by 3.1 to 6.3 mg/week (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015).
c) 6 TO 12 YEARS OF AGE: Maximum dose, 18.8 mg/day (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015)
d) 13 YEARS OF AGE AND OLDER: Maximum dose, 12.5 mg/day (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015)

3) DYANAVEL XR (TM)

a) 6 YEARS OF AGE AND OLDER: Initial dose, 2.5 or 5 mg orally once daily in the morning (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015).
b) 6 YEARS OF AGE AND OLDER: Titration, may increase by 2.5 to 10 mg/day every 4 to 7 days (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015).
c) 6 YEARS OF AGE AND OLDER: Maximum dose, 20 mg/day (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015)
d) 6 YEARS OF AGE AND OLDER: Switching from other amphetamine products, discontinue current amphetamine product and titrate Dyanavel(TM) using the above schedule. Do not substitute on a mg-per-mg basis due to differing amphetamine base compositions and pharmacokinetic profiles (Prod Info DYANAVEL(TM) XR extended-release oral suspension, 2015).

B) AMPHETAMINE SULFATE

1) ADHD

a) 3 TO 5 YEARS OF AGE: Initial, 2.5 mg orally once daily. Dose may be increased by 2.5 mg/day at weekly intervals until optimal response (Prod Info EVEKEO(TM) oral tablets, 2015).
b) 6 YEARS AND OLDER: Initial, 5 mg orally once or twice daily. Dose may be increased by 5 mg/day at weekly intervals until optimal response (Prod Info EVEKEO(TM) oral tablets, 2015).

2) EXOGENOUS OBESITY

a) 12 YEARS AND OLDER: Up to 30 mg daily, in divided doses of 5 to 10 mg administered 30 to 60 minutes before meals (Prod Info EVEKEO(TM) oral tablets, 2015)

3) NARCOLEPSY

a) 6 TO 12 YEARS OF AGE: Initial, 5 mg orally once daily. Dose may be increased by 5 mg/day at weekly intervals until optimal response (Prod Info EVEKEO(TM) oral tablets, 2015).
b) 12 YEARS AND OLDER: Initial, 10 mg orally once daily. Dose may be increased by 10 mg/day at weekly intervals until optimal response (Prod Info EVEKEO(TM) oral tablets, 2015).

C) BENPHETAMINE

1) Not recommended for children less than 12 years (Prod Info DIDREX(R) oral tablets, 2006)

D) LISDEXAMFETAMINE

1) 6 TO 17 YEARS OF AGE: Initially, 30 mg orally once daily in the morning up to a maximum dose of 70 mg once daily for treatment of ADHD; not studied in children less than 6 years of age (Prod Info Vyvanse(R) oral capsules, 2011).

E) PHENDIMETRAZINE

1) Safety and efficacy have not been established. Use is not recommended in children aged less than 17 years (Prod Info phendimetrazine tartrate oral tablets, 2006; Prod Info phendimetrazine tartrate oral extended-release capsules, 2011).

F) PHENTERMINE

1) Safety and efficacy have not been established (Prod Info phentermine hydrochloride oral tablets, 2009).

G) PHENTERMINE/TOPIRAMATE

1) Safety and effectiveness in pediatric patients aged less than 18 years have not been established (Prod Info QSYMIA(TM) extended-release oral capsules, 2012).

Minimum Lethal Exposure

1) BENZPHETAMINE

a) A 16-year-old boy died after ingesting an unknown amount of benzphetamine. At autopsy, 53.1 mg were found in the gastric contents. Blood concentration was approximately 27 times the maximum estimated therapeutic level and indicated that at least 1000 mg was probably ingested (27 x 50 mg tablets = 1350 mg) (Brooks et al, 1982).

2) 4-METHYLTHIOAMPHETAMINE (4-MTA)

a) Ingestion of 4-MTA, an amphetamine derivative, resulted in the death of a 22-year-old man. The patient complained of abdominal cramps and feeling "sick" with the symptoms progressing over 12 hours to include witnessed seizures, difficulty breathing and 'foaming at the mouth'. The patient died approximately 16 hours after exposure despite resuscitation efforts (Elliott, 2000).

3) DEXTROAMPHETAMINE/AMPHETAMINE

Maximum Tolerated Exposure

1) A retrospective chart review over a 4-year-period was conducted to evaluate outcomes following unintentional pediatric amphetamine ingestions. Of 118 patients (average age 3.1 years [range 8 months to 7 years]), 28 patients ingested twice their normal therapeutic amphetamine dose. Twenty-five of the 28 patients developed no or minimal symptoms and were observed at home. Three patients were referred to the emergency department for mild agitation or headache, but were subsequently discharged. Ninety of the 118 patients were amphetamine-naive and had ingested a sibling's medication. Seventy-six patients were evaluated at a healthcare facility. Fifteen patients were agitated and treated with benzodiazepines, and sixteen patients were observed for more than 12 hours before being discharged. The specific doses of amphetamines ingested were not delineated (LoVecchio et al, 2009).

1) Response is variable and tolerance develops in chronic abusers who may use as much as 5 to 15,000 mg/day (Kramer et al, 1967). Symptomatology is clearly recognizable and occurs within one hour of ingestion.
2) Clinical observation of toxic effects is more relevant than attempting to determine the amount ingested. Hyperthermia above 40 degrees C may be life threatening and indicates the need for aggressive sedation and cooling.

1) AMPHETAMINE

a) CASE REPORT: Ingestion of 2.2 grams (28 mg/kg) in a 21-year-old man resulted in severe toxicity (Ginsberg et al, 1970).
b) CASE REPORT: A 13-year-old girl developed hypertension, bigeminy, pulmonary edema, and myocardial infarction after ingesting approximately 20 Adderall(R) (amphetamine/dextroamphetamine) 5-mg and 10-mg tablets. Following supportive care, the patient recovered without further sequelae (Sztajnkrycer et al, 2002).

2) PHENTERMINE

a) CASE SERIES: In a toxicosurveillance study of pediatric exposures to phentermine, 82 children were identified and 52 were less than 24 months of age with total amounts of exposure ranging from 4 to 90 mg (mean 31 mg, +/- SD 19.5). Sixty-three percent (n=33) required no therapy and symptomatology did NOT appear to be dose related. One child was hyperactive after 15 mg (1.3 mg/kg) and another child remained asymptomatic at 90 mg (9 mg/kg). The authors concluded that only minor symptoms occurred with minimal therapy required for children in this study (Mrvos & Krenzelok, 2000).
b) CASE REPORT: A 32-year-old man developed rhabdomyolysis and secondary acute renal failure after taking phentermine as an appetite suppressant at a dose of 37.5 mg twice daily (double the recommended dose) for approximately 1 week. The patient recovered with supportive therapy and discontinuation of phentermine (Steidl et al, 2010).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) Therapeutic drug concentrations for individual compounds are listed below

1) Time to Peak Concentration (Prod Info VYVANSE(R) oral capsules, 2008; Baselt, 2004):

a) DIETHYLPROPION: (Plasma) averaged 0.007 mg/L at 0.5 hours and declined to 0.003 mg/L by 2 hours following a 75 mg oral dose.
b) LISDEXAMFETAMINE: The Tmax of dextroamphetamine after a single oral 30, 50, or 70 milligram dose of lisdexamfetamine dimesylate was given to pediatric patients (n=18; aged 6 to 12 years) after an 8-hour fast was approximately 3.5 hours. The Tmax of lisdexamfetamine dimesylate was approximately 1 hour .
c) MAZINDOL: (Blood) Averaged 2.5 mcg/L at 2 hours and declined to 2.2 mcg/L by 8 hours following a 2 mg oral dose.
d) PHENEDIMETRAZINE: (Serum) Averaged 0.090 mg/L at 1 hour, and declined to 0.045 mg/L by 2 hours and 0.25 mg/L by 4 hours following a 35 mg oral dose.
e) PHENMETRAZINE: (Plasma) 0.13 mg/L (range 0.00 to 0.24) at 2 hours and declined to 0.11 mg/L by 5 hours and 0.06 ,mg/L after 12 hours following a 75 mg oral dose. Following a 75 mg sustained-release tablet, plasma concentration reached 0.07 mg/L at 5 hours.
f) PHENTERMINE: (Blood) Averaged 0.09 mg/L at 4 hours, declined to 0.03 mg/L at 40 hours following a 0.375 mg/kg oral dose (26 mg/70 kg); steady-state plasma concentrations reached 0.18 to 0.51 mg/L after 30 mg daily for 2 weeks.

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) BENZPHETAMINE

1) Fatal drug concentrations in an adolescent male after intentional ingestion of large (not specified) amounts of the drug (Baselt, 2004):

a) Blood - 14 mg/L
b) Liver - 106 mg/L
c) Kidney - 38 mg/L
d) Urine - 8 mg/L

2) DIETHYLPROPION

1) Fatal drug concentrations in an adult following intravenous injection (Baselt, 2004):

a) Blood - 5.4 mg/L
b) Liver - 0.9 mg/L
c) Kidney - 0.9 mg/L
d) Injection Site - 43 mg/L

3) METHAMPHETAMINE

a) Blood and urine levels remained at toxic levels (greater than 1.91 mg/L) for 11 hours in a 33-year-old male following an alcohol and methamphetamine ingestion. The authors suggested that the long half-life of methamphetamine led to probable vascular fatigue resulting in hemorrhage, neurological dysfunction, and death. Postmortem examine was refused by family (Molina & Jejurikar, 1999).
b) Post-mortem blood methamphetamine level in a 31-year-old man, who died from an intracerebral hemorrhage after smoking and insufflating between 0.25 and 0.50 grams of methamphetamine, was 300 ng/mL (McGee et al, 2004).

4) 4-METHYLTHIOAMPHETAMINE - The mean 4-MTA perimortem blood concentration and postmortem femoral blood were 4.0 mg/L and 4.6 mg/L, respectively. Currently, there is minimal data available on 4-MTA; as a comparison a 4 mg/L blood concentration of other amphetamine-related compounds would be considered an overdose or at least excessive usage. The death was found likely related to 4-MTA (Elliott, 2000).
5) PHENDIMETRAZINE

1) Fatal drug concentration following recreational use of the drug in 2 adult males (Baselt, 2004):

a) Blood - 0.3 and 0.7 mg/L

6) PHENMETRAZINE

1) Fatal drug concentrations in a series of 12 fatalities (Baselt, 2004)

a) Blood - 1.1 (range: 0.1 to 4.9) mg/L
b) Liver - 3.1 (range: 0.1 to 20) mg/L
c) Kidney - 1.5 (range: 0.1 to 8.0) mg/L
d) Urine - 21 (range: 0.1 to 90) mg/L

7) PHENTERMINE

1) Fatal drug concentrations in 3 adults following overdose (Baselt, 2004)

a) Blood - 4.0 (range 1.5 to 7.6) mg/L
b) Liver - 10 (range: 1.8 to 15) mg/L
c) Kidney - 14 (range: 12 to 16 mg/L)
d) Urine - 84 (range: 13 to 150 mg/L)

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

AA)

AB)

1) Not Listed

AC)

1) Not Listed

AD)

1) Not Listed

AE)

1) Not Listed

AF)

1) Not Listed

AG)

1) Not Listed

AH)

1) Not Listed

AI)

1) Not Listed

AJ)

1) Not Listed

Toxicity Information

7.7.1)

A) AMPHETAMINE SULFATE

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 9700 mcg/kg (RTECS, 2006)

2) LD50- (ORAL)MOUSE:

a) 10 mg/kg (RTECS, 2006)

3) LD50- (SUBCUTANEOUS)MOUSE:

a) 16 mg/kg (RTECS, 2006)

4) LD50- (INTRAPERITONEAL)RAT:

a) 43200 mcg/kg (RTECS, 2006)

5) LD50- (ORAL)RAT:

a) 32 mg/kg (RTECS, 2006)

Pharmacology Toxicology

Toxicologic Mechanism

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

1) SUMMARY

a) Begin treatment immediately.
b) Keep animal warm and do not handle unnecessarily.
c) Sample vomitus, blood, urine, and feces for analysis.
d) Remove the patient and other animals from the source of contamination.

2) Treatment should always be done on the advice and with the consultation of a veterinarian.
3) Additional information regarding treatment of poisoned animals may be obtained from a Veterinary Toxicologist or the National Animal Poison Control Center.
4) ANIMAL POISON CONTROL CENTERS -

National Animal Poison Control Center
1717 S Philo Road, Suite 36
Urbana, IL  61802
Phone:  800-548-2423 ($30 per case)
        888-426-4435
        900-680-0000 ($30 per case)
NOTE:  On the 800 or 888 line, the charge can be 
billed to the caller's Visa, Mastercard, Discover, 
or American Express.

a) The National Animal Poison Control Center is an emergency telephone service which provides a veterinary toxicologist for consultation. NAPCC will make follow-up calls as needed in critical cases.

5) SMALL ANIMALS: Due to lack of reports of large animal intoxication with this substance, the following sections address small animals (dogs and cats) only.
6) In the case of a poisoning involving large animals, consult a veterinary poison control center.

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) GENERAL TREATMENT

a) EMESIS/GASTRIC LAVAGE - Emesis may be initiated only if in the early period after ingestion, or if the animal is not overly stimulated. Lavage is preferred if the animal is stimulated (administer appropriate sedation) or if emesis is ineffective.

1) CAUTION: Carefully examine patients with chemical exposure before inducing emesis. If signs of oral, pharyngeal, or esophageal irritation, a depressed gag reflex, or central nervous system excitation or depression are present, EMESIS SHOULD NOT BE INDUCED.
2) HORSES OR CATTLE: DO NOT attempt to induce emesis in ruminants (cattle) or equids (horses).
3) DOGS AND CATS

a) IPECAC: If within 2 hours of exposure: induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.
b) APOMORPHINE: Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.

1) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram, although this route may not be as effective.

b) ACTIVATED CHARCOAL: Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
c) CATHARTIC: Administer a dose of a saline or sorbitol cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

Kinetics

11.5.1)

A) SPECIFIC TOXIN

1) Amphetamines are rapidly absorbed from the GI tract (Beasley et al, 1989).

11.5.2)

A) SPECIFIC TOXIN

1) Amphetamine also enters the CSF; CSF concentration is about 80% that of plasma (Beasley et al, 1989).

11.5.4)

A) SPECIFIC TOXIN

1) Elimination is via the kidney and is dependent on pH. Acidifying the urine will speed elimination (Beasley et al, 1989).

Pharmacology Toxicology

1) Amphetamine stimulates catecholamine release centrally and from the adrenal glands; and stimulates cortical centers including the cerebral cortex, reticular activating system, and the medullary respiratory center. Amphetamine is also sympathomimetic and has a greater stimulant activity at sympathetic nerve endings than norepinephrine. It is a monoamine oxidase inhibitor (Beasley et al, 1989).

Other

1) CLINICAL SIGNS/SYMPTOMS

a) DIFFERENTIAL DIAGNOSIS - Toxicoses: strychnine, organochlorine insecticides, methylxanthines, 4-aminopyridine, metaldehyde, and other illicit drugs. The animal's owner may hinder diagnosis by not admitting possession of illicit drugs (Beasley et al, 1989).

Clinical Effects

11.1.13)

A) OTHER

1) Poisoning is uncommon, but not rare. Signs in small animals include hyperthermia, hyperventilation, tachycardia, mydriasis, lactic acidosis, hypoglycemia, hypertension, dysrhythmias, vomiting, diarrhea, and dysuria. Renal failure may occur secondary to rhabdomyolysis. Seizures and coma may occur (Beasley et al, 1989).
2) CASE REPORTS - Probable deliberate poisoning with methamphetamine occurred in three dogs, one of whom died prior to treatment (Bischoff et al, 1998). Symptoms included: bradycardia, hypothermia, labored respirations, mydriasis, and pale mucous membranes. Treatment included gastrointestinal decontamination with hydrogen peroxide and supportive care. Both dogs made a complete recovery.

Treatment

11.2.1)

A) GENERAL TREATMENT

1) SUMMARY

National Animal Poison Control Center
1717 S Philo Road, Suite 36
Urbana, IL  61802
Phone:  800-548-2423 ($30 per case)
        888-426-4435
        900-680-0000 ($30 per case)
NOTE:  On the 800 or 888 line, the charge can be 
billed to the caller's Visa, Mastercard, Discover, 
or American Express.

a) The National Animal Poison Control Center is an emergency telephone service which provides a veterinary toxicologist for consultation. NAPCC will make follow-up calls as needed in critical cases.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) GENERAL TREATMENT

1) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram, although this route may not be as effective.

11.2.5)

A) SEIZURES/CNS EXCITATION -

1) SEIZURES/LARGE ANIMALS: May be controlled with diazepam.

a) HORSES/DIAZEPAM: Neonates: 0.05 to 0.4 milligrams/kilogram; Adults: 25 to 50 milligrams. Give slowly intravenously to effect; repeat in 30 minutes if necessary.
b) CATTLE, SHEEP AND SWINE/DIAZEPAM: 0.5 to 1.5 milligrams/kilogram intravenously to effect.

2) SEIZURES/DOGS & CATS:

a) DIAZEPAM: 0.5 to 2 milligrams/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 1 to 2 minutes to effect.
b) PHENOBARBITAL: 5 to 30 milligrams/kilogram over 5 to 10 minutes intravenously to effect.
c) REFRACTORY SEIZURES: Consider anaesthesia or heavy sedation. Administer pentobarbital to DOGS & CATS at a dose of 3 to 15 milligrams/kilogram intravenously slowly to effect. May need to repeat in 4 to 8 hours. Be sure to protect the airway.

B) HYPERTHERMIA -

1) Monitor body temperature every 2 to 4 hours. Treat hyperthermia by employing whole-body cooling, including alcohol on the foot-pads, packing the animal in ice, and training fans on the animal.

C) MONITORING -

1) Symptomatic patients must be monitored continuously. Refer to an emergency hospital or critical care clinic for 24 hour monitoring.

Range Of Toxicity

11.3.2)

A) ACUTE OVERDOSE

1) LD50 - Estimated at 10 to 30 mg/kg (Beasley et al, 1989).

References

General Bibliography

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

40)

41)

42)

43)

44)

45)

46)

47)

48)

49)

50)

51)

52)

53)

54)

55)

56)

57)

58)

59)

60)

61)

62)

63)

64)

65)

66)

67)

68)

69)

70)

71)

72)

73)

74)

75)

76)

77)

78)

79)

80)

81)

82)

83)

84)

85)

86)

87)

88)

89)

90)

91)

92)

93)

94)

95)

96)

97)

98)

99)

100)

101)

102)

103)

104)

105)

106)

107)

108)

109)

110)

111)

112)

113)

114)

115)

116)

117)

118)

119)

120)

121)

122)

123)

124)

125)

126)

127)

128)

129)

130)

131)

132)

133)

134)

135)

136)

137)

138)

139)

140)

141)

142)

143)

144)

145)

146)

147)

148)

149)

150)

151)

152)

153)

154)

155)

156)

157)

158)

159)

160)

161)

162)

163)

164)

165)

166)

167)

168)

169)

170)

171)

172)

173)

174)

175)

176)

177)

178)

179)

180)

181)

182)

183)

184)

185)

186)

187)

188)

189)

190)

191)

192)

193)

194)

195)

196)

197)

198)

199)

200)

201)

202)

203)

204)

205)

206)

207)

208)

209)

210)

211)

212)

213)

214)

215)

216)

217)

218)

219)

220)

221)

222)

223)

224)

225)

226)

227)

228)

229)

230)

231)

232)

233)

234)

235)

236)

237)

238)

239)

240)

241)

242)

243)

244)

245)

246)

247)

248)

249)

250)

251)

252)

253)

254)

255)

256)

257)

258)

259)

260)

261)

262)

263)

264)

265)

266)

267)

268)

269)

270)

271)

272)

273)

274)

275)

276)

277)

278)

279)

280)

281)

282)

283)

284)

285)

286)

287)

288)

289)

290)

291)

292)

293)

294)

295)

296)

297)

298)

299)

300)

301)

302)

303)

304)

305)

306)

307)

308)

309)

310)

311)

312)

313)

314)

315)

316)

317)

318)

319)

320)

321)

322)

323)

324)

325)

326)

327)

328)

329)

330)

331)

332)

333)

334)

335)

336)

337)

338)

339)

340)

341)

342)

343)

344)

345)

346)

347)

348)

349)

350)

351)

352)

353)

354)

355)

356)

357)

358)

359)

360)

361)

362)

363)

364)

365)

366)

367)

368)

369)

370)

371)

372)

373)

374)

375)

376)

377)

378)

379)

380)

381)

382)

383)

384)

385)

386)

387)

388)

389)

390)

391)

392)

393)

394)

395)

396)

397)

398)

399)

400)

FeedBack

AMPHETAMINES AND RELATED DRUGS

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

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

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

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

Continuing Care

Kinetics

Pharmacology Toxicology

Other

Clinical Effects

Treatment

Range Of Toxicity

General Bibliography