FLUOXETINE

F. DRUG DEPENDENCE

1. CASE REPORT - Two patients treated with fluoxetine with a history of polysubstance abuse increased their daily dose of fluoxetine to obtain "speed-like" effects (Tinsley et al, 1994).

3.19 IMMUNOLOGIC

3.19.2 CLINICAL EFFECTS

A. ALLERGIC REACTION

1. CASE REPORT - A 19-year-old woman developed flu-like symptoms (dyspnea, malaise, myalgias, arthralgia, chill, headache, nasal congestion, cough), along with urticaria, maculopapular rash, and angioedema 2 days following ingestion of 680 mg of fluoxetine.

a. Although this may have represented a hypersensitivity reaction, another possible explanation is a dose-related phenomenon associated with peak metabolite (norfluoxetine) serum concentrations (Kim & Pentel, 1989).

B. ANAPHYLACTOID REACTION

1. Urticaria, angioedema, bronchospasm, and other anaphylactoid events have been reported (Prod Info, 1990).

3.20 REPRODUCTIVE

3.20.1 SUMMARY

A. Fluoxetine has no known teratogenic effect in humans; US FDA pregnancy category C.

3.20.2 TERATOGENICITY

A. LACK OF EFFECT

1. A study of 128 women exposed to fluoxetine during the first trimester showed no increase in major fetal malformations (Pastuszak et al, 1993). There was a tendency for women exposed to fluoxetine or tricyclic antidepressants to report more spontaneous abortions than women exposed to no teratogens.
2. Pregnancy category C (Prod Info, 1999). Reproduction studies have been performed in rats and rabbits at doses nine and eleven times the maximum daily human dose, respectively, and have revealed no evidence of harm to the fetus. It is not known, however, if the drug is a human teratogen (Prod Info, 1988).
3. In a study of 796 pregnancies with known fluoxetine exposure during the first trimester, there was NO increased risk of major fetal malformations. There was also no increase in the number of spontaneous abortions in fluoxetine-exposed pregnancies (Goldstein et al, 1997).
4. In a study of 267 women exposed to SSRIs there was no increase in the risk of major malformations or higher rates of miscarriage, stillbirth or prematurity compared with controls (Kulin et al, 1998).
5. ANIMALS - Fetal viability, weight and morphology were not affected in rat and rabbit pups born to dams exposed to fluoxetine during gestation (Byrd & Markham, 1994).

B. PLACENTAL BARRIER

1. In rats, both fluoxetine and norfluoxetine cross the placenta and distribute within the fetus during the periods of organogenesis and postorganogenesis (Pohland et al, 1989).

C. HYPOGLYCEMIA

1. A 38-weeks gestation child was born to a mother who had been taking fluoxetine during most of her pregnancy (Spencer, 1993). The infant was initially hypoglycemic (33 milligrams/deciliter). Four hours after birth he developed acrocyanosis, tachypnea and jitteriness. Over the next 7 hours he developed temperature instability, increasing jitteriness, poor suck, opisthotonic posturing and lateral roving eye movements. His symptoms peaked at 36 hours of age and resolved by 96 hours. Cord blood fluoxetine level was 26 nanograms/milliliter (therapeutic 40 to 250) and norfluoxetine level was 54 nanograms/milliliter (therapeutic 30 to 325).

D. HEMORRHAGE

1. RAT pups born to dams exposed to fluoxetine during pregnancy had an increased incidence of skin hematomas (Stanford & Patton, 1993).

3.20.3 EFFECTS IN PREGNANCY

A. PREGNANCY CATEGORY

§               FLUOXETINE          C

§               Reference:  Prod Info Prozac(R), 1999.

3.20.4 EFFECTS DURING BREAST-FEEDING

A. BREAST MILK

1. Fluoxetine and its metabolite, norfluoxetine, are excreted in breast milk. The effects on the infant are uncertain. Caution should be exercised when fluoxetine is administered to a nursing woman (Prod Info Prozac(R), 1999).
2. Irritability was noted in a 3-month-old boy within two weeks after the mother began 20 mg/day. Untimed plasma/breast milk levels of fluoxetine were 100.5 ng/mL and 28.8 ng/mL, with norfluoxetine levels of 194.5 ng/mL and 41.6 ng/mL respectively (Isenberg, 1990).

3.21 CARCINOGENICITY

3.21.3 HUMAN STUDIES

A. LACK OF EFFECT

1. There is no evidence of carcinogenicity in patients taking fluoxetine (Prod Info Prozac(R), 1999).

3.21.4 ANIMAL STUDIES

A. LACK OF EFFECT

1. Fluoxetine was not carcinogenic in rats and mice at doses up to 10 milligram/kilogram/day for 24 months (Bendele et al, 1992).

3.23 OTHER

3.23.1 SUMMARY

A. Serotonin syndrome may develop when fluoxetine is administered with other serotonergic agents.

3.23.2 CLINICAL EFFECTS

A. DRUG INTERACTION

1. ACETYLSALICYLIC ACID - A 44-year-old male taking fluoxetine developed hives on the 23rd day of treatment. Fluoxetine was discontinued, yet the hives persisted for 11 days. After being hive-free for a 36 hour period, the patient took two tablets of aspirin for an unrelated joint pain. The hives reappeared. The authors postulate that ASA may have altered the protein binding of fluoxetine and or norfluoxetine, resulting in higher free plasma levels of the drug, sufficient enough to trigger a recurrence of the hives (Shad et al, 1997).
2. BENZTROPINE/NEUROLEPTIC - Three patients developed confusion and delirium after starting a combination of fluoxetine, a neuroleptic and benztropine (Roth et al, 1994). The timing of the delirium suggests that the combination of fluoxetine and benztropine was responsible.
3. CLARITHROMYCIN - A 53-year-old man taking fluoxetine and nitrazepam developed confusion and agitation 24 hours after beginning therapy with clarithromycin (Pollack et al, 1995). This was felt to due to clarithromycin inhibition of fluoxetine metabolism.
4. CYPROHEPTADINE - Cyproheptadine is prescribed for orgasmic dysfunction seen in patients taking anti-depressants. Goldbloom & Kennedy (1991) report three cases of adverse psychiatric effects (mainly re-emergence of bulimia nervosa) in patients taking both fluoxetine and cyproheptadine. Effects disappeared within 7 days of stopping the cyproheptadine in all three patients.
5. DIAZEPAM - Concurrent administration of diazepam, with fluoxetine, may result in increased serum diazepam levels due to inhibition of diazepam metabolism by fluoxetine (Dent & Orrock, 1997).
6. MAO INHIBITORS - The combined use of fluoxetine and MAO inhibitors may induce serotonin syndrome, characterized by hyperthermia, muscle rigidity, autonomic instability, and mental status changes (Prod Info Prozac(R), 1999; Feighner et al, 1990).

a. PHENELZINE - Co-ingestion of 80 mg fluoxetine and 150 mg phenelzine resulted in a tonic-clonic seizure, muscle rigidity, restlessness, disorientation, mydriasis, hypertension, tachycardia, and fever. Because this clinical course was unlike that of a MAO inhibitor overdose, and since combined fluoxetine/norfluoxetine serum concentration was unremarkable (236 ng/mL at 13 hours post-ingestion), an adverse fluoxetine - monoamine oxidase inhibitor interaction is likely (Chiang & Smilkstein, 1989).
b. TRANYLCYPROMINE - A 31-year-old woman was placed on fluoxetine 20 mg/day for depression. However, it was discontinued after fourteen days due to persistent restlessness and nausea. Two days later, she was prescribed tranylcypromine 10 mg/day.

(1) Four days after starting tranylcypromine, she increased her dose to 20 mg/day. Two to three hours later she experienced uncontrollable shivering, diplopia, nausea, confusion, and anxiety. She denied headache or chest pain.
(2) Her blood pressure was 110/80 mm Hg, and her temperature was 37.2 degrees C. There were no extrapyramidal symptoms or focal neurological findings.
(3) Tranylcypromine was withdrawn, and symptoms resolved within 24 hours. This reaction is not like that seen with an MAO inhibitor - tyramine interaction, and is strongly suggestive of the "serotonin syndrome".
(4) The authors postulate a long norfluoxetine half-life as a possible cause, and suggest a five-week interval between the discontinuation of fluoxetine and the institution of a MAO inhibitor (Sternbach, 1988).

c. CASE REPORT - A 48-year-old man developed agitation, confusion, muscle rigidity, diaphoresis and hyperthermia one day after beginning fluoxetine 40 mg/day (Ruiz, 1994). He had been taking 10 mg tranylcypromine daily for 3 years but had discontinued this medication 14 days prior to beginning fluoxetine therapy.
d. MOCLOBEMIDE - is a reversible and selective inhibitor of monoamine oxidase A. Combination treatment with fluoxetine and moclobemide in a controlled study did not provide any indication of development of the serotonin syndrome experienced with other, more typical MAO inhibitors (Dingemanse et al, 1998).

7. NEFAZODONE - Serotonin syndrome has been reported in a man who began nefazodone immediately after tapering his fluoxetine dose over 4 days (Smith & Wenegrat, 2000).
8. TERFENADINE - A 39-year-old woman taking acyclovir ointment, beclomethasone inhaler, pseudoephedrine, ibuprofen, fluoxetine and terfenadine had prolonged QTc on ECG (Marchiando & Cook, 1995). This resolved when terfenadine was discontinued and was postulated to be related to fluoxetine inhibition of terfenadine metabolism.
9. TRAMADOL - A 31-year-old woman on chronic fluoxetine therapy developed serotonin syndrome 4 weeks after beginning tramadol 50 milligrams four times daily (Kesavan & Sobala, 1999).
10. TRICYCLICS - Desipramine and nortriptyline plasma levels are increased up to 11 times baseline when coadministered with fluoxetine (von Ammon Cavanaugh, 1990).
11. TRYPTOPHAN - The addition of L-tryptophan 1 to 4 grams/day to 5 patients receiving fluoxetine resulted in agitation, restlessness, poor concentration, nausea, paresthesia, and aggressive behavior.

a. The presumed mechanism is a "serotonin syndrome" resulting from potent serotonin reuptake inhibition by fluoxetine and a serotonin-releasing action of L-tryptophan (Steiner & Fontaine, 1986).

12. ILLICIT DRUGS - A case of fluoxetine-marijuana interaction which was associated with mania has been reported in a 21-year-old woman. She had been taking fluoxetine 20 mg/day for 4 weeks without incident. After smoking two marijuana cigarettes, she developed grandiose delusions and manic excitement which required sedative treatment for 3 days (Stoll et al, 1991).

a. LITHIUM/LSD - Two adolescent females currently taking lithium and fluoxetine in therapeutic doses for depression and suicidal ideation experienced seizures following ingestion of LSD (Jackson & Hornfeldt, 1991).

13. VENLAFAXINE - Anticholinergic effects (difficulty urinating, dry mouth, blurred vision, constipation) have been reported with simultaneous use of fluoxetine and venlafaxine (Benazzi, 1999).
14. WARFARIN - Concomitant use of warfarin, with fluoxetine, may result in increased serum levels of warfarin due to inhibition of warfarin metabolism by fluoxetine (Dent & Orrock, 1997).

B. WITHDRAWAL SYNDROME

1. A discontinuation syndrome of dizziness, light-headedness, insomnia, fatigue, anxiety, agitation, nausea, headache, and sensory disturbances has been described after abrupt discontinuation of therapy (Zajecka et al, 1997).

4.0 LABORATORY/MONITORING

4.1 MONITORING PARAMETERS/LEVELS

4.1.1 SUMMARY

A. Serum levels are not clinically useful in managing overdose.
B. Obtain an ECG in symptomatic patients.
C. Monitor for evidence of serotonin syndrome.

4.3 METHODS

A. CHROMATOGRAPHY

1. Plasma levels of fluoxetine and norfluoxetine may be obtained by gas chromatography with electron-capture detection (Nash et al, 1982; Wong et al, 1990).

5.0 ABSTRACTS

5.1 CASE REPORTS

A. ACUTE EFFECTS

1. Overdose of fluoxetine alone (up to 1200 mg) has produced ST segment depression and spontaneous emesis but uneventful recovery. Other reports of ingestion of lower doses with or without other drugs (including alcohol) have not produced serious symptoms.

a. Ingestion of 3 g in combination with aspirin resulted in tachycardia, dizziness, blurred vision, unsustained clonus, ECG changes, and generalized seizure activity (9 hours post-ingestion).
b. The patient recovered following gastric lavage. One report of fatality from a suicide attempt occurred following an unknown amount of fluoxetine in combination with other drugs (clobazam, amitriptyline, and pentazocine) (Wernicke, 1985).

2. A 12-year-old boy with a history of ingesting approximately 1,880 mg (26 mg/kg) of fluoxetine was given syrup of ipecac 45 to 75 minutes postingestion, and had a generalized seizure 3.5 hours postingestion.

a. Following the seizure he was sleepy and complained of nausea and abdominal pain.
b. The ECG showed depressed ST segments with no other abnormality. The following morning he had blurred vision, headache, and dizziness.
c. Plasma levels obtained at 90 minutes, 15 hours, and 66 hours postingestion were 427.8 ng/mL, 1,142 ng/mL, and 449.5 ng/mL (Riddle et al, 1989).

3. A 19-year-old woman developed flu-like symptoms (dyspnea, malaise, myalgias, arthralgia, chill, headache, nasal congestion, cough), along with urticaria, maculopapular rash, and angioedema 2 days following ingestion of 680 mg of fluoxetine.

a. She had previously been treated with therapeutic doses for one month prior to the overdose. No cardiovascular effects were observed.
b. Serial serum fluoxetine levels were not obtained; the fluoxetine level was 456 ng/mL (therapeutic 80 ng/mL) 48 hours postingestion. The corresponding norfluoxetine level was 349 ng/mL (therapeutic 150 ng/mL).
c. Although this may have represented a hypersensitivity reaction, another possible explanation is a dose-related phenomenon associated with peak metabolite (norfluoxetine) serum concentrations (Kim & Pentel, 1989).

4. DRUG INTERACTIONS - A 27-year-old female on fluoxetine therapy ingested 80 mg fluoxetine and 150 mg phenelzine. Four hours post-ingestion, restlessness, disorientation, and mydriasis were noted, followed by a tonic-clonic seizure.

a. Ten milligrams intravenous diazepam terminated the seizure, but muscle rigidity persisted. Hypertension, tachycardia, and fever were also noted at this time. After endotracheal intubation, diazepam, hydration, and cooling, rigidity resolved within two hours. She was subsequently extubated 32 hours post-admission without further incident.
b. Combined serum fluoxetine and norfluoxetine concentration 13 hours post-ingestion was 236 ng/mL, and serum phenelzine concentration was 14 ng/mL.
c. Because the patient's course was atypical of MAO inhibitor overdose, and because of the unremarkable fluoxetine level, an adverse fluoxetine-monoamine oxidase inhibitor interaction is suggested (Chiang & Smilkstein, 1989).

B. ADVERSE EFFECTS

1. EMERGENT ADVERSE EFFECTS - Include seizures; suicidal ideation, mania, and paranoia; extrapyramidal effects; cardiac dysrhythmias; hyponatremia and SIADH; serum sickness or flu-like symptoms; and serotonin syndrome (Perse et al, 1991).
2. Stoll et al (1991a) reported that 14 (52%) of 27 patients they studied experienced an adverse effect during high-dose fluoxetine treatment.

5.2 CASE SERIES

A. ROUTE OF EXPOSURE

1. ORAL

a. A retrospective chart review of 127 acute fluoxetine overdose cases seen in 4 regional poison centers reinforced the relative benign course of toxicity (Borys et al, 1990).

(1) Coingestion occurred in 65% of the cases, but of the 37 who took fluoxetine alone, the dose ingested ranged from 20 to 1500 mg or 1.1 to 25.8 mg/kg and 18 (49%) of them were asymptomatic. There were no deaths in this series.
(2) Seven (16%) of these 37 were lethargic, 2 had dizziness and/or ataxia, 1 complained of headache while another had insomnia. Nine had tachycardia, 3 were hypertensive, and 1 had a junctional rhythm. Three had nausea, 2 diarrhea, 1 vomiting, 1 abdominal pain, and 2 tremors.
(3) Ten of these 37 patients were confined at the intensive care unit from 12 to 72 hours, and another 25 stayed at the emergency department for 1 1/2 to 9 hours.

b. A one-year retrospective study of fluoxetine ingestion in 44 patients revealed no serious cardiovascular or neurological complications related to the drug. Confusion was noted in two cases, and a decreased level of consciousness was seen in eight.

(1) In these eight patients, however, ethanol and/or benzodiazepines were also ingested. No cardiovascular changes were observed in any of these patients. The authors concluded that fluoxetine overdose represents a minimal cardiovascular or neurological hazard (Spiller et al, 1990).

c. In a prospective study of patients with fluoxetine and tricyclic antidepressant overdose, those with tricyclic antidepressant overdose manifested greater toxicity (Phillips et al, 1994). Of patients with tricyclic antidepressant overdose 48/124 developed agitation, 61/124 became tachycardic, 39/129 developed QRS prolongation, 42/124 became comatose and 42/124 required intubation. None of the 16 fluoxetine patients developed these complications.

6.0 TREATMENT

6.1 LIFE SUPPORT

A. Support respiratory and cardiovascular function.

6.3 PATIENT DISPOSITION

6.3.1 DISPOSITION/ORAL EXPOSURE

6.3.1.1 ADMISSION CRITERIA/ORAL

A. Admit patients with significant clinical effects including seizures or persistent lethargy or dysrhythmias.

6.3.1.5 OBSERVATION CRITERIA/ORAL

A. Observe patients for 6 hours after ingestion. Patients who are asymptomatic during this period may be discharged after appropriate psychiatric evaluation. Admit those with significant clinical effects including seizures or persistent lethargy or dysrhythmias.

6.4 MONITORING

A. Serum levels are not clinically useful in managing overdose.
B. Obtain an ECG in symptomatic patients.
C. Monitor for evidence of serotonin syndrome.

6.5 ORAL EXPOSURE

6.5.1 PREVENTION OF ABSORPTION/PREHOSPITAL

A. EMESIS/NOT RECOMMENDED -

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

B. ACTIVATED CHARCOAL -

1. PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a. Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion.

(1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should be administered by medical or paramedical personnel capable of airway management to prevent aspiration in the event of spontaneous emesis.

2. CHARCOAL DOSE

a. Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years; and 1 gram/kilogram in infants up to 1 year old (USP DI, 2000; Chyka & Seger, 1997).

(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 (Barceloux et al, 1997).

b. ADVERSE EFFECTS/CONTRAINDICATIONS

(1) Complications: emesis, aspiration (Chyka & Seger, 1997). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
(2) Contraindications: unprotected airway, gastrointestinal tract not anatomically intact, therapy may increase the risk or severity of aspiration; ingestion of most hydrocarbons (Chyka & Seger, 1997).

6.5.2 PREVENTION OF ABSORPTION

A. ACTIVATED CHARCOAL

1. CHARCOAL ADMINISTRATION

a. Consider administration of activated charcoal after a potentially toxic ingestion (Chyka & Seger, 1997). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2. CHARCOAL DOSE

a. Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years; and 1 gram/kilogram in infants up to 1 year old (USP DI, 2000; Chyka & Seger, 1997).

(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 (Barceloux et al, 1997).

b. ADVERSE EFFECTS/CONTRAINDICATIONS

(1) Complications: emesis, aspiration (Chyka & Seger, 1997). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
(2) Contraindications: unprotected airway, gastrointestinal tract not anatomically intact, therapy may increase the risk or severity of aspiration; ingestion of most hydrocarbons (Chyka & Seger, 1997).

B. GASTRIC LAVAGE

1. Ingestions are rarely life threatening; gastric lavage is generally NOT warranted.
2. INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a. Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

3. PRECAUTIONS:

a. SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b. AIRWAY PROTECTION: Alert patients - place in Trendelenburg and left lateral decubitus position, with suction available. Obtunded or unconscious patients - cuffed endotracheal intubation.

4. LAVAGE FLUID:

a. Use small aliquots of liquid. Lavage with 150 to 200 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in children over 5 or adults) and 10 milliliters/kilogram body weight of normal saline in young children. Continue until lavage return is clear.
b. The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c. CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

5. COMPLICATIONS:

a. Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications.
b. Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

6. CONTRAINDICATIONS:

a. Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

6.5.3 TREATMENT

A. SEIZURES

1. SUMMARY

a. Attempt initial control with a benzodiazepine (diazepam or lorazepam). If seizures persist or recur administer phenobarbital. Benzodiazepines and barbiturates are generally preferred over phenytoin for the control of overdose or withdrawal related seizures.
b. Monitor for respiratory depression, hypotension, dysrhythmias, and the need for endotracheal intubation.
c. Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or treat with intravenous dextrose ADULT: 50 milliliters IV, CHILD: 2 milliliters/kilogram 25% dextrose).

2. DIAZEPAM

a. MAXIMUM RATE: Administer diazepam intravenously over 2 to 3 minutes (maximum rate = 5 milligrams/minute).
b. ADULT DIAZEPAM DOSE: 5 to 10 milligrams 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.
c. PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 milligram per kilogram 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.
d. RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (generally use twice the usual initial dose because of decreased absorption), or lorazepam may be given intramuscularly.
e. MIDAZOLAM: has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. PEDIATRIC MIDAZOLAM DOSE: INTRAMUSCULAR: 0.2 milligram/kilogram (maximum 7 milligrams) (Chamberlain et al, 1997); INTRANASAL: 0.2 milligram/kilogram (Lahat et al, 2000). Buccal midazolam, 10 milligrams, 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).

3. LORAZEPAM

a. MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 milligrams/minute (Prod Info Ativan(R), 1999).