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Glutethimide (Systemic)


VA CLASSIFICATION
Primary: CN309

Note: Controlled substance classification—

Note: Controlled substance classification


U.S.—Schedule II
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Sedative-hypnotic—

Indications

Unaccepted
Glutethimide has been used for the short-term treatment of insomnia {04}; however, it has been replaced by safer and more effective sedative-hypnotic agents {05}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    217.27 {01}

Mechanism of action/Effect:

Unknown.


Other actions/effects:

Glutethimide exhibits pronounced anticholinergic activity, which is manifested by decreased intestinal motility, inhibition of salivary secretions, and mydriasis {04}.

Absorption:

Absorbed erratically from the gastrointestinal tract {04}.

Protein binding:

Moderate (about 50%) {04}.

Biotransformation:

Hepatic. Glutethimide is almost completely metabolized. {04}

Half-life:

About 10 to 12 hours {04}.

Onset of action:

Within 30 minutes.

Time to peak plasma concentration

1 to 6 hours following a single oral dose of 500 mg {04}.

Duration of action:

4 to 8 hours.

Elimination:


Renal—
        Less than 2% of a dose is excreted unchanged {04}.



Fecal—
        Up to 2% of a dose may be excreted in the feces.



Precautions to Consider

Carcinogenicity

No carcinogenicity studies in animals have been done {04}.

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in either humans or animals {04}.

Chronic usage during pregnancy may lead to withdrawal symptoms in the neonate {04}.

FDA Pregnancy Category C {04}.

Breast-feeding

Glutethimide is distributed into breast milk {02}; use by a breast-feeding woman may cause sedation in the infant.

Pediatrics

Appropriate studies on the relationship of age to the effects of glutethimide have not been performed in the pediatric population. Safety and efficacy have not been established.


Geriatrics


Elderly patients may be more sensitive to the effects of glutethimide. Also, elderly patients are more likely to have age-related prostatic hypertrophy and renal function impairment, which may require adjustment of dosage in patients receiving glutethimide.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Addictive medications, other, especially central nervous system (CNS) depressants with habituating potential    (prolonged concurrent use may increase the risk of habituation; caution is recommended)


» Alcohol or
» CNS depression–producing medications, other (see Appendix II )    (concurrent use may increase the CNS depressant effects of either these medications or glutethimide; caution is recommended and dosage of one or both agents should be reduced {04})


» Anticoagulants, coumarin- or indandione-derivative    (effects may be decreased when these medications are used concurrently with glutethimide because of accelerated metabolism of anticoagulant secondary to stimulation of hepatic microsomal enzymes; dosage adjustments of anticoagulants may be necessary during and after glutethimide therapy {04})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Phentolamine    (glutethimide may cause false-positive phentolamine test; it is recommended that all medications be withdrawn at least 24 hours, preferably 48 to 72 hours, prior to a phentolamine test)


Urinary steroid determinations    (glutethimide may interfere with the assay for urine 17-ketosteroids or 17-ketogenic steroids {03}, and with the absorbance of urinary 17-hydroxycorticosteroids using the modified Glenn-Nelson technique)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Conditions that might be aggravated by anticholinergic activity, such as:
Bladder neck obstruction
Cardiac arrhythmias
Glaucoma, narrow-angle, predisposition to
Peptic ulcer, stenosing
Prostatic hypertrophy
Pyloroduodenal obstruction
Drug abuse or dependence, history of
Pain, uncontrolled
» Porphyria{04}
Renal function impairment, severe
Sensitivity to glutethimide


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Skin rash{04}

Incidence rare
    
Blood dyscrasias (sore throat and fever; unusual bleeding or bruising; unusual tiredness or weakness)
    
paradoxical reaction (unusual excitement)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Drowsiness, daytime{04}

Incidence less frequent
    
Blurred vision{04}
    
clumsiness or unsteadiness{04}
    
confusion{04}
    
dizziness{04}
    
``hangover'' effect{04}
    
headache{04}
    
nausea{04}
    
vomiting{04}



Those indicating possible withdrawal and the need for medical attention if they occur after medication is discontinued
    
Convulsions{04}
    
fast heartbeat{04}
    
hallucinations{04}
    
increased dreaming{04}
    
muscle cramps or spasms{04}
    
nausea or vomiting{04}
    
nightmares{04}
    
stomach cramps or pain{04}
    
trembling{04}
    
trouble in sleeping{04}




Overdose
For specific information on the agents used in the management of glutethimide overdose, see:
   • Castor oil in Laxatives (Local) monograph; and/or
   • Charcoal, Activated (Oral-Local) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Bluish coloration of skin
    
convulsions
    
fever
    
low body temperature
    
muscle spasms or twitching
    
shortness of breath or slow or troubled breathing
    
slow heartbeat
    
slowness or loss of reflexes
    
weakness, severe
{04}
Chronic
    
Confusion, continuing
    
memory problems
    
slurred speech
    
staggering
    
trembling
    
trouble in concentrating
{04}

Treatment of overdose
Recommended treatment for glutethimide overdose consists of the following: {04}


To decrease absorption:
If the patient is fully conscious, vomiting should be induced.

If emesis or gastric lavage cannot be effected in the fully conscious patient, absorption of glutethimide may be delayed by giving 1 pint of water, milk, or fruit juice; flour or cornstarch suspension; or activated charcoal in water. Then emesis should be induced or gastric lavage performed as soon as possible. Intestinal lavage (100 to 250 mL of 25 to 40% sorbitol or mannitol) should be used to remove unabsorbed glutethimide from the intestines.

In the unconscious patient, gastric lavage should be done, regardless of time elapsed since ingestion of glutethimide, using caution to prevent aspiration of gastric contents or respiratory arrest during manipulation (including prior insertion of a cuffed endotracheal tube or employment of tracheostomy). A 1:1 mixture of castor oil and water should be used as a lavage since larger amounts of glutethimide are removed from the stomach than with aqueous lavage. Fifty mL of castor oil should be left in the stomach as a cathartic.



To enhance elimination:
In severe glutethimide overdosage, in addition to supportive measures and symptomatic treatment, hemodialysis or hemoperfusion should be considered in Grade III or Grade IV coma, when renal shutdown or impaired renal function is manifest, and in life-threatening conditions complicated by pulmonary edema, heart failure, circulatory collapse, significant liver disease, major metabolic disturbance, or uremia.

Although aqueous hemodialysis is less effective for glutethimide than for readily water-soluble compounds, glutethimide blood concentrations may be decreased more rapidly with hemodialysis and the duration of coma may be shortened; however, the efficacy of this procedure is controversial.

Peritoneal dialysis removes some glutethimide; however, it is minimally effective.

Charcoal hemoperfusion has been reported to be more effective than hemodialysis. Also, resin hemoperfusion has been reported to be more effective than hemodialysis, especially in patients with life-threatening coma and lethal blood concentrations of intoxicant drugs.

Drug extraction techniques should be continued for at least 2 hours after the patient regains consciousness since glutethimide is highly lipid soluble and, therefore, rapidly accumulates in lipoid tissue. As glutethimide is removed from the bloodstream by any technique, it is gradually released from fat storage back into the bloodstream. After substantial amounts of glutethimide have been extracted, this blood-concentration rebound may cause coma to persist or recur.



Specific treatment:
If coma is prolonged, appropriate antibiotic therapy is indicated if pulmonary or other infection occurs.



Monitoring:
Continuous electrocardiogram monitoring should be done to detect arrhythmias.

Urinary output should be monitored and maintained, if coma is prolonged.



Supportive care:
Cardiopulmonary supportive measures should be used and include: maintenance of a patent airway with assisted ventilation, if necessary; monitoring of vital signs and level of consciousness; continuous electrocardiogram to detect arrhythmias; and maintenance of blood pressure with plasma volume expanders and, if necessary, pressor agents.

Adequate respiratory gas exchange should be maintained and may require tracheostomy and mechanical assistance.

If coma is prolonged, urinary output should be monitored and maintained while preventing overhydration, which might contribute to pulmonary or cerebral edema.

Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Glutethimide (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to glutethimide

Pregnancy—Chronic usage of glutethimide during pregnancy may cause withdrawal symptoms in the neonate





Breast-feeding—Glutethimide distributed into breast milk; use by a breast-feeding woman may cause sedation in the infant





Use in the elderly—Elderly patients may be more sensitive to effects of glutethimide
Other medications, especially alcohol or other CNS depression–producing medications or coumarin- or indandione-derivative anticoagulants
Other medical problems, especially porphyria

Proper use of this medication
» Importance of not using more medication than the amount prescribed because of habit-forming potential

» Proper dosing

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during prolonged therapy

Checking with physician before discontinuing medication after prolonged use; gradual dosage reduction may be necessary to avoid possibility of withdrawal symptoms

» Avoiding use of alcohol or other CNS depressants

Caution if any laboratory tests required; possible interference with results of metyrapone test

» Suspected overdose: Getting emergency help at once

» Caution if dizziness or daytime drowsiness occurs


Side/adverse effects
Signs of potential side effects, especially blood dyscrasias, paradoxical reaction, and skin rash

Side/adverse effects more likely to occur in elderly patients, who may be more sensitive to effects of glutethimide


General Dosing Information
Prolonged use of larger-than-usual therapeutic doses may result in psychic or physical dependence {04}.

Following prolonged administration, glutethimide should be withdrawn gradually to avoid the possibility of precipitating withdrawal symptoms {04}.

For treatment of dependence
Glutethimide dependence may be treated by gradual, stepwise reduction of dosage over a period of days or weeks. If withdrawal symptoms occur, they may be controlled by readministration of glutethimide, or substitution of pentobarbital, and subsequent gradual withdrawal. {04}


Oral Dosage Forms

GLUTETHIMIDE CAPSULES USP

Usual adult dose
Sedative-hypnotic
Oral, 500 mg at bedtime; dose may be repeated if necessary, but not less than four hours before patient arises {04}.


Note: Geriatric or debilitated patients may be more sensitive to the effects of the usual adult dose. The initial daily dose should not exceed 500 mg at bedtime. {04}


Usual pediatric dose
Sedative-hypnotic
Safety and efficacy have not been established {04}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.

Note: Controlled substance in the U.S.



GLUTETHIMIDE TABLETS USP

Usual adult dose
Sedative-hypnotic
Oral, 250 to 500 mg at bedtime; dose may be repeated if necessary, but not less than four hours before patient arises {04}.


Note: Debilitated patients may be more sensitive to the effects of the usual adult dose. The initial daily dose should not exceed 500 mg at bedtime. {04}


Usual pediatric dose
Sedative-hypnotic
Safety and efficacy have not been established {04}.


Usual geriatric dose
Sedative-hypnotic
Oral, initially 250 mg, not to exceed 500 mg, at bedtime, the dosage being adjusted as needed and tolerated {04}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.

Note: Controlled substance in the U.S.




Revised: 10/03/1997



References
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 1997. p. 344.
  1. Pons G, Rey E, Matheson I. Excretion of psychoactive drugs into breast milk. Clin Pharmacokinet 1994; 27(4): 270-89.
  1. Davies DM, editor. Textbook of adverse drug reactions. 3rd ed. New York: Oxford University Press; 1985. p. 340-1.
  1. Doriden package insert (Rorer—US), Rec 11/88.
  1. Oral hypnotic drugs. Med Lett Drugs Ther 1989 Mar 10; 31(787): 23-4.

Further information

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