GLUTETHIMIDE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for GLUTETHIMIDE (GLUTETHIMIDE).

How it works

Glutethimide is a sedative-hypnotic that acts on the GABA-A receptor complex, enhancing the inhibitory effects of GABA. It has been used as a non-barbiturate hypnotic and is known to induce cytochrome P450 enzymes.

What the body does with it

Metabolism	Primarily hepatic via CYP3A4 and other CYP450 enzymes; undergoes enterohepatic circulation.
Excretion	Renal excretion of unchanged drug (less than 2%) and metabolites (major route). About 50% of a dose is excreted in urine as conjugated metabolites; less than 2% as unchanged drug. Fecal excretion is negligible. Enterohepatic recirculation occurs.
Half-life	Terminal elimination half-life is approximately 10–12 hours in adults with normal renal function. In overdose, half-life may prolong to 40 hours or more due to saturation of metabolism. Accumulation occurs with repeated dosing.
Protein binding	Approximately 50% bound to plasma proteins, primarily albumin.
Volume of Distribution	1.3–1.6 L/kg. Large Vd indicates extensive tissue distribution, including brain.
Bioavailability	Oral bioavailability is approximately 100% (well absorbed).
Onset of Action	Oral: 30 minutes (hypnotic effect). Peak effects at 1–2 hours.
Duration of Action	Oral: 4–6 hours for hypnotic effect. Duration may be prolonged in overdose or hepatic impairment. Tolerance develops with repeated use.

Classification & Brands

Dosing & administration

Oral, 250-500 mg at bedtime for insomnia; maximum 1 g/day.

Dosage form	TABLET
Renal impairment	GFR <50 mL/min: dose reduction of 50% recommended; GFR <10 mL/min: avoid use due to accumulation of active metabolites.
Liver impairment	Child-Pugh Class B or C: dose reduction by 50% to 75% recommended; contraindicated in severe hepatic impairment.
Pediatric use	Not recommended for children under 12 years; safety and efficacy not established.
Geriatric use	Initial dose 250 mg at bedtime; increase with caution due to increased sensitivity, risk of falls, and prolonged half-life.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for GLUTETHIMIDE (GLUTETHIMIDE).

Breastfeeding	Glutethimide excretion into breast milk is unknown; M/P ratio not reported. Due to risk of neonatal sedation and withdrawal, breastfeeding is not recommended during maternal use.
Teratogenic Risk	First trimester: Limited data; animal studies show skeletal and visceral malformations at high doses. Second/third trimester: Chronic use may cause neonatal withdrawal syndrome; no specific structural defects consistently reported. Overall, risk cannot be excluded; avoid if possible.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

None officially listed; however, due to high abuse potential and severe withdrawal symptoms, use should be limited to short-term therapy under strict supervision.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to glutethimide or any component of the formulation","Porphyria (may exacerbate symptoms)","Severe respiratory insufficiency","Concurrent use with other CNS depressants, especially alcohol (risk of severe sedation and respiratory depression)"]

Clinical Precautions

Precautions

["High potential for abuse and dependence; prolonged use may lead to tolerance and addiction.","Abrupt discontinuation may precipitate severe withdrawal symptoms, including seizures and delirium.","May impair cognitive and motor function; avoid driving or operating machinery.","Use with caution in patients with hepatic or renal impairment, as accumulation may occur.","May cause paradoxic excitation in elderly or debilitated patients."]

Clinical Tips & Counseling

Drug interactions

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GLUTETHIMIDE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for GLUTETHIMIDE (GLUTETHIMIDE).

How it works

What the body does with it

Metabolism	Primarily hepatic via CYP3A4 and other CYP450 enzymes; undergoes enterohepatic circulation.
Excretion	Renal excretion of unchanged drug (less than 2%) and metabolites (major route). About 50% of a dose is excreted in urine as conjugated metabolites; less than 2% as unchanged drug. Fecal excretion is negligible. Enterohepatic recirculation occurs.
Half-life	Terminal elimination half-life is approximately 10–12 hours in adults with normal renal function. In overdose, half-life may prolong to 40 hours or more due to saturation of metabolism. Accumulation occurs with repeated dosing.
Protein binding	Approximately 50% bound to plasma proteins, primarily albumin.
Volume of Distribution	1.3–1.6 L/kg. Large Vd indicates extensive tissue distribution, including brain.
Bioavailability	Oral bioavailability is approximately 100% (well absorbed).
Onset of Action	Oral: 30 minutes (hypnotic effect). Peak effects at 1–2 hours.
Duration of Action	Oral: 4–6 hours for hypnotic effect. Duration may be prolonged in overdose or hepatic impairment. Tolerance develops with repeated use.

Classification & Brands

Dosing & administration

Oral, 250-500 mg at bedtime for insomnia; maximum 1 g/day.

Dosage form	TABLET
Renal impairment	GFR <50 mL/min: dose reduction of 50% recommended; GFR <10 mL/min: avoid use due to accumulation of active metabolites.
Liver impairment	Child-Pugh Class B or C: dose reduction by 50% to 75% recommended; contraindicated in severe hepatic impairment.
Pediatric use	Not recommended for children under 12 years; safety and efficacy not established.
Geriatric use	Initial dose 250 mg at bedtime; increase with caution due to increased sensitivity, risk of falls, and prolonged half-life.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for GLUTETHIMIDE (GLUTETHIMIDE).

Breastfeeding	Glutethimide excretion into breast milk is unknown; M/P ratio not reported. Due to risk of neonatal sedation and withdrawal, breastfeeding is not recommended during maternal use.
Teratogenic Risk	First trimester: Limited data; animal studies show skeletal and visceral malformations at high doses. Second/third trimester: Chronic use may cause neonatal withdrawal syndrome; no specific structural defects consistently reported. Overall, risk cannot be excluded; avoid if possible.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

None officially listed; however, due to high abuse potential and severe withdrawal symptoms, use should be limited to short-term therapy under strict supervision.