DRUGDEX® Evaluations
GLYCERIN
0.0 Overview
1) Class
a) This drug is a member of the following class(es):
Antiglaucoma
Cardiovascular Agent
Diuretic, Osmotic
Gastrointestinal Agent
Laxative, Hyperosmotic
Laxative, Stool Softener
Lubricant, Ocular
Protectant, Dental
Protectant, Dermatological
2) Contraindications
a) Hypersensitivity to any component in the preparation
b) Well-established anuria
c) Severe dehydration
d) Frank or impending acute pulmonary edema
e) Severe cardiac decompensation
1.0 Dosing Information
Drug Properties
Storage and Stability
Adult Dosage
Pediatric Dosage
1.1 Drug Properties
A) Information on specific products and dosage forms can be obtained by referring to the Tradename List (Product Index)
B) Synonyms
Glycerin
Glycerine
Glycerol
C) Physicochemical Properties
1) Molecular Weight
a) 92.09
1.2 Storage and Stability
A) Extemporaneous Formulation - Intravenous route
1) An intravenous (IV) injection of glycerin is not commercially available. An IV preparation can be prepared by adding 100 grams (g)
glycerin and 45.5 g anhydrous dextrose to 1 liter water (yields 10% glycerin and 5% dextrose solution). Sodium chloride is then added
to make a solution of 10% glycerin, 5% dextrose and 0.45 to 0.9% sodium chloride (Frank et al, 1981).
2) MD Anderson Hospital utilized glycerin USP and dextrose 5% water to prepare a 10% v/v solution containing 0.125 grams/milliliter
(g/mL). A volume of 100 mL of glycerine was added to 900 mL of sterile dextrose solution. The solution was then autoclaved according
to liquid sterilization guidelines at 250 F for 29 minutes in the Authovac model B autoclave. An expiration date of 30 days was put on the
bottle, at which time it was autoclaved again. The solution was filtered by a 0.45 micron filter to remove any extraneous particulate
matter that might have been present in the glycerin (Bedikian et al, 1980).
3) Small volumes of anhydrous glycerin for trigeminal cistern injection may be sterilized using dry heat autoclave or slow careful
filtration through a 0.45 micron Millipore(R) filter (Pers Comm, 1983a; Pers Comm, 1983b).
4) Glycerin may be sterilized by maintaining a temperature of 150 degrees for 1 hour (Reynolds, 1989).
1.3 Adult Dosage
Normal Dosage
Dosage in Hepatic Insufficiency
1.3.1 Normal Dosage
Ophthalmic route
Rectal route
Cerebral edema
Neoplasm of central nervous system
Occlusive stroke
Primary angle-closure glaucoma
Raised intracranial pressure
Raised intraocular pressure
1.3.1.A Ophthalmic route
1) Hypertonic agents, such as glycerin, are effective for short- or long-term treatment of epithelial edema by reducing corneal edema
and improving visual acuity. The long-term use of ocular glycerin is not well tolerated and instillation is painful. Glycerin may also be
used prior to ophthalmoscopy or gonioscopy when the cornea is too edematous to permit a diagnosis. To facilitate diagnosis, 1 to 3
drops of glycerin should be instilled ocularly prior to examination. A local anesthetic should be instilled prior to the instillation of glycerin
(AMA Department of Drugs, 1990b).
1.3.1.B Rectal route
1) The recommended adult dose for glycerin suppositories to promote fecal evacuation is 3 grams (AMA Department of Drugs, 1990b);
suppositories should be retained for 15 minutes (Olin, 1991).
2) If liquid glycerin is administered rectally, gently insert stem with steady pressure with the tip pointing toward the navel and squeeze
the unit until almost all the liquid has been delivered; a small amount of liquid will remain. The unit should then be withdrawn (Olin,
1991).
1.3.1.C Cerebral edema
1) Initially, glycerin 25 to 50 grams orally or 0.5 to 1 gram/kilogram (g/kg) intravenously (over 30 minutes) should be administered
(Troup et al, 1971; Frank et al, 1981b). Subsequent doses of 0.25 to 0.5 g/kg orally every 4 to 6 hours may be administered (Frank et al,
1981b).
1.3.1.D Neoplasm of central nervous system
1) Preoperative doses of glycerin 1.5 to 2 grams/kilogram (g/kg) via a nasogastric tube given 30 minutes prior to dura incision produces
a significant reduction in brain volume, lasting several hours. Intravenous doses of 1 g/kg (over 30 minutes) are equally effective (Frank
et al, 1981b).
2) For prolonged control of elevated intracranial pressure, glycerin doses of 1 gram/kilogram every 6 hours orally or intravenously for
the first several days are recommended (Frank et al, 1981b).
1.3.1.E Occlusive stroke
1) Recommended doses are glycerin 1.5 grams/kilogram/day orally (6 divided doses) or 1.2 grams/kilogram/day intravenously (in 5%
dextrose and saline) (Katzman et al, 1977).
1.3.1.F Primary angle-closure glaucoma
See Drug Consult reference: DRUG THERAPY OF GLAUCOMA
1.3.1.G Raised intracranial pressure
1) The glycerin dose should be titrated to achieve the desired intracranial pressure reduction; 0.75 to 1.75 grams/kilogram were
administered every 2 hours to maintain an intracranial pressure of less than or equal to 15 mmHg. The dose was given by continuous
intravenous infusion, with half the dose given over the first 30 minutes and the remainder over the next 1.5 hours (Nahata et al, 1981a).
1.3.1.H Raised intraocular pressure
1) The usual recommended oral dose of glycerin 50% to reduce intraocular pressure is 2 to 3 milliliters/kilogram (approximately 120 to
180 mL per patient) administered 1 to 1.5 hours prior to surgery (Prod Info Osmoglyn(R), 1994a).
2) The recommended dose is 1 to 1.5 grams/kilogram orally as a 50% to 75% solution (Gilman et al, 1990)(AMA Department of Drugs,
1990b; Frank et al, 1981b). Glycerin may be administered more than once daily, if required. Palatability may be improved by adding
lemon juice or instant coffee to unflavored preparation or pouring the solution over crushed ice and drinking the solution through a
straw. Patients should not drink additional water (AMA Department of Drugs, 1990b). The total daily dose of glycerin should not exceed
120 grams (Gilman et al, 1990).
1.3.1.I INTRAVENOUS RATE OF ADMINISTRATION
1) Intravascular hemolysis is associated with the high infusion rates of glycerin (greater than 500 mL of 10% solutions over 4 hours)
that are required to minimize cerebral edema related to strokes. Clinically significant hemolysis may be avoided by observing an
infusion rate below 125 mL/hour (Kumana et al, 1991).
1.3.1.J MAXIMUM DOSE
1) The maximum daily dose of glycerin is 120 grams (Gilman et al, 1990).
1.3.1.K TRIGEMINAL CISTERN INJECTION
1) Glycerin 0.2 to 0.4 milliliter administered via a trigeminal cistern injection was beneficial in relieving paroxysmal facial pain in
numerous conditions unresponsive to previous therapy. The injections were beneficial in the treatment of pain secondary to trigeminal
neuralgia, cluster headache, and atypical facial pain (Waltz et al, 1985).
1.3.3 Dosage in Hepatic Insufficiency
A) The clearance of glycerin as determined in available human studies is usually lower than normal liver blood flow, indicating the drug
may not undergo a significant first-pass effect (Frank et al, 1981b).
1.4 Pediatric Dosage
Normal Dosage
Dosage in Hepatic Insufficiency
1.4.1 Normal Dosage
Oral route
Rectal route
Raised intracranial pressure
1.4.1.A Oral route
1) The dose of glycerin in children to reduce intraocular pressure and vitreous volume prior to surgery is 1 to 1.5 grams/kilogram given
as a 50% or 75% solution (AMA Department of Drugs, 1990b).
2) At Columbus Children's Hospital, 50% oral solutions are prepared by mixing with orange juice or lemon juice to decrease nausea
and improve palatability (Frank et al, 1981b).
1.4.1.B Rectal route
1) The recommended dose for children younger than 6 years of age of glycerin suppositories to promote fecal evacuation is 1 to 1.5
grams (AMA Department of Drugs, 1990b); suppositories should be retained for 15 minutes (Olin, 1991).
1.4.1.C Raised intracranial pressure
1) Relatively high intravenous doses of glycerin 0.2 to 1 gram/kilogram/hour which produce plasma concentrations of 1 to 3
milligrams/milliliter (10 to 30 milliosmoles/milliliter) are required to control intracranial hypertension in children with cerebral edema.
Glycerin serum concentrations may be estimated from serum osmolality (Pitlick et al, 1982).
1.4.3 Dosage in Hepatic Insufficiency
A) Glycerin clearance was not related to hepatic function in a series of patients with Reye's syndrome. Total body clearance of glycerin
ranged from 1.99 to 5.1 milliliters/kilogram/minute (Nahata et al, 1981a). This is consistent with the mean clearance of glycerin, 2.17
milliliters/kilogram/minute, in patients with normal liver function. It is speculated that since the drug is metabolized largely by the liver
(80%) and liver function is disturbed in patients with Reye's syndrome, the clearance of glycerin may be higher in other diseases with
normal liver function (Frank et al, 1981b).
B) The clearance of glycerin as determined in available human studies is usually lower than normal liver blood flow, indicating the drug
may not undergo a significant first-pass effect (Frank et al, 1981b).
2.0 Pharmacokinetics
Onset and Duration
ADME
2.1 Onset and Duration
A) Onset
1) Initial Response
a) Intracranial pressure reduction, intravenous: 10 to 30 minutes (Frank et al, 1981a).
1) GLYCERIN has a slower onset of action than UREA or MANNITOL administered intravenously (AMA Department of Drugs, 1990).
b) Intracranial pressure reduction, oral: 10 to 30 minutes (Frank et al, 1981a).
c) Intraocular pressure reduction, intravenous: 10 to 30 minutes (Frank et al, 1981a).
1) GLYCERIN has a slower onset of action than UREA or MANNITOL administered intravenously (AMA Department of Drugs, 1990).
d) Intraocular pressure reduction, oral: 10 to 30 minutes (Frank et al, 1981.
e) Fecal evacuation, rectal: 15 to 30 minutes (AMA Department of Drugs, 1990).
2) Peak Response
a) Intraocular pressure reduction, oral: 1 hour (Gilman et al, 1990)(AMA Department of Drugs, 1990; Friedman et al, 1980)
B) Duration
1) Single Dose
a) Intracranial pressure reduction, oral: 2 to 4 hours (Frank et al, 1981a).
1) Intracranial pressure reduction usually persists for 2 to 4 hours following a 1-g/kg oral or intravenous dose (Frank et al, 1981a).
b) Intraocular pressure reduction, oral: 5 hours (AMA Department of Drugs, 1990); (Gilman et al, 1990).
1) The reduction of intraocular pressure and vitreous volume diminishes 5 hours following oral administration of GLYCERIN (AMA
Department of Drugs, 1990); (Gilman et al, 1990).
2.3 ADME
Absorption
Distribution
Metabolism
Excretion
Elimination Half-life
2.3.1 Absorption
A) Bioavailability
1) Oral, syrup: well absorbed (Reynolds, 1991); (Gilman et al, 1990)
a) Following oral administration, GLYCERIN is well absorbed and rapidly metabolized (Reynolds, 1991); (Gilman et al, 1990)
2.3.2 Distribution
A) Distribution Sites
1) OTHER DISTRIBUTION SITES
a) EXTRACELLULAR SPACE (Frank et al, 1981a).
1) GLYCERIN distribution is reported to correspond to the extracellular space (50% to 65% of total body weight) (Frank et al, 1981a).
2.3.3 Metabolism
A) Metabolism Sites and Kinetics
1) LIVER, 80% (Reynolds, 1991; Frank et al, 1981a)
a) Metabolism is dependent on GLYCERIN kinase. Following phosphorylation, approximately 70% to 90% is oxidized by glycerin-3phosphate dehydrogenase to dihydroxyacetone phosphate. This enters the Embden-Meyerhof pathway at the level of glyceraldehyde-3phosphate. The remainder combines with free fatty acids to form triglycerides (Frank et al, 1981a).
2) KIDNEY, 10% to 20% (Reynolds, 1991; Frank et al, 1981a)
a) Metabolism is dependent on GLYCERIN kinase. Following phosphorylation, approximately 70% to 90% is oxidized by glycerin-3phosphate dehydrogenase to dihydroxyacetone phosphate. This enters the Embden-Meyerhof pathway at the level of glyceraldehyde-3phosphate. The remainder combines with free fatty acids to form triglycerides (Frank et al, 1981a).
2.3.4 Excretion
A) Kidney
1) GLYCERIN is filtered and in concentrations up to 0.15 mg/mL, undergoes complete renal tubular reabsorption. In higher
concentrations, however, GLYCERIN begins to appear in the urine and induces an osmotic diuresis (Swanson & Thompson, 1969;
Frank et al, 1981a).
2.3.5 Elimination Half-life
A) Parent Compound
1) Elimination half-life: 30 to 45 minutes (Frank et al, 1981a).
3.0 Cautions
Contraindications
Precautions
Adverse Reactions
Teratogenicity/Effects in Pregnancy/Breastfeeding
Drug Interactions
3.1 Contraindications
A) Hypersensitivity to any component in the preparation
B) Well-established anuria
C) Severe dehydration
D) Frank or impending acute pulmonary edema
E) Severe cardiac decompensation
3.2 Precautions
A) Administer with caution to patients with cardiac, renal, or hepatic disease
B) Diabetes
C) Hemolytic anemia
D) Altered hydration may lead to pulmonary edema and/or congestive heart failure
3.3 Adverse Reactions
Cardiovascular Effects
Endocrine/Metabolic Effects
Gastrointestinal Effects
Hematologic Effects
Hepatic Effects
Neurologic Effects
Ophthalmic Effects
Otic Effects
Renal Effects
Other
3.3.1 Cardiovascular Effects
3.3.1.A Cardiovascular finding
1) HYPERTENSION developed in 1 patient following the use of oral glycerin (50% solution) (D'Alena & Ferguson, 1966).
2) Cardiac ARRHYTHMIAS have been reported with the administration of glycerin (Reynolds, 1991).
3.3.3 Endocrine/Metabolic Effects
3.3.3.A Hyperglycemia
1) Glycerin can produce hyperglycemia (Gilman et al, 1990)(Frank et al, 1981; Freund, 1968) and HYPEROSMOLARITY, which is
usually clinically significant only in patients with diabetes or a prediabetic condition (Freund, 1968; Frank et al, 1981).
HYPEROSMOLAR NONKETOTIC HYPERGLYCEMIA has rarely developed following oral administration (Reynolds, 1991; AMA
Department of Drugs, 1990a; Sears, 1976; Oakley & Ellis, 1976), and deaths have occurred. The most susceptible patients are
maturity-onset, elderly diabetics with acute or chronic diseases that predispose them to fluid depletion; oral glycerin should be avoided
in these patients. If glycerin is used in patients who are predisposed, measures should be taken to prevent hyperosmolar nonketotic
hyperglycemia and dehydration (Reynolds, 1991).
2) NONKETOTIC HYPEROSMOLAR HYPERGLYCEMIA was reported in 2 patients following use of glycerin via nasogastric (NG) tube
for cerebral edema. A 63-year-old maturity-onset diabetic female received 60 grams glycerin 4 times daily via NG tube for 3 days.
Laboratory data revealed serum glucose of 950 mg%, osmolarity 322 mOsm/L, central venous pressure (CVP) less than 1 cm H2O,
blood urea nitrogen (BUN) 25 mg%, sodium 137 mEq/L and 4+ glycosuria. The patient also developed hypotension (70/50 mmHg).
Glycerin was discontinued, and insulin, dextrose, saline and bicarbonate were administered. Levarterenol was administered to treat
hypotension; however, the patient died secondary to refractory hypotension and ventricular fibrillation. The second patient, a 66-yearold, non-diabetic male, received 90 g glycerin 4 times daily via NG tube for 15 days. Laboratory data at that time revealed osmolarity of
364 mOsm/L, glucose 850 mg%, CVP less than 1 cm H2O, BUN 60 mg%, serum sodium 159 mEq/L and 4+ glycosuria. This patient
was treated similarly to the other, but died due to cerebral edema (Sears, 1976).
3) Hyperosmolar NONKETOTIC COMA was described in a 29-year-old male diabetic following oral administration of glycerin (50%)
120 mL twice daily for 1 day for treatment of acute neovascular glaucoma. The patient developed increasing lethargy, anorexia, nausea
and vomiting during a 24-hour period. Chronic renal failure developed. Serum osmolality was 366 mOsm/kg, cerebrospinal fluid glucose
532 mg%, and blood glucose 1129 mg%. Blood pH after 1 day of therapy was 6.98. Urinalysis revealed specific gravity of 1.020, 3+
proteinuria and 4+ glucosuria. Electrocardiogram revealed left ventricular hypertrophy, and occult blood was detected in stools. The
patient was given 8.3 L of intravenous hypotonic saline, albumin and pack cells. A total of 600 units of regular insulin and 6 ampules of
sodium bicarbonate were administered, successfully increasing blood glucose and pH. The patient eventually recovered from
KETOACIDOSIS, but remained in chronic renal failure. The authors suggest that the primary goal of treatment of these cases is
reversible dehydration by employing hypotonic solutions (Oakley & Ellis, 1976).
3.3.4 Gastrointestinal Effects
3.3.4.A Gastrointestinal tract finding
1) NAUSEA and VOMITING have been reported following oral administration of glycerin (Reynolds, 1991; AMA Department of Drugs,
1990a; Krupin et al, 1970; Charan & Sarda, 1967; Leone & Callahan, 1967; Buckell & Walsh, 1964); DIARRHEA occurs less frequently
(Reynolds, 1991; AMA Department of Drugs, 1990a).
2) Increased THIRST may develop following the administration of glycerin (Reynolds, 1991).
3.3.5 Hematologic Effects
3.3.5.A Hematology finding
1) INTRAVASCULAR HEMOLYSIS and hemoglobinuria may result from glycerin administration (Reynolds, 1991; Cantore et al, 1965;
Mickell et al, 1977; Nahata et al, 1981; Gilsanz et al, 1975; Hagnevik et al, 1974); (Welch, 1974). Hemolysis appears to be related to the
rate of administration of glycerin as well as the tonicity of the solution. Available data would suggest that hemolysis can be minimized if
intravenous glycerin 5% to 10% is administered in 5% dextrose with normal saline, at rates equal to or less than 6 mg/kg/minute (Frank
et al, 1981).
2) Intravascular hemolysis is associated with the high infusion rates of glycerin (greater than 500 mL of 10% solutions over 4 hours)
that are required to minimize cerebral edema related to strokes. Clinically significant hemolysis may be avoided by observing an
infusion rate below 125 mL/hour. The addition of a small amount of fructose to glycerin solutions has also been proposed as a method
of minimizing hemolysis (Kumana et al, 1991).
3.3.6 Hepatic Effects
3.3.6.A Hepatotoxicity
1) Transient HEPATOMEGALY may occur during glycerin therapy secondary to glycogen storage; however, this is reversible (Frank et
al, 1981).
3.3.9 Neurologic Effects
3.3.9.A Central nervous system finding
1) HEADACHE has been reported following oral glycerin administration (Reynolds, 1991; AMA Department of Drugs, 1990a; Buckell &
Walsh, 1964; Leone & Callahan, 1967; Krupin et al, 1970); DIZZINESS and MENTAL CONFUSION may also develop (Reynolds, 1991).
CONFUSION and AMNESIA may occur in elderly patients (AMA Department of Drugs, 1990a).
3.3.10 Ophthalmic Effects
3.3.10.A Eye / vision finding
1) The topical application of glycerin can damage the endothelial cells of the cornea. Caution should be used when applying glycerin to
the cornea (Reynolds, 1991).
3.3.11 Otic Effects
3.3.11.A Ototoxicity
1) Temporary HEARING LOSS occurred in a 42-year-old male following a glycerin test with salt loading (Bodo et al, 1984). Transient
hearing loss also developed following the ingestion of glycerin for a test for Meniere's disease (Reynolds, 1991).
3.3.13 Renal Effects
3.3.13.A Nephrotoxicity
1) RENAL TOXICITY and failure has occurred secondary to glycerin administration secondary to hemolysis and hemoglobinuria
(Reynolds, 1991; Hagnevik et al, 1974; Gilsanz et al, 1975). Other evidence indicates that renal toxicity, not associated with myoglobin,
is related to a type of renal toxin that might be produced (Frank et al, 1981). A decrease in renal tubular flow rate secondary to glycerin
may precipitate renal failure, and renal damage might be prevented by increasing glomerular flow rates with intravenous mannitol or
sodium ascorbate (Frank et al, 1981).
2) Acute RENAL FAILURE was reported in a 69-year-old male following the administration of 40% glycerin (1.5 g/minute) by
intravenous infusion over 10 minutes. Immediately following infusion, the patient developed chills, cyanosis, trembling, mild
hypertension, mental confusion, and disorientation. Oligo-anuria developed with serum creatinine levels reaching 5 mg%. Hemolysis
and HEMOGLOBINURIA were present. GLYCOSURIA and ALKALURIA persisted for 1 month, suggesting a renal tubular lesion. The
patient was treated with mannitol, sodium bicarbonate and normal saline, resulting in recovery (Novarini et al, 1979).
3) RENOCEREBRAL OXALOSIS was reported in a patient given 50 g of 10% glycerin solution (in 0.9% sodium chloride) over 20
minutes (Krausz et al, 1977).
3.3.16 Other
3.3.16.A Abuse of laxatives
1) Typical symptoms of laxative abuse include abdominal pain, weakness, fatigue, thirst, vomiting, edema, bone pain (due to
osteomalacia), fluid and electrolyte imbalance, hypoalbuminemia (due to protein-losing gastroenteropathy), and syndromes that mimic
colitis (Longe & DiPiro, 1992). If the bowel has not been permanently damaged, it may require several months to retrain the bowel
without the assistance of laxatives (Curry, 1993).
3.4 Teratogenicity/Effects in Pregnancy/Breastfeeding
A) Teratogenicity/Effects in Pregnancy
1) U.S. Food and Drug Administration's Pregnancy Category: Category C (Prod Info Osmoglyn(R), 1994) (All Trimesters)
a) Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled
studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the
potential risk to the fetus.
See Drug Consult reference: PREGNANCY RISK CATEGORIES
2) Crosses Placenta: Unknown
3) Clinical Management
a) Use of glycerin as a hyperosmotic agent is not recommended during pregnancy due to concern that intravascular influx of fluid will
lead to escape of intravascular fluid into the lungs and brain (Cunningham et al, 1993). Ophthalmic use of glycerin probably does not
constitute any risk to the fetus.
4) Literature Reports
a) There have been no epidemiological studies or case reports concerning the use of glycerin in pregnant women.
B) Breastfeeding
1) Thomson Lactation Rating: Infant risk cannot be ruled out.
a) Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk when used during
breastfeeding. Weigh the potential benefits of drug treatment against potential risks before prescribing this drug during breastfeeding.
2) Clinical Management
a) No reports describing the use of glycerin 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 glycerin affects the quantity and composition of breastmilk. Until more data is available,
use caution when considering glycerin in lactating women.
3) Literature Reports
a) No reports describing the use of glycerin during human lactation or measuring the amount, if any, of the drug excreted into milk have
been located.
3.5 Drug Interactions
3.5.1 Drug-Drug Combinations
Arsenic Trioxide
Licorice
3.5.1.A Arsenic Trioxide
1) Interaction Effect: increased risk of QT prolongation
2) Summary: Caution should be used when prescribing drugs known to induce hypokalemia or hypomagnesemia, such as diuretics, as
they may precipitate QT prolongation (Prod Info TRISENOX(R) IV injection, 2006).
3) Severity: major
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: Arsenic trioxide should be administered with extreme caution to patients who may be at risk for development
of prolonged QT syndrome (e.g. hypokalemia or hypomagnesemia) (Prod Info TRISENOX(R) IV injection, 2006).
7) Probable Mechanism: induction of hypokalemia or hypomagnesemia
3.5.1.B Licorice
1) Interaction Effect: increased risk of hypokalemia and/or reduced effectiveness of the diuretic
2) Summary: Cases have been reported in which patients experienced hypokalemia and hypertension with concomitant use of licorice
and diuretics (Harada et al, 2002a; deKlerk et al, 1997a; Folkerson et al, 1996; Farese et al, 1991a). Symptoms of congestive heart
failure and hypokalemia occurred in a patient taking licorice, furosemide, and digoxin (Harada et al, 2002a). Hypokalemic paralysis has
resulted from licorice use; concomitant diuretic use increased the risk (Hussain, 2003; Lin et al, 2003; Shintani et al, 1992a; Corsi et al,
1983). Licorice alone has been reported to be the likely cause of hypokalemia, hypertension, and cardiac arrhythmia (Dellow et al,
1999a; Eriksson et al, 1999; Kageyama et al, 1997; Bernardi et al, 1994; Blachley & Knochel, 1980; Wash & Bernard, 1975). The
glycyrrhetinic acid component of licorice is metabolized to 3-monoglucuronyl-glycyrrhetinic acid (3MGA), which inhibits 11-betahydroxysteroid dehydrogenase and reduces cortisol breakdown, resulting in a hypermineralocorticoid effect (Kato et al, 1995; Walker &
Edwards, 1994).
3) Severity: moderate
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Avoid concurrent use of licorice and diuretics.
7) Probable Mechanism: pseudoaldosteronism from licorice ingestion resulting in hypokalemia
8) Literature Reports
a) An 84-year-old male developed hypokalemia and symptoms of congestive heart failure after 7 days of concurrent use of a licoricecontaining Chinese herbal laxative with digoxin and furosemide. The patient complained of fatigue, appetite loss, and lower extremity
edema. Pulse rate was 30 beats per minute, potassium was 2.9 milliequivalents/Liter (mEq/L), and digoxin level 2.9 nanograms/milliliter
(ng/mL). Chest radiograph revealed an enlarged cardiac silhouette and lung congestion. Partial arterial oxygen pressure and saturation
was low, carbon dioxide pressure was high. Plasma renin activity was 0.3 ng/mL/hour (normal 0.3 to 2.9 ng/mL/hour) and aldosterone
was 3.8 nanograms/deciliter (ng/dL) (normal 3.6 to 24 ng/dL). Digoxin and the herbal laxative were stopped; after 18 days, the patient's
pulse increased to 60 beats per minute and symptoms of congestive heart failure were relieved. Potassium increased to 4.3 mEq/L,
renin activity was 1 ng/mL/hour, aldosterone was 12 ng/dL, and digoxin level was 0.6 ng/mL (Harada et al, 2002).
b) Fifty-nine cases of glycyrrhizin-induced hypokalemic myopathy (GIHM) were reviewed. The combined use of licorice and
hypotensive diuretic agents increased the risk of GIHM in the majority of cases. Of 56 cases which were reported, serum potassium was
1.98 milliequivalents/liter (mEq/L). Average blood aldosterone in 30 patients was normal, though 15 of those patients had below-normal
values. Plasma renin activity averaged 0.17 nanograms/milliliter/hour (ng/mL/hour) (normal: 0.8-4.4 ng/mL/hour) in 27 patients.
Complete cure was attained in 57 of the 59 cases of GIHM when licorice ingestion was discontinued and potassium supplementation
given (Shintani et al, 1992).
c) A 49-year-old female presented with persistent hypertension and hypokalemia (2.6 mmol/L; normal 3.3 to 4.8 mmol/L) following
consumption of licorice. Blood pressure was found to be volume-sensitive and plasma renin activity and plasma aldosterone were low.
The patient's hypokalemia was unresponsive to amiloride but normalized with spironolactone. Prior to discontinuing her regular licorice
intake, her blood pressure control was unsatisfactory on a combination of furosemide 120 mg daily, felodipine 2.5 mg daily, monoxidine
0.2 mg daily, spironolactone 75 mg daily, and doxazosin 4 mg daily. The patient then admitted to consuming 30 to 40 Pontefract cakes,
a licorice-based sweet, per week (approximately 0.25 kilograms). After discontinuing the Pontefract cakes, blood pressure fell steadily
allowing progressive withdrawal of antihypertensive treatment (Dellow et al, 1999).
d) A 21-year-old female developed headache and hypertension (190/120 mmHg), associated with licorice consumption (100 grams
daily) along with an oral contraceptive. She was advised to discontinue eating licorice. Blood pressure remained elevated with treatment
combining atenolol, lisinopril, hydrochlorothiazide, and amlodipine. Drug treatment was discontinued, and 2 weeks later blood pressure
was 180/110 mmHg, potassium 2.6 mmol/L (normal 3.8 to 5.0 mmol/L), bicarbonate 35.9 mmol/L (normal 23 to 29 mmol/L). Plasma
aldosterone was 160 picomoles/liter (pmol/L) (normal 320 to 2000 pmol/L). The patient then admitted to replacing her licorice intake with
two packets of Stimerolol Sugar Free(R) chewing gum per day. This chewing gum contains 585 mg licorice in each 15 gram packet,
which equals 8% to 12% glycyrrhizinic acid. Her glycyrrhizinic acid intake was calculated to be 120 mg daily. Within 3 weeks of
discontinuing the gum, her blood pressure and potassium level normalized (deKlerk et al, 1997).
e) A 35-year-old woman taking an oral contraceptive and chlorothiazide experienced hypokalemia (2.2 mmol/L). Her blood pressure
was 140/80 mmHg. Chlorothiazide was stopped and potassium chloride 600 mg three times daily was started. After one week,
potassium remained abnormal at 2.0 mmol/L, after 2 weeks it decreased further to 1.5 mmol/L. Intravenous potassium supplementation
was started. Although she denied licorice use, it was discovered that she used BenBits Cool Mint(R) chewing gum (Leaf, United
Kingdom), 3 packets daily. This product contained 160 mg licorice in each 16 gram packet, of which 10% was glycyrrhizinic acid. After 2
days of intravenous potassium and 15 days of oral potassium, and within 3 weeks of discontinuing the chewing gum, edema
disappeared, blood pressure decreased to 110/80 mmHg and potassium increased to 4.2 mmol/L. The authors attributed the
hypokalemia to the licorice intake (deKlerk et al, 1997).
f) A 38-year-old male was hospitalized with respiratory and kidney failure due to complications of somnolence, flaccid paralysis of the
extremities, arterial hypertension, edema and severe hypokalemia. He had been ingesting 200 grams of licorice daily for 10 weeks
together with a thiazide diuretic for 2 weeks (Folkersen et al, 1996).
g) A 70-year-old male developed hypokalemia (1.9 millimoles/Liter (mmol/L)) and rhabdomyolysis while treated with a thiazide diuretic.
Blood pressure and potassium were normalized following treatment with spironolactone, potassium chloride, and verapamil. It was
discovered that he had been eating 60 to 100 grams of licorice candies daily for 4 to 5 years, containing 0.3% glycyrrhizic acid. Licorice
ingestion was discontinued, then spironolactone and potassium were discontinued. Rechallenge with licorice (300 mg glycyrrhetinic
acid) per day resulted in subnormal potassium (3.4 mmol/L), blood pressure 154/72 mmHg, and increased body weight by 4.9 kg.
Licorice caused plasma renin activity to fall from 2.4 nanograms/Liter/second (ng/L/second) (normal 0.14 to 1.8 mg/L/second) to 0.2
mg/L/second after the week of licorice. Following the study, verapamil was continued while the patient abstained from licorice. Blood
pressure and potassium remained normal (Farese et al, 1991).
4.0 Clinical Applications
Monitoring Parameters
Patient Instructions
Place In Therapy
Mechanism of Action / Pharmacology
Therapeutic Uses
Comparative Efficacy / Evaluation With Other Therapies
4.1 Monitoring Parameters
A) Therapeutic
1) Reduction in intraocular or intracranial pressure.
B) Toxic
1) Renal function tests (renal toxicity)
2) Serum osmolality (hyperosmolality)
3) Blood glucose levels (hyperglycemia)
4) Urinalysis (hemoglobinuria)
5) CBC
4.2 Patient Instructions
A) Glycerin (Rectal)
Glycerin
Treats occasional constipation by making bowel movements regular. This medicine is a laxative.
When This Medicine Should Not Be Used:
You should not use this medicine if you have had an allergic reaction to glycerin. You should not use this medicine if you have rectal
bleeding.
How to Use This Medicine:
Suppository
Your doctor will tell you how much of this medicine to use and how often. Do not use more medicine or use it more often than your
doctor tells you to.
This medicine comes with patient instructions. Read and follow these instructions carefully. Ask your doctor or pharmacist if you have
any questions.
Never take rectal suppositories by mouth.
Wash your hands with soap and water before and after using this medicine. Remove the foil or wrapper from the suppository before
inserting it.
Lie on your left side with your left leg straight or slightly bent, and your right knee bent upward. Gently push the pointed end of the
suppository into the rectum about 1 inch.
Keep lying down for about 15 minutes to keep the suppository from coming out before it melts. Then, wash your hands again.
This medicine should cause you to have a bowel movement within 15 minutes to 1 hour.
If a Dose is Missed:
If you miss a dose or forget to use your medicine, use it as soon as you can. If it is almost time for your next dose, wait until then to use
the medicine and skip the missed dose. Do not use extra medicine to make up for a missed dose.
How to Store and Dispose of This Medicine:
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light.
You may store the suppositories in the refrigerator, but do not freeze them.
Ask your pharmacist, doctor, or health caregiver about the best way to dispose of the used medicine applicator(s), containers, and any
leftover medicine after you have finished your treatment. You will also need to throw away old medicine after the expiration date has
passed.
Keep all medicine away from children and never share your medicine with anyone.
Drugs and Foods to Avoid:
Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines, vitamins, and herbal products.
Make sure your doctor knows if you have been using any other laxative for more than 1 week prior to using this medicine.
Warnings While Using This Medicine:
Make sure your doctor knows if you are pregnant or breast feeding.
Make sure your doctor knows if you have stomach pain, nausea, vomiting, or if you have had a sudden change in bowel habits lasting
longer than 2 weeks.
If you do not have a bowel movement after using this medicine, stop using it and talk to your doctor.
If your symptoms do not improve or if they get worse, call your doctor.
This medicine should not be used for longer than one week.
Possible Side Effects While Using This Medicine:
Call your doctor right away if you notice any of these side effects:
Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your mouth or throat, chest tightness, trouble
breathing.
Bleeding from your rectum.
If you notice these less serious side effects, talk with your doctor:
Irritation or burning pain in your rectal area.
If you notice other side effects that you think are caused by this medicine, tell your doctor.
4.3 Place In Therapy
A) Glycerin is an osmotic diuretic which is effective in reducing elevated intracranial pressure associated with stroke, cerebral
infarction, Reye's syndrome, and tumors of the central nervous system. The drug is also effective in treating cerebral edema resulting
from head injuries.
B) In ophthalmology, glycerin is used for short-term reduction of intraocular pressure and vitreous volume. Glycerin is usually used in
patients not responding to miotics and carbonic anhydrous inhibitors. Orally administered glycerin is considered safer than intravenous
mannitol or urea; however, the onset of action of glycerin is slower and intraocular pressure returns to pretreatment levels sooner.
C) When compared with mannitol, glycerin offers the advantages of oral administration, less diuresis and electrolyte loss, and less
rebound cerebral overhydration (Frank et al, 1981). These advantages warrant formulary inclusion of glycerin.
4.4 Mechanism of Action / Pharmacology
A) MECHANISM OF ACTION
1) Glycerin (glycerol) is a potent hypertonic agent primarily used in the treatment of elevated intracranial pressure. The drug rapidly
lowers both intraocular and intracranial pressure within 30 minutes following oral or intravenous dose. The absolute increase in serum
osmolality required to result in significant cerebral and intraocular dehydration is not clear (Frank et al, 1981a).
2) The main effect of glycerin results from its osmotic dehydrating effects, although other mechanisms have been postulated for its
effect in lowering intracranial pressure. This includes an increase in blood flow to ischemic areas, decreases in serum free fatty acids
and increases in synthesis of glycerides in the brain. These effects might be beneficial in the treatment of intracranial hypertension since
free fatty acids are capable of producing coma, elevating in intracranial pressure, cerebral edema, and mitochondrial swelling in
experimental animals. Free fatty acids are also increased in Reye's syndrome (Frank et al, 1981a).
3) Similarly, glycerin produces its ocular hypotensive effects secondary to increases in hyperosmolality of the blood (McCurdy et al,
1966), although evidence indicates that other mechanisms may be involved (Friedman et al, 1980) such as a reduction in aqueous
humor (AMA Department of Drugs, 1990). Oral administration of glycerin in 42 cataract patients resulted in significant ocular
hypotension 30 minutes post-administration (maximal effects at 60 minutes). However, peak increases in serum osmolarity occurred
much later (90 to 120 minutes). Thus, other mechanisms are most likely involved in the ocular hypotensive effects of glycerin.
4) Due to its osmotic effect, glycerin softens, lubricates, and facilitates the elimination of inspissated feces. Additionally, this agent may
stimulate rectal contractions (Gilman et al, 1990)(AMA Department of Drugs, 1990).
B) REVIEW ARTICLES
1) A
a) comprehensive review of glycerin metabolism and documentation supportive of glycerin as a potential energy substrate is available
which includes a discussion of the toxicity and adverse effects of glycerin administration (Tao et al, 1983).
2) A review on the pharmacokinetics, adverse effects, and therapeutic use of glycerin is available (Frank et al, 1981a).
3) A comprehensive review of the use of glycerin in the treatment of ischemic brain edema (Winter et al, 1995).
4.5 Therapeutic Uses
Bacterial meningitis; Adjunct
Cerebral edema
Cogan's syndrome
Constipation
Ménière's disease; Diagnosis
Meningoencephalitis - Viral meningitis
Neoplasm of central nervous system
Obesity
Occlusive stroke
Pain in face
Primary angle-closure glaucoma
Raised intracranial pressure
Raised intraocular pressure
Reye's syndrome
Trigeminal neuralgia
4.5.A Bacterial meningitis; Adjunct
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Pediatric, Evidence favors efficacy
Recommendation: Pediatric, Class IIb
Strength of Evidence: Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
In a prospective, multicenter, randomized, double-blind, double-dummy clinical trial in children aged 2 months through 16 years with
bacterial meningitis (n=654), adjuvant treatment with oral glycerol (85% solution), alone or in combination with intravenous
dexamethasone, led to improved outcomes of severe neurological sequelae and/or death compared to adjuvant dexamethasone alone
or placebo (Peltola et al, 2007)
3) Pediatric:
a) Adjuvant therapy with oral glycerol, either alone or in combination with intravenous (IV) dexamethasone, improved severe
neurological sequelae and/or death compared to dexamethasone alone or placebo in a prospective, multicenter, randomized, doubleblind, double-dummy clinical trial in children aged 2 months through 16 years with bacterial meningitis. Meningitis was defined by the
following: a cerebrospinal fluid (CSF) culture positive for meningitis-causing bacteria, characteristic CSF findings, and positive blood
culture results or a CSF sample with a positive latex agglutination test results, and signs/symptoms compatible with bacterial meningitis.
Patients pretreated with antimicrobials were included in the study provided therapy comprised of oral or no greater than 1 parenteral
dose administration. All patients received IV ceftriaxone 80 to 100 milligrams per kilogram (mg/kg) once daily for 7 to 10 days. Patients
were randomly assigned to one of the following 4 arms: IV dexamethasone (n=166), IV dexamethasone and oral glycerol (n=159), oral
glycerol (n=166), and placebo (n=163). Both dexamethasone and glycerol (85% solution) were administered 15 minutes prior to the
ceftriaxone dose, and were dosed as 0.15 mg/kg and 1.5 grams/kilogram (1.5 milliliters/kilogram), respectively, every 6 hours for 48
hours. Nasogastric tubes were routinely used in study patients. In the event of vomiting within 30 minutes, the glycerol dose was
repeated. Neurological, developmental, and hearing sequelae assessments occurred at hospital discharge; patients with deficits were
scheduled for a follow-up visit 1-2 months later. The primary endpoints were death, severe neurological sequelae, and profound hearing
loss (determined by brain stem evoked response audiometry or traditional audiometry). Severe neurological sequelae, which included
blindness, quadriparesis or quadriplegia, hydrocephalus (requiring a shunt), or severe psychomotor retardation, was combined with
death as a composite endpoint. Assessments were performed primarily at hospital discharge. Overall, 37% of patients received prior
antibiotic therapy. At hospital discharge, 13% (n=86/654) of patients died, 8% (n=44/556) had severe neurological sequelae, and 8%
(n=43/534) had profound hearing loss. An intent-to-treat analysis revealed that the incidence of severe neurological sequelae was
significantly reduced in patients receiving glycerol alone (odds ratio (OR), 0.31; 95% confidence interval (CI), 0.13-0.76; p vs
placebo=0.01) or in combination with dexamethasone (OR, 0.39; 95% CI, 0.17-0.93; p=0.033) compared to dexamethasone alone (OR,
0.48; 95% CI, 0.21-1.07; p=0.72). Similarly, for the composite endpoint of death and severe neurological sequelae, significant
reductions occurred in the glycerol-only and dexamethasone-glycerol groups (OR, 0.44; 95% CI, 0.25-0.76; p=0.003 and OR, 0.55; 95%
CI, 0.32-0.93; p=0.027, respectively) compared to the dexamethasone-only group (OR, 0.65; 95% CI, 0.39-1.09; p=0.1). None of the
adjunctive treatments (dexamethasone, glycerol, or the combination) significantly affected death or profound hearing loss. Pretreatment
with antimicrobials, including their timing of administration with respect to study initiation, did not affect the results. The primary endpoint
results are shown in the table. A post-hoc analysis of patients with Haemophilus influenzae type b meningitis (n=181) revealed that
dexamethasone treatment prevented profound hearing loss (OR, 0.27; 95% CI, 0.09-0.77; p=0.014); however, the statistical
significance was lost when receipt of pretreatment antimicrobials was taken into account. Of the 484 patients where a causative agent
was identified, 222 were H. influenzae type b, 132 were S. pneumoniae, and 110 were N. meningitidis. Among adverse events, visible
blood in stool occurred in 5% (n=6/111), 5% (n=5/101), 1% (n=1/113), and 2% (n=2/99) of patients in the dexamethasone-only,
dexamethasone-glycerol, glycerol-only, and placebo groups, respectively. Vomiting and diarrhea were not more common in the glycerolonly group. There were no severe adverse drug events in any of the groups (Peltola et al, 2007).
Outcome
DXM and placebo (n; %)
DXM and glycerol (n; %)
Glycerol and placebo (n; %)
Death
23/166 (14%)
20/159 (13%)
17/166 (10%)
Severe neurological sequelae
10/139 (7%)
8/134 (6%)
7/147 (5%)
Severe neurological sequelae or death
33/162 (20%)
27/153 (18%)
24/164 (15%)
Profound hearing loss
10/135 (7%)
9/132 (7%)
12/136 (9%)
Key: DXM = dexamethasone; n = number of patients; * = determined by chi square test between 4 groups (for heterogeneity)
4.5.B Cerebral edema
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Effective in the treatment of CEREBRAL EDEMA secondary to central nervous system or CNS TRAUMA
3) Adult:
a) GLYCERIN, administered intravenously or orally, has been effective in the treatment of CEREBRAL EDEMA secondary to central
nervous system or CNS TRAUMA (Buckell & Walsh, 1964a; Bovet et al, 1961; Troup et al, 1971). Oral doses of 25 to 50 grams or
intravenous doses of 0.5 to 1 gram/kilogram (g/kg) over 30 minutes are effective in acute situations. In severe cases, 1 g/kg every 2
hours by constant intravenous infusion is effective. For prolonged therapy, 0.25 to 0.5 g/kg every 4 to 6 hours has been successful
(Frank et al, 1981b).
b) Effective results were reported in intracranial hypertension due to HEAD INJURIES with GLYCERIN 75 milliliters orally 1 to 3 times
daily diluted in water or fruit juice. Nausea was the only side effect reported (Buckell & Walsh, 1964a).
c) Effective lowering of intracranial pressure in BRAIN INJURY patients was reported within one hour following oral doses of 25 to 50
grams (Troup et al, 1971).
d) Administration of GLYCERIN was helpful in preventing the development of cerebral edema in some patients receiving brain
irradiation for metastatic brain neoplasms. Symptoms associated with increased intracranial pressure (headache, nausea, vomiting,
blurred vision) were graded prior irradiation therapy in all 44 patients entering the trial. Additionally, neurological signs were recorded
prior GLYCERIN treatment and reevaluated during the treatment period at least 2 times a week. Irrespective of tumor size or
progression of the disease, all patients received whole-brain irradiation (3000 to 4500 rads). Patients were given oral GLYCERIN
(Osmoglin (R)) over 20 to 30 minutes every 6 hours (1.2 to 2 grams/Kilogram body weight) throughout the period of brain irradiation and
for 14 days thereafter. Patients in critical condition unable to take oral GLYCERIN received a 10% intravenous solution in dextrose 5%.
The 12 patients beginning treatment without symptoms, remained stable without clinical deterioration; improvement in symptoms was
evident in over 90% of those presenting with headache, nausea, and vomiting. Although more than half of the patients with confusion,
paralysis, paresis and papilledema improved, 11 of the 32 patients presenting with symptoms failed to respond adequately and were
changed from GLYCERIN to dexamethasone therapy (Bedikian et al, 1980a).
4.5.C Cogan's syndrome
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Possibly effective in one case report
3) Adult:
a) A 25-year-old female with Cogan's syndrome treated with oral glycerin 100 grams/day for 4 days and 100 milligrams every 8 hours
for 2 further days received concomitant therapy with TRIAMCINOLONE, MECLIZINE, NIACIN and CHLOROQUINE. Marked
improvement in hearing after each dose of GLYCERIN was observed and audiograms improved. The authors suspect the drug may
Placebo (n; %)
26/163 (16%)
19/136 (14%)
46/163 (28%)
12/131 (9%)
reduce hydrops in the cochlea by acting as a hyperosmolar agent. Further studies are required to evaluate efficacy (Beckman &
Trotsky, 1970).
4.5.D Constipation
FDA Labeled Indication
1) Overview
FDA Approval: Adult, yes; Pediatric, yes
Efficacy: Adult, Effective; Pediatric, Effective
Recommendation: Adult, Class IIa; Pediatric, Class IIa
Strength of Evidence: Adult, Category B; Pediatric, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Aids in fecal evacuation and are also used to soften and lubricate feces
3) Adult:
a) The use of glycerin suppositories rectally aids in fecal evacuation by stimulating rectal contraction via its hyperosmotic and irritant
actions. Glycerin suppositories are also used to soften and lubricate inspissated feces, in bowel retraining programs, and to re-establish
normal bowel function in patients who are laxative dependent (AMA Department of Drugs, 1990b).
4) Pediatric:
a) The use of glycerin suppositories rectally aids in fecal evacuation by stimulating rectal contraction via its hyperosmotic and irritant
actions. Glycerin suppositories are also used to soften and lubricate inspissated feces, in bowel retraining programs, and to re-establish
normal bowel function in patients who are laxative dependent (AMA Department of Drugs, 1990b).
4.5.E Ménière's disease; Diagnosis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Limited value in the diagnosis of Meniere's disease, but has been used previously
3) Adult:
a) The glycerin test has been helpful in the selection process of suitable patients for endolymphatic sac operations. Hearing tests were
performed on 60 patients before, 2.5 hours after, and 5 hours after the administration of glycerin 1.5 grams/kilogram. A positive test
occurred if both an improvement in pure tone average (PTA), 15 db or more improvement in PTA for frequencies of 500, 1000, and
2000 Hz, and speech discrimination occurred (10% or greater). As determined by caloric response and vestibular examination, a
positive response to the glycerin test (27 of 60 patients) failed to correlate with the stage of Meniere's disease (Karjalainen et al, 1984).
4.5.F Meningoencephalitis - Viral meningitis
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Lowered intracranial pressure in a 19-year-old with VIRAL MENINGOENCEPHALITIS
3) Adult:
a) Effective lowering of intracranial pressure was reported in a 19-year-old with VIRAL MENINGOENCEPHALITIS. GLYCERIN was
administered orally in doses of 70 milliliters every 6 hours (a 50% solution in 0.15 molar sodium chloride) for a period of 3 weeks.
Occasional vomiting was the only side effect (Newkirk et al, 1972).
4.5.G Neoplasm of central nervous system
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Oral and intravenous GLYCERIN have been effective in the treatment of intracranial hypertension secondary to CNS TUMORS or
SPACE OCCUPYING LESIONS
3) Adult:
a) Both oral and intravenous GLYCERIN have been effective in the treatment of intracranial hypertension secondary to CNS TUMORS
or SPACE OCCUPYING LESIONS (Frank et al, 1981b); (Cantori et al, 1965). Good results have been reported with doses of 0.5 to 2
grams/kilogram (g/kg) (30% to 50% oral solutions), usually initiated with 1 gram/kilogram followed by 0.5 g/kg every 3 hours (Frank et al,
1981b).
b) The recommended dose for patients with central nervous system tumors, space occupying lesions, and during NEUROSURGICAL
PROCEDURES is a one-time preoperative dose of 1.5 to 2 grams/kilogram (g/kg) via nasogastric tube, one-half hour prior to dura
incision. Alternatively, doses of 1 g/kg orally or intravenously every 6 hours for the first several days may produce more prolonged
control of elevated intracranial pressure (Frank et al, 1981b).
c) Administration of GLYCERIN was helpful in preventing the development of cerebral edema in some patients receiving brain
irradiation for metastatic brain neoplasms. Symptoms associated with increased intracranial pressure (headache, nausea, vomiting,
blurred vision) were graded prior irradiation therapy in all 44 patients entering the trial. Additionally, neurological signs were recorded
prior GLYCERIN treatment and reevaluated during the treatment period at least 2 times a week. Irrespective of tumor size or
progression of the disease, all patients received whole-brain irradiation (3000 to 4500 rads). Patients were given oral GLYCERIN
(Osmoglin (R)) over 20 to 30 minutes every 6 hours (1.2 to 2 grams/Kilogram body weight) throughout the period of brain irradiation and
for 14 days thereafter. Patients in critical condition unable to take oral GLYCERIN received a 10% solution in dextrose 5%
intravenously. The 12 patients beginning treatment without symptoms remained stable without clinical deterioration; improvement in
symptoms was evident in over 90% of those presenting with headache, nausea, and vomiting. Although more than half of the patients
with confusion, paralysis, paresis and papilledema improved, 11 of the 32 patients presenting with symptoms failed to respond
adequately and were changed from GLYCERIN to DEXAMETHASONE therapy (Bedikian et al, 1980a).
4.5.H Obesity
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Ineffective in suppressing hunger or reducing weight
3) Adult:
a) Several studies have suggested a role of GLYCERIN in the treatment of obesity by regulation of adipose tissue mass. GLYCERIN
was compared to placebo in 8 obese patients in a controlled study. GLYCERIN 80, 160, or 360 milligrams/kilogram was administered
three times daily in fruit juice for 8 weeks. No significant changes in body weight or appetite occurred with GLYCERIN on any dose
compared to placebo. No differences in serum glucose, creatinine, blood urea nitrogen or serum electrolytes were observed (Greenway
et al, 1981).
b) GLYCERIN 100 grams in 200 milliliters water was ineffective in suppressing hunger or reducing weight when provided as a daily
supplement to obese patients on 1000-kcal/day diets (Leibel et al, 1980).
4.5.I Occlusive stroke
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Improved global performance and motor and sensory functions in patients with mild-to-moderate disability
No effect on reducing mortality in 26 patients with ischemic cerebral infarction with mild-to-severe disability
3) Adult:
a) Many reports have described the efficacy of glycerin in controlling elevated intracranial pressure in patients with STROKE (Meyer et
al, 1971; Meyer et al, 1971a; Fawer et al, 1978; Fawer et al, 1977; Mathew et al, 1972; Massey & Brannon, 1977); (Frithz & Warner,
1975). However, despite the efficacy of glycerin in reducing brain edema in stroke, there is no evidence to indicate that glycerin will
improve the long-term outlook for these patients (Katzman et al, 1977). Glycerin has effectively improved global performance and motor
and sensory functions in patients with mild-to-moderate disability, but had no effect on reducing mortality in 26 patients with ischemic
cerebral infarction with mild-to-severe disability (Fawer et al, 1977). These data suggest that patients with severe deficits will not
respond at all to glycerin infusions. Patients in this study received 10% glycerin in 5% dextrose in normal saline (25 grams glycerin twice
daily for 6 days).
b) In a double-blind, placebo-controlled study involving 61 patients, both glycerin and the combination of glycerin plus dextran were
ineffective in the treatment of acute stroke. Patients were assigned to placebo, intravenous glycerin 10% 500 milliliters (mL) over 4
hours, or glycerin in the same doses plus dextran 50 grams or dextrose 25 grams (Rheomacrodex(R)) 500 mL intravenously over 3
hours. Patients received the regimens for 7 days following hospital admission (initiated 24 to 32 hours following the appearance of the
first stroke symptoms). Neurologic scores according to a modified Matthew scale demonstrated no effect of either regimen on acute
ischemic stroke. In addition, 98% of patients receiving glycerin developed signs of hemolysis. It was felt that neither glycerin or dextran
have any value in the treatment of acute stroke (Frei et al, 1987).
4.5.J Pain in face
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Beneficial in the treatment of pain secondary to trigeminal neuralgia, cluster headache, and atypical facial pain
3) Adult:
a) GLYCERIN 0.2 to 0.4 milliliter administered via trigeminal cistern injection relieved paroxysmal facial pain in numerous conditions
unresponsive to previous therapy. GLYCERIN was beneficial in the treatment of pain secondary to trigeminal neuralgia, cluster
headache, and atypical facial pain (Waltz et al, 1985).
4.5.K Primary angle-closure glaucoma
See Drug Consult reference: DRUG THERAPY OF GLAUCOMA
4.5.L Raised intracranial pressure
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence is inconclusive
Recommendation: Adult, Class III
Strength of Evidence: Adult, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Oral GLYCERIN effectively lowered intracranial pressure associated with pseudotumor cerebri in several isolated reports
3) Adult:
a) Oral GLYCERIN, in several isolated reports, was effective in lowering intracranial pressure associated with pseudotumor cerebri
BENIGN INTRACRANIAL HYPERTENSION (or ELEVATED INTRACRANIAL PRESSURE). The drug effectively decreased
papilledema and headaches, and improved the blind spot. GLYCERIN doses of 0.25 to 1 gram/kilogram orally 3 to 6 times daily have
been effective (Frank et al, 1981b).
4.5.M Raised intraocular pressure
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Effective
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Oral glycerin is used to reduce the intraocular pressure and vitreous volume prior to various ophthalmologic procedures
3) Adult:
a) Oral GLYCERIN is used to reduce the intraocular pressure and vitreous volume prior to various ophthalmologic procedures such as
CATARACT EXTRACTION (AMA Department of Drugs, 1990b; Krupin et al, 1970a; Leone & Callahan, 1967a; Charan & Sarda, 1967a;
Awasthi et al, 1967; Kornblueth et al, 1966), IRIDECTOMY, and sometimes for short-term treatment of GLAUCOMA or SECONDARY
GLAUCOMAS. GLYCERIN may not be as effective in treating inflammatory secondary glaucomas since its action is dependent on an
intact blood aqueous humor barrier. In acute-closure glaucoma, preoperative GLYCERIN reduces intraocular pressure and CORNEAL
EDEMA rapidly. When the pressure is high, the iris sphincter may become ischemic and the miotic agent may not be effective until the
pressure is reduced initially. In chronic glaucomas, GLYCERIN is used only for pre- and postoperative treatment (AMA Department of
Drugs, 1990b; Frank et al, 1981b). GLYCERIN is used pre- and postoperatively in CONGENITAL GLAUCOMA, RETINAL
DETACHMENT SURGERY, and KERATOPLASTY (AMA Department of Drugs, 1990b). Although GLYCERIN is considered safer than
UREA or MANNITOL, GLYCERIN reduces intraocular pressure slower than the other agents (AMA Department of Drugs, 1990b;
Trevor-Roper, 1964).
b) The effect of GLYCERIN on intraocular pressure (IOP) was evaluated in glaucomatous patients and normal subjects. Oral
GLYCERIN in doses of 1 to 1.5 grams/kilogram (g/kg) for 10 to 25 days was effective in reducing IOP in 15 normal subjects and 32
patients with glaucoma (Consul & Kulshrestha, 1965). Additionally, an oral dose of 1.5 g/kg of a GLYCERIN 50% solution successfully
reduced IOP in 14 patients with glaucoma (Drance, 1964).
c) Hypertonic agents, such as GLYCERIN, are effective for short- or long-term treatment of epithelial edema by reducing corneal
edema and improving visual acuity. The long-term use of ocular GLYCERIN is not well tolerated and instillation is painful. GLYCERIN
may also be used prior to ophthalmoscopy or gonioscopy when the cornea is too edematous to permit a diagnosis. A local anesthetic
should be instilled prior to the instillation of GLYCERIN (AMA Department of Drugs, 1990b).
d) Significant reduction in intraocular pressure (IOP) was reported within 3 hours of administration of GLYCERIN in a 2-year-old boy
who developed increased IOP secondary to EYE TRAUMA (a blow in the eye). The patient received 1 gram/kilogram orally for 2 days
(Hill, 1964).
4.5.N Reye's syndrome
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Pediatric, Evidence is inconclusive
Recommendation: Pediatric, Class III
Strength of Evidence: Pediatric, Category C
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Elevated intracranial pressure associated with Reye's syndrome has been effectively controlled with GLYCERIN
3) Pediatric:
a) The elevated intracranial pressure associated with Reye's syndrome has been effectively controlled with GLYCERIN in doses of 0.75
to 2 grams/kilogram intravenously every 2 hours (Mickell et al, 1977a; Nahata et al, 1981a; Frank et al, 1981b).
b) GLYCERIN effectively controlled intracranial hypertension in 9 patients with Reye's syndrome. GLYCERIN (10% solution in 5%
dextrose with 0.45% sodium chloride) was administered by continuous intravenous (IV) infusion; doses of 0.75 to 1.75 grams/kilogram
were administered every 2 hours. One-half of the total dose was administered during the first 30 minutes and the remainder over the
next 1.5 hours. This was repeated every 2 hours, with the dose of GLYCERIN being adjusted to maintain an intracranial pressure of
less than or equal to 15 mmHg. Serum concentrations of GLYCERIN ranged from 1.48 to 5.3 milligrams/milliliter and total body
clearance from 1.99 to 5.1 milliliters/kilogram/minute. The authors suggest that due to substantial intersubject variability of GLYCERIN
kinetics, that the drug be titrated IV to achieve the desired intracranial pressure. Patients did not develop rebound intracranial
hypertension (Nahata et al, 1981a).
4.5.O Trigeminal neuralgia
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Injection of GLYCERIN by the anterior percutaneous route into the trigeminal cistern was effective in alleviating pain in 86% of 75
patients with trigeminal neuralgia
3) Adult:
a) Peripheral GLYCERIN injection was successful in the treatment of 13 patients (17 nerves affected) suffering from idiopathic
trigeminal neuralgia. The area of 12 nerves remained pain free for periods of 6 to 26 months, 2 nerves failed to respond to treatment
whereas a decreased sensation was noticed in the area of 6 nerves. Although peripheral GLYCERIN injections compare well to results
obtained from percutaneous retrogasserian GLYCERIN rhizotomy, the author felt that his preliminary results needed further clinical
substantiation with longer follow-up periods (Stajcic, 1989).
b) GLYCERIN 0.2 to 0.4 milliliters via trigeminal cistern injection was reported beneficial in relieving paroxysmal facial pain in numerous
conditions unresponsive to previous therapy. The injections were beneficial in the treatment of pain secondary to trigeminal neuralgia,
cluster headache and atypical facial pain (Waltz et al, 1985).
c) Percutaneous retrogasserian GLYCERIN injection (PRGI) appears to relieve trigeminal neuralgia in patients without changing facial
sensation. This was demonstrated in 30 patients with TIC DOULOUREUX refractory to medical therapy. Small volumes (0.15 to 0.35
milliliter) of sterile GLYCERIN were precisely placed, by first insuring the anatomy of the trigeminal cistern using METRIZAMIDE.
Nineteen of the 30 patients had no change in facial sensation following the injection. Although the long-term relief of tic douloureux
following PRGI remains to be determined, preliminary results indicate that 23 patients have remained pain-free 5 to 12 months after the
procedure (Lunsford, 1982).
d) Injection of GLYCERIN 0.2 to 0.4 milligram by the anterior percutaneous route into the trigeminal cistern was effective in alleviating
pain in 86% of 75 patients with trigeminal neuralgia. Injection was visualized by the aid of METRIZAMIDE. GLYCERIN may act on
demyelinated nerve fibers, which may be involved in the triggering mechanism of trigeminal neuralgia (Hakanson, 1981).
4.6 Comparative Efficacy / Evaluation With Other Therapies
Bisacodyl
Carbamide Peroxide
Dexamethasone
Dienestrol
Xylitol
4.6.A Bisacodyl
4.6.A.1 Bowel care
a) In patients with upper motor neuron spinal cord lesions (n=15), total bowel care time was reduced by use of polyethylene glycolbased BISACODYL (PGB) suppositories compared with hydrogenated vegetable oil-based BISACODYL (HVB) suppositories. PGB
suppositories compared with GLYCERINE-DOCUSATE MINI-ENEMAS (Theravac(R) SB mini-enemas) showed generally similar time
requirements for bowel care. Total time for bowel care was 74.5 minutes, 43 minutes, and 37 minutes using HVB suppositories, PGB
suppositories, and Theravac mini-enemas, respectively (p=0.01, PGB versus HVB; p less than 0.458, PGB vs Theravac). The step
which showed the greatest variation in time requirements was time to flatus after application of the suppository or mini-enema (HBV, 32
minutes; PGB, 15 minutes; Theravac, 15 minutes; p less than 0.026, PGB vs HVB; p less than 0.983, PGB vs Theravac). Stool volume
and the number of incontinence episodes were not significantly different between the 3 therapies. Factoring in nursing time, costs of the
3 treatments were $22.60-HVB; $13.39- PGB; and $12.19-Theravac. Bowel care was performed using a consistent protocol. HVB and
PGB suppositories both contained 10 milligrams (mg) of bisacodyl. Theravac mini-enemas were polyethylene glycol-based and
contained a 4-milliliter combination of glycerine 275 mg and docusate sodium 283 mg. Patients were randomized to treatment
sequence; investigators, nurses, and patients were unaware of the type of suppository used in a bowel care session (House & Stiens,
1997).
4.6.B Carbamide Peroxide
4.6.B.1 Removal of ear wax
a) SUMMARY: Carbamide peroxide can facilitate earwax removal far better than glycerol but it is of variable efficacy compared to other
cerumenolytics (Fahmy & Whitefield, 1982; Mehta, 1985).
b) A double-blind clinical trial comparing Exterol(R) (5% carbamide peroxide) and glycerol showed significant superiority of Exterol(R)
over glycerol (Fahmy & Whitefield, 1982). All hard earwaxes treated with Exterol(R) were dispersed with ease and only 25% of the very
hard ones entailed difficult syringing whereas only 75% of the hard earwaxes treated with glycerol were removed with ease and almost
all 14 (88%) of the very hard ones entailed difficult syringing.
4.6.C Dexamethasone
4.6.C.1 Bacterial meningitis; Adjunct
a) Adjuvant therapy with oral glycerol, either alone or in combination with intravenous (IV) dexamethasone, improved severe
neurological sequelae and/or death compared to dexamethasone alone or placebo in a prospective, multicenter, randomized, doubleblind, double-dummy clinical trial in children aged 2 months through 16 years with bacterial meningitis. Meningitis was defined by the
following: a cerebrospinal fluid (CSF) culture positive for meningitis-causing bacteria, characteristic CSF findings, and positive blood
culture results or a CSF sample with a positive latex agglutination test results, and signs/symptoms compatible with bacterial meningitis.
Patients pretreated with antimicrobials were included in the study provided therapy comprised of oral or no greater than 1 parenteral
dose administration. All patients received IV ceftriaxone 80 to 100 milligrams per kilogram (mg/kg) once daily for 7 to 10 days. Patients
were randomly assigned to one of the following 4 arms: IV dexamethasone (n=166), IV dexamethasone and oral glycerol (n=159), oral
glycerol (n=166), and placebo (n=163). Both dexamethasone and glycerol (85% solution) were administered 15 minutes prior to the
ceftriaxone dose, and were dosed as 0.15 mg/kg and 1.5 grams/kilogram (1.5 milliliters/kilogram), respectively, every 6 hours for 48
hours. Nasogastric tubes were routinely used in study patients. In the event of vomiting within 30 minutes, the glycerol dose was
repeated. Neurological, developmental, and hearing sequelae assessments occurred at hospital discharge; patients with deficits were
scheduled for a follow-up visit 1-2 months later. The primary endpoints were death, severe neurological sequelae, and profound hearing
loss (determined by brain stem evoked response audiometry or traditional audiometry). Severe neurological sequelae, which included
blindness, quadriparesis or quadriplegia, hydrocephalus (requiring a shunt), or severe psychomotor retardation, was combined with
death as a composite endpoint. Assessments were performed primarily at hospital discharge. Overall, 37% of patients received prior
antibiotic therapy. At hospital discharge, 13% (n=86/654) of patients died, 8% (n=44/556) had severe neurological sequelae, and 8%
(n=43/534) had profound hearing loss. An intent-to-treat analysis revealed that the incidence of severe neurological sequelae was
significantly reduced in patients receiving glycerol alone (odds ratio (OR), 0.31; 95% confidence interval (CI), 0.13-0.76; p vs
placebo=0.01) or in combination with dexamethasone (OR, 0.39; 95% CI, 0.17-0.93; p=0.033) compared to dexamethasone alone (OR,
0.48; 95% CI, 0.21-1.07; p=0.72). Similarly, for the composite endpoint of death and severe neurological sequelae, significant
reductions occurred in the glycerol-only and dexamethasone-glycerol groups (OR, 0.44; 95% CI, 0.25-0.76; p=0.003 and OR, 0.55; 95%
CI, 0.32-0.93; p=0.027, respectively) compared to the dexamethasone-only group (OR, 0.65; 95% CI, 0.39-1.09; p=0.1). None of the
adjunctive treatments (dexamethasone, glycerol, or the combination) significantly affected death or profound hearing loss. Pretreatment
with antimicrobials, including their timing of administration with respect to study initiation, did not affect the results. The primary endpoint
results are shown in the table. A post-hoc analysis of patients with Haemophilus influenzae type b meningitis (n=181) revealed that
dexamethasone treatment prevented profound hearing loss (OR, 0.27; 95% CI, 0.09-0.77; p=0.014); however, the statistical
significance was lost when receipt of pretreatment antimicrobials was taken into account. Of the 484 patients where a causative agent
was identified, 222 were H. influenzae type b, 132 were S. pneumoniae, and 110 were N. meningitidis. Among adverse events, visible
blood in stool occurred in 5% (n=6/111), 5% (n=5/101), 1% (n=1/113), and 2% (n=2/99) of patients in the dexamethasone-only,
dexamethasone-glycerol, glycerol-only, and placebo groups, respectively. Vomiting and diarrhea were not more common in the glycerolonly group. There were no severe adverse drug events in any of the groups (Peltola et al, 2007).
Outcome
DXM and placebo (n; %)
DXM and glycerol (n; %)
Glycerol and placebo (n; %)
Placebo (n; %)
Death
23/166 (14%)
20/159 (13%)
17/166 (10%)
26/163 (16%)
Severe neurological sequelae
10/139 (7%)
8/134 (6%)
7/147 (5%)
19/136 (14%)
Severe neurological sequelae or death
33/162 (20%)
27/153 (18%)
24/164 (15%)
46/163 (28%)
Profound hearing loss
10/135 (7%)
9/132 (7%)
12/136 (9%)
12/131 (9%)
Key: DXM = dexamethasone; n = number of patients; * = determined by chi square test between 4 groups (for heterogeneity)
4.6.D Dienestrol
4.6.D.1 Atrophy of vagina
a) Dienestrol cream (0.01%) and a non-hormonal vaginal gel consisting of glycerin and mineral oil (Replens(R)) demonstrated
essentially equivalent efficacy in a randomized, 3-month study of 39 postmenopausal women with symptoms of vaginal atrophy.
Dienestrol 0.5 milligram was administered daily for 2 weeks, then 3 times weekly thereafter; the non-hormonal gel was administered 3
times weekly for the duration of the study. Vaginal dryness improved with both treatments as early as the first week, with a significant
difference in favor of dienestrol from the first week on (p less than 0.0001 to 0.0024), and other symptoms including itching, irritation,
and dyspareunia decreased for both groups, without marked intergroup differences. The non-hormonal gel may offer an adequate
alternative to estrogen for treatment of vaginal dryness (Bygdeman & Swahn, 1996).
4.6.E Xylitol
4.6.E.1 Dental caries; Prophylaxis
a) The twice daily use of a dentifrice containing xylitol and glycerin for 3 months was associated with a significantly lower level of
Streptococcus mutans in saliva compared to those individuals using a sorbitol-containing dentifrice. Streptococcus mutans are strongly
associated with the development of dental caries. Whether the use of a xylitol/glycerin dentifrice actually minimizes the development of
dental caries is unknown and further studies are required (Svanberg & Birkhed, 1991).
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