Diazoxide (Oral-Systemic)
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VA CLASSIFICATION
Primary: HS508
Secondary: GA900
Commonly used brand name(s): Proglycem.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antihypoglycemic—
Indications
Accepted
Hypoglycemia (treatment)—Diazoxide is indicated orally for the management of hypoglycemia due to hyperinsulinism associated with inoperable islet cell adenoma or carcinoma, or extrapancreatic malignancy; leucine sensitivity; islet cell hyperplasia; nesidioblastosis; or adenomatosis. {06} {07} Diazoxide should only be used in hypoglycemia that is confirmed to be caused by hyperinsulinism unresponsive to other treatment. {06} {07}
Unaccepted
Although oral diazoxide reduces blood pressure gradually, it is not used in the chronic treatment of hypertension because of its side effects.
Diazoxide is not recommended for use in the treatment of functional hypoglycemia. {06} {07}
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Chemical group—
Diazoxide is a nondiuretic thiazide derivative. {07}
Molecular weight—
230.67 {03}
pKa—
8.5
Mechanism of action/Effect:
Hyperglycemic effect is due primarily to inhibition of insulin release from the pancreas, as well as an extrapancreatic (catecholamine-induced) effect. {06}
Absorption:
Readily absorbed following oral administration; the suspension may produce higher blood concentrations than the capsule form in some patients. {06}
Protein binding:
Very high (more than 90%) to serum proteins; {01} {06} reduced in uremia.
Biotransformation:
Hepatic.
Half-life:
Normal renal function—28 ±8.3 hours. {06} {07}
Anuria—20 to 53 hours; may also be prolonged with overdosage. {06} {07}
Onset of action:
1 hour. {06}
Duration of action:
Normal renal function— 8 hours or less. {01} {06}
Elimination:
Renal; approximately 50% unchanged. {06}
In dialysis—Diazoxide is dialyzable; {06} a higher dose or additional doses may be required when patients are being dialyzed.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients sensitive to thiazide diuretics or other sulfonamide-type medications may be sensitive to this medication also. {06} {07}
Carcinogenicity/Mutagenicity
Studies have not been done in either animals or humans. {07}
Pregnancy/Reproduction
Pregnancy—
Diazoxide crosses the placenta. Adequate studies in humans have not been done. Possible adverse effects in infants of mothers who received diazoxide include transient hyperglycemia, hyperbilirubinemia, alopecia, hypertrichosis, and thrombocytopenia.
In rats, increased fetal resorptions, fetal skeletal abnormalities, and delayed parturition were seen. In rabbits, some teratogenic (skeletal, pancreatic, and cardiac) effects have been observed. {06}
FDA Pregnancy Category C. {07}
Labor—
Diazoxide may inhibit labor, {06} although oxytocin will reverse this effect.
Breast-feeding
It is not known whether diazoxide is distributed into breast milk. However, problems in humans have not been documented. {07}
Pediatrics
Diazoxide-induced edema occurs most frequently in infants. In susceptible patients, this may lead to congestive heart failure.
The development of abnormal facial features has been reported in 4 children who were treated chronically (more than 4 years) with diazoxide for hypoglycemia due to hyperinsulinism. {08}
Geriatrics
No information is available on the relationship of age to the effects of diazoxide in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require a reduction in dosage and/or a longer dosing interval. {06}
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.
Alpha-adrenergic blocking agents,{01}{06} such as:
Labetalol
Phenoxybenzamine
Phentolamine
Prazosin
Tolazoline or
Other medications with alpha-adrenergic blocking action, such as:
Dihydroergotamine
Ergoloid mesylates
Ergotamine
Haloperidol
Loxapine
Phenothiazines
Thioxanthenes (concurrent use antagonizes the inhibition of insulin release by diazoxide)
Anticoagulants, coumarin- or indandione-derivative{01}{06} (increased anticoagulant effects may occur because of displacement of the anticoagulant from protein-binding sites; adjustment of anticoagulant dosage may be necessary)
» Anticonvulsants, hydantoin{01}{07} (concurrent use is generally not recommended since it may result in decreased efficacy of either medication)
Antigout medications (diazoxide may raise the concentration of blood uric acid; dosage adjustment of antigout medications may be necessary)
Beta-adrenergic blocking agents, ophthalmic, if significant systemic absorption occurs or
Beta-adrenergic blocking agents, systemic (concurrent use prevents diazoxide-induced tachycardia; however, risk of hypotension may be increased)
Diuretics, loop{07} or
Diuretics, thiazide{01}{06} or
Indapamide (may potentiate the antihypertensive, hyperglycemic, and hyperuricemic actions of diazoxide; when used concurrently, adjustment of diazoxide dosage may be necessary)
» Hypotension-producing medications, other, (See Appendix II ){01}{06} or
» Vasodilators, peripheral, for example, cyclandelate, hydralazine, isoxsuprine, nicotinyl alcohol, nylidrin, papaverine (concurrent use with diazoxide may result in an additive hypotensive effect, which may be severe; dosage adjustments may be necessary, and patients should be continuously observed for excessive fall in blood pressure for several hours after concurrent administration)
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
Insulin response to glucagon{07} (false-negative results {07})
With physiology/laboratory test values
Alkaline phosphatase{06} and
Aspartate aminotransferase (AST [SGOT]){06} and
Free fatty acid{06} and
Sodium and
Uric acid{06} (serum concentrations may be increased)
Blood pressure{06} (may be increased {06})
Creatinine clearance and
Electrolytes, urine, such as chloride,{06}{07} bicarbonate, potassium, and sodium{06}{07} and
Hematocrit{06} and
Hemoglobin{06} and
Immunoglobulin G (IgG), plasma{06}{07} (may be decreased)
Glucose and
Urea nitrogen (BUN){06} (blood concentrations may be increased {06})
Heart rate{06} (may be transiently increased {06})
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
» Acute aortic dissection
» Compensatory hypertension, such as that associated with aortic coarctation or arteriovenous shunt
» Coronary or cerebral insufficiency
Gout, history of or{06}
Hyperuricemia (may be exacerbated {06})
Hepatic function impairment
Hypokalemia{06} (hyperglycemic effects are potentiated {06})
» Inadequate cardiac reserve, such as uncompensated congestive heart failure{06}
Renal function impairment (half-life of diazoxide may be prolonged; reduced dosage may be necessary with frequent use {06})
Sensitivity to diazoxide, sulfonamides, or thiazides
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Aspartate aminotransferase (AST [SGOT]), serum{07} and
Creatinine clearance{07} and
Hematocrit{07} and
Leukocyte count, differential and total{07} and
Platelet count{07} and
Urea nitrogen, blood, (BUN){07} and
Uric acid, serum{07} (determinations recommended at periodic intervals during prolonged therapy)
» Glucose{06}{07} (measurement of blood or urine concentrations is recommended at periodic intervals in patients taking diazoxide until hypoglycemia is corrected and stabilized)
» Ketones (results of monitoring for ketones in urine reported by the patient to the physician provides frequent and relatively inexpensive monitoring of the condition {06} {07})
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 more frequent
Edema (decreased urination; rapid weight gain; swelling of feet or lower legs){06}
Note: Edema occurs most commonly in young infants and adults and may lead to congestive heart failure in susceptible patients.
Incidence less frequent
Tachycardia (fast heartbeat)
{06}
Incidence rare
Allergic reaction (fever; skin rash)
angina pectoris, myocardial infarction, or myocardial ischemia (chest pain{06}{07}; unexplained shortness of breath)—most commonly occurring during physical exertion
thrombocytopenia (unusual bleeding or bruising){06}
transient focal cerebral ischemic attacks (confusion; numbness of the hands)
With long-term use
Extrapyramidal effects (stiffness of limbs; trembling and shaking of hands and fingers){06}
Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
Changes in ability to taste {06}
ileus (constipation){06}{07}
loss of appetite {06}
nausea
stomach pain {06}
vomiting {06}
With long-term use
Hypertrichosis (increased hair growth on forehead, back, arms, and legs){06}
Overdose
For specific information on the agents used in the management of diazoxide overdose, see Insulin (Systemic) 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:
Hyperglycemia{06} or ketoacidosis{06} (continuing loss of appetite; drowsiness; flushed, dry skin; fruit-like breath odor; increased urination; unusual thirst)—more likely when administered during intercurrent illness{06}
Treatment of overdose
Specific treatment—Administration of insulin to treat hyperglycemia and prevent ketoacidosis. {06}
Monitoring—Monitoring the patient for up to 7 days, especially if severe hyperglycemia occurs. {06}
Supportive care—Restoration of fluid and electrolyte balance. {06} 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, Diazoxide (Oral).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to diazoxide, thiazide diuretics, or other sulfonamide-type medications
Pregnancy—Studies in animals have demonstrated teratogenicity; effects on infants born to mothers who received diazoxide may include hyperglycemia, hyperbilirubinemia, alopecia, hypertrichosis, and thrombocytopenia
Labor—May inhibit labor
Other medications, especially hydantoin anticonvulsants, other hypotension-producing medications, or peripheral vasodilators
Other medical problems, especially acute aortic dissection, compensatory hypertension, coronary or cerebral insufficiency, or inadequate cardiac reserve
Proper use of this medication
» Not taking more or less medication than the amount prescribed; taking at same time each day
» Importance of diet in helping control condition
» Testing for sugar in urine or blood, and ketones in urine
» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses
» Proper storage
Precautions while using this medication
» Regular visits to physician to check progress, especially during the first few weeks of treatment
» Caution if any kind of surgery (including dental surgery) or emergency treatment is required
» Not taking other medications, especially OTC sympathomimetics, unless discussed with physician
» Symptoms of hyperglycemia or ketoacidosis
Symptoms of hypoglycemia
Side/adverse effects
Possibility of excessive hair growth, which is reversible in several weeks or months when medication is withdrawn
Signs of potential side effects, especially edema, tachycardia, allergic reaction, angina pectoris, myocardial infarction or ischemia, thrombocytopenia, transient focal cerebral ischemic attacks, and extrapyramidal effects
General Dosing Information
Diazoxide is often administered concurrently with a diuretic to prevent congestive heart failure due to fluid retention. {06}
In some patients, the oral suspension dosage form of diazoxide produces higher blood concentrations than the capsule form; caution is recommended when a patient is switched from one dosage form to another.
Hyperglycemia is usually transient after intravenous administration of diazoxide (persisting 24 to 48 hours), but may be more persistent after prolonged oral administration and may rarely progress to ketoacidosis or hyperosmolar coma.
If diazoxide is not effective within 2 to 3 weeks in the treatment of hypoglycemia, it is recommended that therapy with the medication be re-evaluated. {01} {06} {07}
Oral Dosage Forms
DIAZOXIDE CAPSULES USP
Usual adult and adolescent dose
Antihypoglycemic
Initial: Oral, 1 mg per kg of body weight every eight hours, adjusted according to clinical response. {06} {07} {08}
Maintenance: Oral, 3 to 8 mg per kg of body weight a day, divided into two or three equal doses every twelve or eight hours, respectively. {06} {07} {08}
Usual adult prescribing limits
Oral, up to 15 mg per kg of body weight a day.
Usual pediatric dose
Antihypoglycemic
Neonates and infants:
Initial—Oral, 3.3 mg per kg of body weight every eight hours, adjusted according to clinical response. {06} {07} {08}
Maintenance—Oral, 8 to 15 mg per kg of body weight a day, divided into two or three equal doses every twelve or eight hours, respectively. {06} {07} {08}
Children:
See Usual adult and adolescent dose.
Strength(s) usually available
U.S.—
50 mg (Rx) [Proglycem]{05}
Canada—
50 mg (Rx) [Proglycem (lactose)]{06}
100 mg (Rx) [Proglycem (lactose)]{06}
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.
DIAZOXIDE ORAL SUSPENSION USP
Usual adult and adolescent dose
See Diazoxide Capsules USP.
Usual pediatric dose
See Diazoxide Capsules USP.
Strength(s) usually available
U.S.—
50 mg per mL (Rx) [Proglycem (alcohol 7.25%)]{05}{07}{08}
Canada—
50 mg per mL (Rx) [Proglycem (alcohol 7.25%) (parabens)]{06}
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 tight container. Protect from light. Protect from freezing.
Auxiliary labeling:
• Shake well before using.
Revised: 05/24/1994
References
- Proglycem (Medical Market Specialties). In: PDR Physicians' desk reference. 42nd ed. 1988. Oradell, NJ: Medical Economics Company, 1988: 1274-5.
- Not used.
- USAN/DDN 1988.
- Not used.
- Proglycem (Medical Market Specialties). In: PDR Physicians' desk reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989: 1268.
- Proglycem (Schering). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 23rd ed. Ottawa: Canadian Pharmaceutical Association, 1988: 749.
- Proglycem package insert (Schering—US), Rev 6/83, Rec 1/25/85.
- Proglycem capsules/suspension package insert (Medical Market Specialties—US), Rev 4/89, Rec 8/28/89.
- Proglycem capsules package insert (Medical Market Specialties—US), Rev 4/89, Rec 8/28/89.
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