PROGLYCEM®
(diazoxide) Capsules Suspension, USP
For Oral Administration
PROGLYCEM® (diazoxide) is a nondiuretic benzothiadiazine
derivative taken orally for the management of symptomatic hypoglycemia.
PROGLYCEM® Capsules contain 50 mg diazoxide, USP. The Suspension contains 50 mg
of diazoxide, USP in each milliliter and has a chocolate-mint flavor; alcohol
content is approximately 7.25%. Other ingredients: Sorbitol solution, chocolate
cream flavor, propylene glycol, magnesium aluminum silicate,
carboxymethycellulose sodium, mint flavor, sodium benzoate, methylparaben,
poloxamer 188, propylparaben, and purified water. Hydrochloric acid or sodium
hydroxide may be added to adjust pH.
Diazoxide has the following structural formula:
Diazoxide is 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine
1,1-dioxide with the empirical formula C8H7CIN2O2S and the
molecular weight 230.7. It is a white powder practically insoluble to sparingly
soluble in water.
INDICATIONS
PROGLYCEM® (ORAL
DIAZOXIDE) is useful in the management of hypoglycemia due to hyperinsulinism
associated with the following conditions:
Adults
Inoperable islet
cell adenoma or carcinoma, or extrapancreatic
malignancy.
Infants and
Children: Leucine sensitivity,
islet cell hyperplasia, nesidioblastosis, extrapancreatic malignancy, islet
cell adenoma, or adenomatosis. PROGLYCEM® may be used preoperatively as a
temporary measure, and postoperatively, if hypoglycemia persists.
PROGLYCEM® should
be used only after a diagnosis of hypoglycemia due to one of the above
conditions has been definitely established. When other specific medical therapy
or surgical management either has been unsuccessful or is not feasible,
treatment with PROGLYCEM® should be considered.
DOSAGE
AND ADMINISTRATION
Patients should be
under close clinical observation when treatment with PROGLYCEM® is initiated.
The clinical response and blood glucose level should be
carefully monitored until the patient's condition has stabilized satisfactory;
in most instances, this may be accomplished in several days. If administration
of PROGLYCEM® is not effective after two or three weeks, the drug should be
discontinued.
The dosage of
PROGLYCEM® must be individualized based on the severity of the hypoglycemic
condition and the blood glucose level and clinical response of the patient. The
dosage should be adjusted until the desired clinical and laboratory effects are
produced with the least amount of the drug. Special care should be taken to
assure accuracy of dosage in infants and young children.
Adults and
Children
The usual daily
dosage is 3 to 8 mg/kg, divided into two or three equal doses every 8 or 12
hours. In certain instances, patients with refractory hypoglycemia may require
higher dosages. Ordinarily, an appropriate starting dosage is 3 mg/kg/day,
divided into three equal doses every 8 hours. Thus an average adult would
receive a starting dosage of approximately 200 mg daily.
Infants and
Newborns
The usual daily
dosage is 8 to 15 mg/kg divided into two or three equal doses every 8 to 12
hours. An appropriate starting dosage is 10 mg/kg/day, divided into three equal
doses every 8 hours.
PROGLYCEM®
(diazoxide capsules, USP), 50 mg, half opaque orange and half clear capsules,
branded in black with BNP 6000: bottle of 100 (NDC 0575-6000-01).
PROGLYCEM®
suspension, 50 mg/mL, a chocolate-mint flavored suspension; bottle of 30 ml
(NDC0575-6200-30), with dropper calibrated to deliver 10, 20, 30, 40 and 50 mg
diazoxide. Shake well before each use. Protect from light. Store in carton
until contents are used. Store in light resistant container as defined in the
USP. Store PROGLYCEM® Capsules and Suspension at 25°C (77°F) excursions
permitted 15°-30°C (59-86°F). [See USP Controlled Room Temperature].
Distributed
by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454. Revised: Sep 2015
SIDE EFFECTS
Frequent and
Serious
Sodium and fluid
retention is most common in young infants and in adults and may
precipitate congestive heart failure in patients with
compromised cardiac reserve. It usually responds to diuretictherapy
(See DRUG INTERACTIONS).
Infrequent but
Serious
Diabetic ketoacidosis and hyperosmolar
nonketotic coma may develop very rapidly. Conventional therapy with insulin and restoration of
fluid and electrolyte balance is usually
effective if instituted promptly. Prolonged surveillance is essential in view
of the long half-life of PROGLYCEM® (SeeOVERDOSAGE).
Other Frequent
Adverse Reactions
Hirsutism of the lanugo type,
mainly on the forehead, back and limbs, occurs most commonly in children and women
and may be cosmetically unacceptable. It subsides on discontinuation of the
drug.
Hyperglycemia or glycosuria may
require reduction in dosage in order to avoid progression to ketoacidosis or
hyperosmolar coma.
Gastrointestinal intolerance may
include anorexia, nausea, vomiting,
abdominal pain, ileus, diarrhea,
transient loss of taste.
Tachycardia, palpitations, increased levels of serum
uric acid are common.
Thrombocytopenia with or without purpura may
require discontinuation of the drug. Neutropenia is
transient, is not associated with increased susceptibility to infection, and
ordinarily does not require discontinuation of the drug. Skin rash, headache,
weakness, and malaise may also occur.
Other Adverse
Reactions Which Have Been Observed Are
Cardiovascular: hypotension occurs occasionally,
which may be augmented by thiazide diuretics given concurrently. A few cases of
transient hypertension, for which no explanation
is apparent, have been noted. Chest pain has been reported rarely. Pulmonary hypertension has been reported in
neonates and young infants (see WARNINGS).
Hematologic: eosinophilia;
decreased hemoglobin / hematocrit;
excessive bleeding, decreased IgG.
Hepato-renal: increased
AST, alkaline phosphatase; azotemia, decreased
creatinine clearance, reversible nephrotic syndrome, decreased urinary
output, hematuria, albuminuria.
Neurologic: anxiety, dizziness, insomnia, polyneuritis, paresthesia, pruritus,
extrapyramidal signs.
Ophthalmologic: transient
cataracts, subconjunctival hemorrhage,
ring scotoma, blurred vision, diplopia, lacrimation.
Skeletal, integumentary; monilial dermatitis, herpes, advance in bone age; loss
of scalp hair. Systemic: fever, lymphadenopathy.
Other; gout acute pancreatitis/pancreatic necrosis, galactorrhea,
enlargement of lump in breast.
Since diazoxide is
highly bound to serum proteins, it may displace other substances which are also
bound to protein, such as bilirubin or coumarin and its derivatives, resulting
in higher blood levels of these substances. Concomitant administration of oral
diazoxide and diphenylhydantoin may result in a loss of seizure control. These
potential interactions must be considered when administering PROGLYCEM®
Capsules or Suspension.
The concomitant
administration of thiazides or other commonly used diuretics may potentiate the
hyperglycemic and hyperuricemic effects of diazoxide.
Drug/Laboratory
Test Interactions
The hyperglycemic
and hyperuricemic effects of diazoxide preclude proper assessment of these
metabolic states. Increased renin secretion, IgG concentrations and
decreased cortisol secretions
have also been noted. Diazoxide inhibits glucagon-stimulated insulin release
and causes a false-negative insulin response to glucagon.
WARNINGS
The antidiuretic
property of diazoxide may lead to significant fluid retention, which in
patients with compromised cardiac reserve, may precipitate congestive heart failure. The fluid retention will
respond to conventional therapy with diuretics.
It should be noted
that concomitantly administered thiazides may potentiate the hyperglycemic and
hyperuricemic actions of diazoxide (See DRUG INTERACTIONS and Animal Pharmacology And/Or Toxicology).
Ketoacidosis and nonketotic
hyperosmolar coma have been reported in patients treated with recommended doses
of PROGLYCEM® usually during intercurrent illness. Prompt recognition and
treatment are essential (See OVERDOSAGE), and prolonged surveillance following
the acute episode is necessary because of the long drug half-life of
approximately 30 hours. The occurrence of these serious events may be reduced
by careful education of patients regarding the need for monitoring the urine
for sugar and ketones and for prompt reporting of abnormal findings and unusual
symptoms to the physician. Transient cataracts occurred in association with
hyperosmolar coma in an infant, and subsided on correction of the
hyper-osmolarity. Cataracts have been observed in several animals receiving
daily doses of intravenous or oral diazoxide.
The development of
abnormal facial features in four children treated chronically ( > 4 years)
with PROGLYCEM® for hypoglycemia hyperinsulinism in the same clinic has been
reported.
Pulmonary
Hypertension In Neonates And Infants
There have been
postmarketing reports of pulmonary hypertension occurring in infants and
neonates treated with diazoxide. The cases were reversible upon discontinuation
of the drug. Monitor patients, especially those with risk factors for pulmonary hypertension, for respiratory distress
and discontinue diazoxide if pulmonary hypertension is suspected.
General
Treatment with
PROGLYCEM® should be initiated under close clinical supervision, with careful
monitoring of blood glucose and clinical response
until the patient's condition has stabilized. This usually requires several
days. If not effective in two to three weeks, the drug should be discontinued.
Prolonged treatment
requires regular monitoring of the urine for sugar and ketones, especially
under stress conditions, with
prompt reporting of any abnormalities to the physician. Additionally, blood
sugar levels should be monitored periodically by the physician to determine the
need for dose adjustment.
The effects of
diazoxide on the hematopoietic system and the level
of serum uric acid should be kept in
mind; the latter should be considered particularly in patients with hyperuricemia or
a history of gout.
In some patients,
higher blood levels have been observed with the oral suspension than with the
capsule formulation of PROGLYCEM®. Dosage should be adjusted as necessary in
individual patients if changed from one formulation to the other.
Since the plasma
half-life of diazoxide is prolonged in patients with impaired renal function, a
reduced dosage should be considered. Serum electrolyte levels should also be evaluated
for such patients.
The antihypertensive effect of other drugs
may be enhanced by PROGLYCEM®, and this should be kept in mind when
administering it concomitantly with antihypertensive agents.
Because of the
protein binding, administration of PROGLYCEM® with coumarin or its derivatives
may require reduction in the dosage of the anticoagulant, although there has been no
reported evidence of excessive anticoagulant effect. In addition, PROGLYCEM®
may possibly displace bilirubin from albumin; this should be kept in
mind particularly when treating newborns with increased bilirubinemia.
Pulmonary
hypertension has been reported in neonates and young infants treated with
diazoxide. (see WARNINGS)
Laboratory
Tests
The following
procedures may be especially important in patient monitoring (not necessarily
inclusive); blood glucose determinations (recommended at periodic intervals in
patients taking diazoxide orally for treatment of hypoglycemia, until
stabilized); blood urea nitrogen (BUN) determinations and creatinine
clearance determinations; hematocrit determinations; platelet count determinations; total
and differential leukocyte counts; serum aspartate aminotransferase (AST) level
determinations; serum uric acid level determinations; and urine testing for glucose
and ketones (in patients being treated with diazoxide for hypoglycemia,
semiquantitative estimation of sugar and ketones in serum performed by the
patient and reported to the physician provides frequent and relatively
inexpensive monitoring of the condition).
Carcinogenesis,
Mutagenesis, Impairment Of fertility
No long-term animal
dosing study has been done to evaluate the carcinogenic potential of
diazoxide. No laboratory study of mutagenic potential or animal study of
effects on fertility has been done.
Pregnancy
Category C
Reproduction
studies using the oral preparation in rats have revealed increased fetal
resorptions and delayed parturition, as well as fetal skeletal
anomalies; evidence of skeletal and cardiac teratogeniceffects
in rabbits has been noted with intravenous administration. The drug has also
been demonstrated to cross the placental barrier in animals and to cause
degeneration of the fetal pancreatic beta cells (See Animal Pharmacology And/Or Toxicology). Since there are no
adequate data on fetal effects of this drug when given to pregnant women,
safety in pregnancy has not been established. When the use of PROGLYCEM® is
considered, the indications should be limited to those specified above for
adults (See INDICATIONS AND USAGE), and the potential benefits to the
mother must be weighed against possible harmful effects to the fetus.
Non-teratogenic
Effects
Diazoxide crosses
the placental barrier and appears in cord blood. When given to the mother
prior to delivery of the infant, the drug may produce fetal or neonatal hyperbilirubinemia, thrombocytopenia, altered carbohydrate
metabolism, and possibly other side effects that have occurred in adults.
Alopecia and hypertrichosis
lanuginosa have occurred in infants whose mothers received oral diazoxide
during the last 19 to 60 days of pregnancy.
Labor And
Delivery
Since intravenous
administration of the drug during labor may cause cessation of uterine
contractions, and administration of oxytocic agents may be required to
reinstate labor, caution is advised in administering PROGLYCEM® at that time.
Nursing Mothers
Information is not
available concerning the passage of diazoxide in breast milk. Because many
drugs are excreted in human milk and because of the potential for adverse
reactions from diazoxide in nursing infants, a decision should be made whether
to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
OVERDOSE
An overdosage of
PROGLYCEM® causes marked hyperglycemia which may be associated
with ketoacidosis. It
will respond to prompt insulin administration and
restoration of fluid and electrolytebalance.
Because of the drug's long half-life (approximately 30 hours), the symptoms of
overdosage require prolonged surveillance for periods up to seven days until
the blood sugar level stabilizes within the normal range. One investigator
reported successful lowering of diazoxide blood levels by peritoneal dialysis in one patient and by hemodialysis in
another.
The use of
PROGLYCEM® for functional hypoglycemia is contraindicated. The drug should not
be used in patients hypersensitive to diazoxide or to other thiazides unless
the potential benefits outweigh the possible risks.
CLINICAL
PHARMACOLOGY
Diazoxide
administered orally produces a prompt dose-related increase in blood glucose level, due primarily
to an inhibition of insulin release from the
pancreas, and also to an extrapancreatic effect.
The hyperglycemic
effect begins within an hour and generally lasts no more than eight hours in
the presence of normal renal function.
PROGLYCEM®
decreases the excretion of sodium and water, resulting in fluid retention which
may be clinically significant.
The hypotensive effect
of diazoxide on blood pressure is usually not marked with the oral preparation.
This contrasts with the intravenous preparation of diazoxide (see ADVERSE REACTIONS).
Other pharmacologic
actions of PROGLYCEM® include increased pulse rate; increased serum
uric acid levels due to decreased excretion; increased serum levels of
free fatty acids' decreased chloride
excretion; decreased para-aminohippuric acid; (PAH) clearance with no appreciable effect
on glomerular filtration rate.
The concomitant
administration of a benzothiazide diuretic may intensify the
hyperglycemic and hyperuricemic effects of PROGLYCEM®. In the presence of hypokalemia,
hyperglycemic effects are also potentiated.
PROGLYCEM®-induced hyperglycemia is reversed by the
administration of insulin or tolbutamide. The inhibition of insulin release by
PROGLYCEM® is antagonized by alphaadrenergic blocking agents.
PROGLYCEM® is
extensively bound (more than 90%) to serum proteins, and is excreted in the
kidneys. The plasma half-life following I.V. administration is 28 ± 8.3 hours.
Limited data on oral administration revealed a half-life of 24 and 36 hours in
two adults. In four children aged four months to six years, the plasma
half-life varied from 9.5 to 24 hours on long-term oral administration. The
half-life may be prolonged following overdosage, and in patients with impaired
renal function.
Animal
Pharmacology And/Or Toxicology
Oral diazoxide in
the mouse, rat, rabbit, dog, pig, and monkey produces a rapid and transient
rise in blood glucose levels. In dogs, increased blood glucose is accompanied
by increased free fatty acids, lactate, and pyruvate in the serum. In mice, a
marked decrease in liver glycogen and an increase in the blood urea nitrogen level occur.
In acute toxicity
studies the LD50 for oral diazoxide suspension is > 5000 mg/kg in the rat,
> 522 mg/kg in the neonatal rat, between 1900 and
2572 mg/kg in the mouse, and 219 mg/kg in the guinea pig. Although the oral LD50 was
not determined in the dog, a dosage of up to 500 mg/kg was well tolerated.
In subacute oral
toxicity studies, diazoxide at 400 mg/kg in the rat produced growth
retardation, edema, increases in liver and kidney weights, and adrenal
hypertrophy. Daily dosages up to 1080 mg/kg for three months produced
hyperglycemia, an increase in liver weight and an increase in mortality. In
dogs given oral diazoxide at approximately 40 mg/kg/day for one month, no
biologically significant gross or microscopic abnormalities were
observed. Cataracts, attributed to markedly disturbed carbohydrate metabolism,
have been observed in a few dogs given repeated daily doses of oral or
intravenous diazoxide. The lenticular changes resembled those which occur
experimentally in animals with increased blood glucose levels. In chronic
toxicity studies, rats given a daily dose of 200 mg/kg diazoxide for 52 weeks
had a decrease in weight gain and an increase in heart, liver, adrenal
and thyroidweights.
Mortality in drug-treated and control groups was not different. Dogs treated
with diazoxide at dosages of 50, l00, and 200 mg/kg/day for 82 weeks had higher
blood glucose levels than controls. Mild bone marrow stimulation and
increased pancreas weights were evident in the drug-treated dogs; several
developed inguinal hernias, one had a testicular seminoma, and another had a
mass near the penis. Two females had inguinal
mammary swellings. The etiology of these changes was
not established. There was no difference in mortality between drug-treated and
control groups. In a second chronic oral toxicity study, dogs given milled
diazoxide at 50, l00, and 200 mg/kg/day had anorexia and sever weight loss,
causing death in a few. Hematologic, biochemical, and histologic examination
did not indicate any cause of death other than inanition. After one year of
treatment, there is no evidence of herniation or
tissue swelling in any of the dogs.
When diazoxide was
administered at high dosages concomitantly with either chlorothiazide to rats
or trichlormethiazide to dogs, increased toxicity was observed. In rats, the
combination was nephrotoxic;
epithelial hyperplasia was observed in the collecting tubules. In dogs, a
diabetic syndrome was produced which resulted in ketosis and death. Neither of
the drugs given alone produced these effects.
Although the data
are inconclusive, reproduction and teratology studies in several species of
animals indicate that diazoxide, when administered during the critical period
of embryo formation, may interfere with normal fetal development, possibly
through altered glucose metabolism. Parturition was occasionally
prolonged in animals treated at term. Intravenous administration of diazoxide
to pregnant sheep, goats, and swine produced in the fetus an appreciable
increase in blood glucose level and degeneration of the beta cells of the Islets of Langerhans. The reversibility of these
effects was not studied.
PATIENT
INFORMATION
During treatment
with PROGLYCEM® the patient should be advised to consult regularly with the
physician and to cooperate in the periodic monitoring of his condition by
laboratory tests. In addition, the patient should be advised:
to take the drug on a regular
schedule as prescribed, not to skip doses, not to take extra doses;not to use this drug with other
medications unless this is done with the physician's advice;not to allow anyone else to take this
medication;to follow dietary instructions;to report promptly any adverse
effects (i.e., increased urinary frequency, increased thirst, fruity
breath odor);to report pregnancy or to discuss
plans for pregnancy.
