Diazoxide

DIAZOXIDE- diazoxide suspension
Par Pharmaceutical, Inc

DESCRIPTION

Diazoxide Oral Suspension, USP is a nondiuretic benzothiadiazine derivative taken orally for the management of symptomatic hypoglycemia. The Suspension contains 50 mg of diazoxide, USP in each milliliter and has a chocolate-mint flavor; alcohol content is approximately 7.29%. Other ingredients:Sorbitolsolution,chocolate mint typeflavor,propyleneglycol,magnesiumaluminumsilicate,carboxymethycellulosesodium,sodiumbenzoate,methylparaben,poloxamer 188, propylparaben,FD&C Red No. 40, FD&CYellow No. 6 and purifiedwater.Hydrochloric acid may be added to adjustpH.
Diazoxidehas the followingstructuralformula:

structure

Diazoxideis 7-chloro-3-methyl-2H -1,2,4-benzothiadiazine1,1-dioxidewiththeempiricalformulaC8H7CIN2O2S andthemolecularweight 230.7. It is a whitepowderpracticallyinsoluble to sparinglysoluble in water.

CLINICAL PHARMACOLOGY


Diazoxideadministeredorally produces a promptdose-relatedincrease in bloodglucoselevel,dueprimarily to an inhibition of insulinreleasefromthepancreas,andalso to an extrapancreaticeffect. The hyperglycemiceffectbegins within an hour and generallylasts no more thaneight hours in the presence of normalrenalfunction.

Diazoxidedecreases theexcretion of sodium and water,resulting in fluidretentionwhichmay be clinicallysignificant.

The hypotensiveeffect of diazoxide on blood pressure is usually not marked withtheoralpreparation.This contrastswiththeintravenous preparation of diazoxide(seeADVERSEREACTIONS).

Otherpharmacologicactions of diazoxideincludeincreasedpulserate;increasedserumuricacidlevels due to decreasedexcretion;increasedserumlevels of freefattyacids’decreasedchlorideexcretion;decreasedpara-aminohippuricacid;(PAH)clearancewith no appreciableeffect on glomerularfiltrationrate.

The concomitantadministration of a benzothiazidediuretic may intensify the hyperglycemic and hyperuricemiceffects of diazoxide.Inthepresence of hypokalemia,hyperglycemiceffects are alsopotentiated.

Diazoxide-inducedhyperglycemia is reversed by the administration of insulin or tolbutamide. The inhibition of insulinrelease by diazoxide is antagonizedbyalphaadrenergicblockingagents.

Diazoxideis extensively bound (morethan 90%) to serumproteins, and is excreted in thekidneys. The plasmahalf-lifefollowingI.V.administrationis 28 ± 8.3 hours.Limited data onoraladministrationrevealed a half-life of 24 and 36 hours in twoadults.Infour children agedfour months to sixyears, the plasmahalf-lifevariedfrom 9.5 to 24 hours on long-termoraladministration. The half-life may be prolongedfollowingoverdosage, and in patients withimpaired renal function.

INDICATIONS & USAGE

Diazoxide Oral Suspension, USP is useful in the management of hypoglycemia due to hyperinsulinism associated with the following conditions:

Adults:Inoperableisletcelladenoma or carcinoma, or extrapancreaticmalignancy.

Infants and Children: Leucine sensitivity, islet cell hyperplasia, nesidioblastosis, extrapancreatic malignancy, islet cell adenoma, or adenomatosis. Diazoxide Oral Suspension, USP may be used preoperatively as a temporary measure, and postoperatively, if hypoglycemia persists.

Diazoxide Oral Suspension, USP 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 Diazoxide Oral Suspension, USP should be considered.

CONTRAINDICATIONS

The use of Diazoxide Oral Suspension, USP 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.

WARNINGS


The antidiureticproperty of diazoxidemay lead to significantfluidretention,which in patients withcompromisedcardiacreserve, may precipitatecongestive heart failure.Thefluidretentionwillrespond to conventionaltherapywithdiuretics.

Itshould be notedthatconcomitantlyadministeredthiazides maypotentiatethehyperglycemic and hyperuricemicactions of diazoxide(SeeDRUG INTERACTIONS and ANIMALPHARMACOLOGYAND/ORTOXICOLOGY).

Ketoacidosis and nonketotic hyperosmolar coma have been reported in patients treated with recommended doses of Diazoxide Oral Suspension, USP usually during intercurrent illness. Prompt recognition and treatment are essential(SeeOVERDOSAGE), and prolongedsurveillancefollowing the acuteepisode is necessarybecause of the long drug half-life of approximately 30 hours. The occurrence of theseserious events may be reduced bycarefuleducation of patients regarding the need formonitoring the urineforsugar and ketones and for prompt reporting of abnormal findings and unusualsymptoms to the physician.Transientcataracts occurred in associationwith hyperosmolarmain an infant, and subsidedoncorrection of the hyper-osmolarity.Cataracts have been observed in severalanimals receiving daily doses of intravenous or oraldiazoxide.

The development of abnormal facial features in four children treated chronically (>4 years) with Diazoxide Oral Suspension, USP for hypoglycemia hyperinsulinism in the same clinic has been reported.

Pulmonary Hypertension in Neonates and Infants

Therehavebeenpostmarketingreports of pulmonaryhypertensionoccurring in infants and neonatestreatedwithdiazoxide.Thecases werereversibleupondiscontinuation of the drug.Monitorpatients,especiallythosewithriskfactors for pulmonary hypertension,forrespiratory distress and discontinuediazoxide if pulmonaryhypertension is suspected.

PRECAUTIONS

GENERAL PRECAUTIONS

Treatment with Diazoxide Oral Suspension, USP 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.

Prolongedtreatmentrequires regularmonitoring of the urineforsugar and ketones,especially under stressconditions,withpromptreporting of any abnormalities to the physician.Additionally, blood sugarlevels should be monitoredperiodicallyby the physician to determinetheneedfordoseadjustment.

The effects of diazoxideon the hematopoieticsystem and the level of serumuricacidshould be kept in mind;thelattershould be consideredparticularly in patients withhyperuricemia or a historyofgout.

Insomepatients,higherbloodlevels havebeenobservedwith the oralsuspensionthanwith the capsuleformulation of diazoxide.Dosageshould be adjusted as necessary in individualpatients if changedfrom one formulation to the other.

Sincetheplasmahalf-lifeof diazoxide is prolonged in patients withimpairedrenalfunction, a reduceddosageshouldbe considered.Serumelectrolytelevels shouldalso be evaluatedforsuch patients.

The antihypertensive effect of other drugs may be enhanced by Diazoxide Oral Suspension, USP and this should be kept in mind when administering it concomitantly with antihypertensive agents. Because of the protein binding, administration of Diazoxide Oral Suspension, USP with coumarin or its derivatives may require reduction in the dosage of the anticoagulant, although there has been no reportedevidence of excessiveanticoagulanteffect.In addition, diazoxidemay possibly displacebilirubinfromalbumin;this should be kept in mindparticularlywhentreatingnewborns withincreasedbilirubinemia.

Pulmonaryhypertension has been reportedinneonates and younginfants treatedwithdiazoxide.(seeWARNINGS)

INFORMATION FOR PATIENTS

During treatment with Diazoxide Oral Suspension, USP 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 takethe drug on a regularschedule as prescribed, not to skipdoses, not to takeextradoses;
  • not to use this drug withothermedications unless this is done withthephysician’s advice;
  • not to allow anyoneelseto take this medication;
  • to follow dietaryinstructions;
  • to reportpromptly any adverseeffects(i.e.,increased urinary frequency,increasedthirst,fruitybreath odor);
  • to reportpregnancy or to discuss plans forpregnancy.

LABORATORY TESTS

The followingprocedures may be especiallyimportant in patientmonitoring (not necessarilyinclusive); blood glucosedeterminations (recommendedatperiodicintervals inpatients takingdiazoxideorallyfortreatment of hypoglycemia,untilstabilized);bloodureanitrogen(BUN)determinations and creatinineclearancedeterminations;hematocritdeterminations;platelet count determinations;total and differentialleukocytecounts;serumaspartateaminotransferase(AST)leveldeterminations;serumuricacidleveldeterminations; and urinetestingforglucose and ketones (in patients beingtreatedwithdiazoxideforhypoglycemia,semiquantitativeestimation of sugar and ketones in serumperformed by the patientandreported to the physicianprovides frequentandrelativelyinexpensivemonitoring of the condition).

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