Label: DIAZOXIDE suspension

  • NDC Code(s): 0254-1010-19
  • Packager: Par Pharmaceutical, Inc
  • Category: HUMAN PRESCRIPTION DRUG LABEL

Drug Label Information

Updated September 2, 2021

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  • 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).

    DRUG INTERACTIONS

    Sincediazoxideis highly bound to serumproteins,it may displaceothersubstances whicharealso bound to protein,such as bilirubin or coumarin and its derivatives,resulting in higher blood levels of thesesubstances.Concomitantadministration of oraldiazoxideanddiphenylhydantoinmayresult in a loss of seizurecontrol.Thesepotentialinteractions must be consideredwhenadministeringDiazoxideCapsules or Suspension.

    The concomitantadministration of thiazides or othercommonlyuseddiuretics may potentiate the hyperglycemic and hyperuricemiceffects of diazoxide.

    DRUG & OR LABORATORY TEST INTERACTIONS

    The hyperglycemic and hyperuricemic effects of diazoxide preclude proper assessment of these metabolic states.Increased renin secretion,IgG concentrations and decreased cortisolsecretions have alsobeennoted.Diazoxide inhibits glucagon-stimulated insulin release and causes a false-negative insulinresponse to glucagon.

    CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY

    Nolong-termanimaldosing study has been done to evaluatethecarcinogenicpotential of diazoxide.Nolaboratory study of mutagenicpotential or animalstudyofeffects on fertility has been done.

    PREGNANCY


    PregnancyCategory C:


    Reproductionstudies using the oral preparation in rats haverevealedincreasedfetalresorptions anddelayedparturition, as well as fetalskeletalanomalies;evidence of skeletal and cardiacteratogeniceffects in rabbits has been noted withintravenous administration.The drug has alsobeendemonstrated to cross the placentalbarrier in animals and to causedegeneration of the fetalpancreaticbetacells (SeeANIMALPHARMACOLOGYAND/ORTOXICOLOGY).Sincethere 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 Diazoxide oral suspension, USP 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-teratogeniceffects:

    Diazoxidecrosses the placentalbarrier and appears in cord blood.Whengiven to the motherprior to deliveryof the infant,the drug may produce fetal or neonatalhyperbilirubinemia,thrombocytopenia,alteredcarbohydratemetabolism, and possibly other sideeffects thathaveoccurred in adults.

    Alopeciaand hypertrichosis lanuginosahaveoccurred in infants whosemothers received oral diazoxide during the last19 to 60 daysofpregnancy.

    LABOR & DELIVERY

    Since intravenous administration of the drug during labormay cause cessation of uterine contractions, and administration of oxytocic agents may be required to reinstate labor, caution is advised in administering Diazoxide oral suspension, USP 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 potentialforadverse reactions from diazoxide in nursing infants, a decision should be made whethertodiscontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

    PEDIATRIC USE

    (See INDICATIONS AND USAGE).

  • ADVERSE REACTIONS


    Frequent and Serious:

    Sodium and fluidretention is mostcommon in younginfants and in adults and may precipitatecongestiveheartfailure in patients withcompromisedcardiacreserve.Itusuallyresponds to diuretictherapy (See DRUG INTERACTIONS).

    Infrequent but Serious:
    Diabeticketoacidosis and hyperosmolarnonketoticcomamaydevelopveryrapidly.Conventionaltherapywithinsulin and restoration of fluid and electrolytebalance is usuallyeffective if instituted promptly. Prolonged surveillance is essential in view of the long half-life of Diazoxide oral suspension, USP (SeeOVERDOSAGE).


    Other frequentadversereactions:

    Hirsutism of the lanugotype,mainly on the forehead, back and limbs,occursmostcommonly in childrenandwomen and may be cosmeticallyunacceptable.Itsubsides on discontinuation of the drug.

    Hyperglycemiaor glycosuriamay require reductionindosage in order to avoidprogression to ketoacidosis or hyperosmolarcoma.

    Gastrointestinalintolerancemay include anorexia,nausea,vomiting,abdominalpain,ileus,diarrhea,transientloss of taste.

    Tachycardia,palpitations,increasedlevels of serum uric acid are common.

    Thrombocytopeniawithorwithoutpurpura may require discontinuation of the drug.Neutropenia is transient, is notassociatedwithincreasedsusceptibility to infection, and ordinarily does not requirediscontinuation of the drug.Skinrash,headache,weakness, and malaise may also occur.

    Other adversereactions whichhavebeenobservedare:

    Cardiovascular:hypotensionoccurs occasionally, which may be augmentedbythiazidediureticsgivenconcurrently. A fewcases of transienthypertension,forwhich no explanation is apparent,have been noted.Chestpainhas been reportedrarely. Pulmonary hypertension has been reported in neonates and younginfants (seeWARNINGS).

    Hematologic:eosinophilia;decreasedhemoglobin / hematocrit;excessivebleeding,decreasedIgG.
    Hepato-renal:increasedAST,alkalinephosphatase;azotemia,decreasedcreatinineclearance,reversiblenephroticsyndrome,decreasedurinary output, hematuria,albuminuria.Neurologic:anxiety,dizziness,insomnia,polyneuritis,paresthesia,pruritus,extrapyramidalsigns.

    Ophthalmologic:transientcataracts,subconjunctivalhemorrhage, ring scotoma,blurredvision,diplopia,lacrimation.Skeletal,integumentary;monilialdermatitis,herpes,advance in boneage;loss of scalp hair. Systemic:fever,lymphadenopathy.Other; goutacutepancreatitis/pancreaticnecrosis,galactorrhea,enlargement of lump in breast.

  • OVERDOSAGE

    An overdosage of Diazoxide oral suspension, USP causes marked hyperglycemia which may be associated with ketoacidosis. It will respond to prompt insulin administration and restoration of fluid and electrolyte balance. 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 normalrange.Oneinvestigatorreportedsuccessfulloweringofdiazoxidebloodlevels by peritonealdialysis in one patient and by hemodialysis in another.

  • DOSAGE & ADMINISTRATION


    Patients should be under close clinical observation when treatment with Diazoxide oral suspension, USP isinitiated. 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 Diazoxide oral suspension, USP is not effective after two or three weeks, the drug should be discontinued.

    The dosage of Diazoxide oral suspension, USP must be individualized based on the severity of the hypoglycemicconditionand the bloodglucoselevel and clinicalresponse of thepatient.Thedosageshould be adjusteduntilthedesiredclinical and laboratoryeffects are producedwiththeleastamount of the drug.Specialcareshould be taken to assureaccuracyofdosage in infants and young children.

    Adults and children:

    The usualdailydosage is 3 to 8 mg/kg,divided into two or threeequaldoses every 8 or 12 hours.Incertaininstances,patientswithrefractoryhypoglycemia may require higherdosages.Ordinarily, an appropriatestartingdosage is 3 mg/kg/day, divided intothreeequaldoses every 8 hours. Thus an average adult wouldreceive a startingdosage of approximately 200 mg daily.

    Infants and newborns: The usualdailydosage is 8 to 15 mg/kgdivided into two or threeequaldoses every 8 to 12 hours.Anappropriatestartingdosage is 10 mg/kg/day, divided into threeequaldosesevery 8 hours.

  • ANIMAL PHARMACOLOGY & OR TOXICOLOGY


    Oraldiazoxide in themouse, rat, rabbit,dog,pig, and monkey produces a rapid and transientrise in blood glucoselevels.Indogs,increasedbloodglucose is accompanied by increasedfreefattyacids,lactate, and pyruvate in theserum.Inmice, a markeddecrease in liverglycogen and an increase in the bloodureanitrogenlevel occur.

    In acute toxicitystudies theLD50for oral diazoxidesuspension is >5000mg/kg in the rat,>522mg/kg in the neonatalrat,between 1900 and 2572 mg/kg in the mouse,and219mg/kg in the guineapig.Although the oralLD50was not determined in thedog, a dosage of up to 500 mg/kgwas welltolerated.

    Insubacuteoraltoxicity studies, diazoxide at 400 mg/kg in the rat producedgrowthretardation,edema,increases in liverand kidney weights, and adrenalhypertrophy. Daily dosages up to 1080 mg/kgfor three months producedhyperglycemia, an increase in liverweightand an increase in mortality.Indogsgiven oral diazoxide at approximately 40 mg/kg/dayfor one month, no biologicallysignificantgross or microscopicabnormalities wereobserved.Cataracts,attributed to markedlydisturbedcarbohydratemetabolism,have been observed in a few dogsgivenrepeateddailydoses of oral or intravenous diazoxide. The lenticularchanges resembledthosewhichoccurexperimentally in animalswithincreasedbloodglucoselevels.Inchronictoxicitystudies, rats given a dailydose of 200 mg/kgdiazoxidefor 52 weeks had a decrease in weightgain and an increase in heart, liver,adrenalandthyroidweights.Mortalityindrug-treated and controlgroups was not different.Dogs treated withdiazoxide at dosages of 50, l00, and 200 mg/kg/dayfor 82 weeks had higher blood glucoselevels than controls.Mild bone marrow stimulation and increasedpancreasweights wereevident in thedrug-treateddogs;severaldevelopedinguinalhernias, one had a testicularseminoma,andanotherhad a mass nearthepenis.Twofemales hadinguinalmammaryswellings. The etiologyofthesechanges was not established.Therewas no difference in mortalitybetweendrug-treated and controlgroups.In a secondchronicoraltoxicitystudy,dogsgiven milled diazoxide at 50, l00, and 200mg/kg/day had anorexia and severweightloss,causing death in a few.Hematologic,biochemical, and histologicexamination did not indicate any cause of death otherthaninanition.Afteroneyear of treatment,there is no evidence of herniation or tissueswelling in any of the dogs.

    Whendiazoxidewas administered at highdosages concomitantlywitheitherchlorothiazide to rats or trichlormethiazide to dogs,increasedtoxicitywas observed.Inrats, the combinationwasnephrotoxic;epithelialhyperplasiawas observed in the collectingtubules.Indogs, a diabetic syndromewas produced whichresulted in ketosis anddeath.Neither of thedrugsgiven alone produced theseeffects.

    Although the data are inconclusive,reproduction and teratologystudies in severalspecies of animalsindicatethatdiazoxide,whenadministered during thecriticalperiod of embryoformation, may interferewithnormalfetaldevelopment,possiblythroughalteredglucosemetabolism.Parturitionwas occasionally prolonged in animals treatedatterm.Intravenous administration of diazoxide to pregnantsheep,goats, and swineproduced in the fetus an appreciableincrease in blood glucoselevel and degeneration of the betacells of the Islets of Langerhans. The reversibility of these effects was not studied.

  • HOW SUPPLIED

    Diazoxide Oral Suspension, USP 50 mg/mL, a white to light brown colored, chocolate-mint flavored suspension; bottle of 30 mL (NDC 0254-1010-19), with dropper calibrated to deliver 10, 20, 30, 40 and 50 mg diazoxide, USP.

    Shake well before each use. Protect from light. Store in carton until contents areused.Storeinlightresistantcontaineras defined in theUSP.Store Diazoxide Oral Suspension, USP at 25°C (77°F), excursions permitted to 15°-30°C (59-86°F). [See USP Controlled Room Temperature].

    Rx only

    Manufactured by:

    Novitium Pharma LLC

    70 Lake Drive, East Windsor New Jersey 08520


    Distributed by:

    Par Pharmaceutical

    Chestnut Ridge, NY 10977


    Issued: 06/2020


    OS1010-01-16-02

  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

    Carton Label for Diazoxide Oral Suspension, USP

    carton
    Container label for Diazoxide Oral Suspension, USP

    container

  • INGREDIENTS AND APPEARANCE
    DIAZOXIDE 
    diazoxide suspension
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0254-1010
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    DIAZOXIDE (UNII: O5CB12L4FN) (DIAZOXIDE - UNII:O5CB12L4FN) DIAZOXIDE50 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    SORBITOL (UNII: 506T60A25R)  
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    CARBOXYMETHYLCELLULOSE SODIUM (UNII: K679OBS311)  
    SODIUM BENZOATE (UNII: OJ245FE5EU)  
    METHYLPARABEN (UNII: A2I8C7HI9T)  
    POLOXAMER 188 (UNII: LQA7B6G8JG)  
    PROPYLPARABEN (UNII: Z8IX2SC1OH)  
    FD&C RED NO. 40 (UNII: WZB9127XOA)  
    FD&C YELLOW NO. 6 (UNII: H77VEI93A8)  
    WATER (UNII: 059QF0KO0R)  
    ALCOHOL (UNII: 3K9958V90M)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    MAGNESIUM ALUMINUM SILICATE (UNII: 6M3P64V0NC)  
    Product Characteristics
    Color    Score    
    ShapeSize
    FlavorCHOCOLATE (Chocolate-mint) Imprint Code
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:0254-1010-191 in 1 CARTON07/21/2020
    130 mL in 1 BOTTLE, DROPPER; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21079907/21/2020
    Labeler - Par Pharmaceutical, Inc (092733690)