Hypercalcemia (1 of 9)

1 Routine blood test reveals hypercalcemia or patient presents w/ signs & symptoms which suggest hypercalcemia

2 DIAGNOSIS Is hypercalcemia parathyroid-dependent or parathyroid- independent?

Parathyroid-dependent Parathyroid-independent hypercalcemia hypercalcemia

3 TREATMENT TREATMENT DECISION See next page Should patient be treated surgically?

Yes No

A Parathyroidectomy B Measures to lower serum calcium • In asymptomatic patients C Pharmacological therapy • Estrogen replacement in menopausalMIMS patients

D © Follow-up

Not all products are available or approved for above use in all countries. Specifi c prescribing information may be found in the latest MIMS.

B127 © MIMS 2019 HYPERCALCEMIA C B • • • Hypercalcemia More Severe • Hypercalcemia Mild &Symptoms Signs • • HYPERCALCEMIA HYPERCALCEMIA • OF MALIGNANCY severe hypercalcemia severe Usually as presents Pharmacological therapy Pharmacological calcium serum tolower Measures - Coma - - Lethargy - Depression - Weakness - Milddrowsiness - Neurological groans” & stones moans, abdominal “bones, econstellation as manifestations ofclinical are commonly described rise levels Ca serum as Symptoms more severe usuallybecome Usually asymptomatic - >10.5mg/dL(>2.5mmol/L) Ca Serum Hypercalcemia: 8-10mg/dL(2-2.5mmol/L) level: Ca serum Normal • • • • hyporefl exia Hypotonia, Stupor albumin<4g/dL 1g/dLdrop inserum forevery level foralbuminconcentration, corrected level Ca Ca Use adding0.8 total mg/dL totheserum by totalserum © Corticosteroid hormones Calcitonin diuretics Loop Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing • - Peptic ulcer disease Peptic ulcer disease - Anorexia - &vomiting Nausea - Constipation - Gastrointestinal (PUD) PARATHYROID INDEPENDENT 1 Hypercalcemia (2of9) HYPERCALCEMIA HYPERCALCEMIA Determine etiology Determine INTOXICATION DIAGNOSIS

B128 MIMS 2 • Dehydration - nocturia Polyuria, - Nephrocalcinosis - Nephrolithiasis - - Nephrogenic - Renal filtration rate (GFR) glomerular Decreased (DI) insipidus diabetes C B Pharmacological therapy Pharmacological calcium serum tolower Measures • Corticosteroid hormones • Cardiomyopathy - Hypertension - - Hypotension - Shortened - Increased - Cardiovascular GRANULOMATOUS GRANULOMATOUS arrhythmias Syncope from ventricular systole contractility myocardial • eg Sarcoidosiseg DISEASES © MIMS 2019 HYPERCALCEMIA • • Hypercalcemia Parathyroid-Independent • Hypercalcemia Parathyroid-Dependent Etiologies • • (Cr)Excretion &Creatinine Calcium Urinary 24-hour Measure • • • Parathyroid Hormone (PTH) Serum Measure • Results Chemistry Routine Prior Review Exam, Physical History, Detailed Obtain • Confi Hypercalcemia rm Tests,Lab &History Exam Physical • • • • Increased vitamin D/1,25(OH) vitamin Increased metastases Multiple myeloma &osteolytic - Other humoral syndromes - Parathyroid (PTHrP)-dependent hormone-related peptide - Malignancy syndrome (MEN) hyperparathyroidism neoplasia ofmultiple are part endocrine primary Some - ofhypercalcemia cause Leading - hyperparathyroidism Primary - - hypercalcemia preferable hypocalciuric tobe familial indiagnosing clearance oftheCalculation Ca/Cr ratio isbelieved excretion islow Ca the urinary hypercalcemia, In patients hypocalciuric w/familial ofhypercalcemia for unusual search causes isnotpresent, Ifmalignancy - known) be already will malignancy Evaluate (many patient times, formalignancy - parathyroid parathyroid-independent serum suggests hormone hypercalcemia Low-undetectable Diagnosis: - hyperparathyroidism primary orinappropriately parathyroid serum w/hypercalcemia normal hormone usuallyindicates Elevated Diagnosis: Immunoassays specifi (intact ispreferred parathyroid usingdoubleantibody c for intact molecules hormone) use diuretic orthiazide Lithium - Vitamin &mineral ingestion - Fatigue - pain Bone - Weight loss - Fractures - stones kidney Past - Inquire about: twice at least Ca &ionized Ca totalserum Measure - diuretics iazide - Milk-alkali syndrome - Vitamin A - Medications Immobilization Adrenal insuffi (AI) ciency yrotoxicosis Williams syndrome - Granulomatous disease - intoxication Calcitriol - Topical Danalogues vitamin - Vitamin Dingestion - patients w/hyperparathyroidism whilearatio of>0.02ispresent hypercalcemia, in hypocalciuric A ratio familial of<0.01usuallyindicates Cr] x24-hrurine CA [Serum &Crconcentrations Cr]/ Ca xserum clearance Ca/Cr ratio CA formula: =[24-hrurine usingthe below totalserum collection measured &simultaneously of24-hoururine the from eratio results iscalculated malignant neoplasm Exceptions: Familialhypocalciurichypercalcemia(FHH),autonomousparathyroidsecretion&rarelyectopic eophylline © Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing 2 D Hypercalcemia (3of9) 2 DIAGNOSIS

B129 MIMS © MIMS 2019 HYPERCALCEMIA • • • • • • • - Cr - >400mg/24hr Ca Urinary - limitofnormal upper >0.25mmol/L(1mg/dL)above Ca Serum - present: hyperparathyroidism ifany are ofthe patients following forasymptomatic w/primary isindicated Surgery hyperparathyroidism istheSurgery treatment ofchoice orcomplications forpatients symptoms w/classic ofprimary parathyroidectomy: to facilitate targeted or minimally invasive are used e following isthe Surgery onlypermanent cure - management arguments are medical some against compliance follow-up Cost, &long-term - management surgical vs hypercalcemic patientsControversy ofmedical ofasymptomatic hyperparathyroidism An optionforpatients w/primary Complications: VocalComplications: permanent hypoparathyroidism cord paralysis, Eff ects: hormone &intraoperative measurement ofcirculating ultrasound intact parathyroid localization, for preoperative nephrocalcinosis or severe psychoneurologic disorder psychoneurologic nephrocalcinosis or severe W/ complicationsofprimaryhyperparathyroidismincludingosteoporosis(Tscore<-2.5SDatanysite), Patient old <50years - Cl reduced by >30% by reduced 95% of patients achieve normocalcemia if performed by experienced surgeon &pathologist experienced by ifperformed normocalcemia 95% ofpatients achieve 3 © TREATMENT DECISION - INDICATIONS FOR SURGERY A PARATHYROIDECTOMY Hypercalcemia (4of9)

B130 MIMS 99m Tc-sestamibi scanning © MIMS 2019 HYPERCALCEMIA • • • • unsuccessful: proves If diuresis • • • • Fluids • • • Hypercalcemia Severe Acute • • • • Hypercalcemia Asymptomatic Mild • • Diuretics Loop Hypercalcemia Severe Acute • Bisphosphonates • • Replacement Estrogen Hyperparathyroidism Primary • Add phosphate supplements ifnecessary todiet - Phosphate concentration monitored tobe needs 0.7-3mmol/L(3-12mg/dL) by lowered may Ca be Serum - Eff in24-48hours remove 5-12.5mmol(200-500mg)ofCa can dialysis peritoneal Ca-free ofdialysis: ects inCa oforlow bath free Dialysis shouldbe isthe treatmentHemodialysis ofchoice prevented tobe K &Mg needs depletion toimprove diuresis added may diuretic be Loop - calciuria increase NaCl0.9%at which will 2-6L/day IV Infuse - >3mmol/L(12mg/dL) Ca If serum liquids Ca serumCa>2.8mmol/L(11.2mg/dL),patientneedstobeinstructeddrink2-3L/dayoflow If concentrating urinary Patient inanitionordefective ability isusuallydehydrated vomiting, from - hydration normal Restore hyperparathyroidism benefi will Primary surgery immediate t from treatment Ca-lowering shouldoccur whileaggressive isinitiated testing Diagnostic the tocatheterize bladder may need Monitorcentral electrolytes, orurine venous pressure, plasma - ifusingforced diuresis Monitor patient especially setting closely preferably inICU toasurgeon referred immediately shouldbe they If patient symptomatic, becomes - Maintain adequate hydration - Avoid immobilization prolonged - patientCounsel to: Patient shouldavoid alldiuretics - Stop any that medications may diuretics hypercalcemia thiazide cause eg - Ca serum todecrease measures Start or nosymptoms inmild which results hyperparathyroidism have hypercalcemia, often mild&prolonged Patients w/primary - Urine Ca excretion Urine may Ca >25mmol/dL exceed - 24hours ≥1mmol/L(4mg/dL)within by may Ca decrease Serum - eff calciuretic Direct (Furosemide w/highdoses 100mg/hr) achieved may be ects - Eff ects: patient’s aggressivelyAdminister as as status cardiac allow will Further studyisneededtoproveusefulnessinmildhypercalcemiacausedbyprimary hyperparathyroidism loss bone against Protects women,In postmenopausal estrogen replacement w/noeff Ca may serum lower onparathyroidect hormone hyperparathyroidism primary ere isnoconvincing the eff data tosupport management therapy inlong-term ofmedical of ectiveness vomiting ordiarrhea attentionPatient medical immediate that forillness shouldseek may severe dehydration cause especially © Stimulates which natriuresis isaccompanied calciuresis by Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not B Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing MEASURES TO LOWER SERUM CALCIUM CALCIUM SERUM LOWER TO MEASURES C PHARMACOLOGICAL THERAPY Hypercalcemia (5of9)

B131 MIMS © MIMS 2019 HYPERCALCEMIA • • • • • • Cinacalcet forHypercalcemia Drugs Other • • Diseases Granulomatous • • • Vitamin DIntoxication • • • • Hormones Corticosteroid • • • Calcitonin • • • • Bisphosphonates (Cont’d) Hypercalcemia Severe Acute • • • Medically Patient Managed Hyperparathyroidism Primary • • PatientPost-parathyroidectomy impairment It therapy anoptioninpatients isalso renal inwhomIV iscontraindicated duetosevere bisphosphonate therapy Studies that have shown itiseff to forthe managementective refractory ofhypercalcemia ofmalignancy (RANKL) ligand ofnuclear kappa-beta activator receptor against factor directed antibody A monoclonal levels Ca ofserum normalization prolonged have trials shown Clinical parathyroid Ca inconcomitant inserum gland; results decrease onthe receptor oftheIt the Ca-sensing sensitivity parathyroid increasing directlylowers by levels hormone agentA calcimimetic forhypercalcemic patients indicated w/parathyroid carcinoma intake &vitamin Ca Limit Avoid excessive sunlight exposure Ensure adequate hydration intake Ca dietary Restrict Discontinue D vitamin Eff Dintoxication vitamin by intreating &sarcoidosis hypercalcemiaective caused cancer &Hodgkin’s disease Benefi breast multiple leukemia, myeloma, malignancies, certain by osteolytic inhypercalcemia caused t isseen Eff ects: eff have May cytolytic also adirect tumor cells onsome ect - balance skeletal Ca negative Cause - absorption Actions: take effect incombinationMay use w/rehydration the within &salinediuresis 1st24 hoursoftreatment until bisphosphonates Ca ofserum Minimallowering - Eff ects: renal reabsorption tubular Ca Actions: side effects oughrelated structurally, diff bisphosphonates er inpotency, effi (depending isprolonged onagent, Normocalcemia foramonth may be orlonger) - cacy, route ofadministration, toxicity & Eff ects: resorption bone forhypercalcemiaUseful duetoenhanced osteoclastic resorption High affiActions: turnover where inhibit bone bone they of increased in areas especially nity for bone Perform yearly abdominal radiographs, urinary Ca & bone mineral density (BMD)tests &bone Ca urinary Perform radiographs, abdominal yearly BP,Measure &Crat visit each Ca serum Follow 6months uppatient every density bone supplement Ca to increase Give for≥1year toavoid orhypercalcemia Ca hypo- &urine Monitor serum Hypocalcemic eff Hypocalcemic days several over develops ect hoursofadministration afew within seen be Can days onagent toreach may normocalcemia takeafew Depending used Blocks bone resorption through receptors on osteoclasts, increases urinary Ca excretion by blocking excretion blocking by Ca urinary increases through on receptors osteoclasts, resorption bone Blocks © inintestinal Ca excretion &decrease Ca inurinary anincrease cause doses In pharmacologic Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not C Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing PHARMACOLOGICAL THERAPY (CONT’D) Hypercalcemia (6of9) D FOLLOW-UP

B132 MIMS © MIMS 2019 HYPERCALCEMIA clodronate) Disodium (Clodronate, acid Clodronic incadronate) Disodium (Incadronate, acid Incadronic (Ibandronate) (Etidronate) Drug Products listed above may not be mentioned in the disease management chart but have been have but chart management disease the in mentioned be not may above listed Products placed here based on indications listed in regional manufacturers’ product information. product manufacturers’ regional in listed indications on based here placed & non-elderly adults w/ normal renal & hepatic function unless otherwise stated. otherwise unless function &hepatic renal w/ normal adults & non-elderly All dosage recommendations are for non-pregnant & non-breastfeeding women, women, &non-breastfeeding non-pregnant for are recommendations dosage All

© 2wk 2-4 hrxevery over infusion 10 mgIV respond patient not does if repeated may be Dose single dose a 2hras over 4 mgIV ≥3mmol/L: Ca Serum single dose a 2hras over 2 mgIV <3mmol/L: Ca Serum hr once dailyx3-7days 2-4 over 7.5 mg/kgIV 10days duration: Max once dailyx3-5days 2-4hr over 300 mgIV or 2-3 doses 24hrly x 1.6 -2.4gPO Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing Dosage Dosage Guidelines Hypercalcemia (7of9) BISPHOSPHONATES • Instructions Special • Reactions Adverse • Instructions Special • Reactions Adverse • s • t c ffe E • • Instructions Special • Reactions Adverse • • s • t c ffe E • • • Instructions Special • Reactions Adverse B133 condition, cardiac disease &the elderlycondition, disease cardiac generalUse w/ caution inrenal impairment, poor MIMSFever, disorder consciousness hypotension, treatment phosphate, Mg during &renal function Monitor Ca, s t c ff e e impairment quickly,function too ifadministered GI fl renal disturbances, electrolyte u-like symptoms, & fever including reactions thrombophlebitis, Local effHypocalcemic for3-4wk last ects 1wk within isusuallyreached Normocalcemia Use w/caution inpatients w/renal impairment 2-3 days oftreatment toavoid hypocalcemia quicklyInterrupt therapy the within too drops 1st ifCa s t c ff e e impairmentrenal quickly, function too ifadministered GI chronic therapy toosteomalacia, Cr; lead can in serum transient including reactions rise thrombophlebitis, Local resorption formation alongw/blocking bone Inhibits effHypocalcemic forweeks last ects dayreach nadirby 7 day by 2ofadministration tofall & start levels Ca Serum administration IV during phosphate &CBC Ca, renal function, Suggest liver enzymes, monitoring Avoid renal impairment in patients w/moderate-severe taken onanemptyOral preparation shouldbe stomach impairment quickly, too ifadministered GIeffects renal function disturbances, electrolyte reactions, Local Remarks © MIMS 2019 HYPERCALCEMIA (Zoledronate) acid Zoledronic pamidronate) Disodium (Pamidronate, salmon) (Calcitonin Calcitonin Drug Drug Products listed above may not be mentioned in the disease management chart but have been have but chart management disease the in mentioned be not may above listed Products placed here based on indications listed in regional manufacturers’ product information. product manufacturers’ regional in listed indications on based here placed & non-elderly adults w/ normal renal & hepatic function unless otherwise stated. otherwise unless function &hepatic renal w/ normal adults & non-elderly All dosage recommendations are for non-pregnant & non-breastfeeding women, women, &non-breastfeeding non-pregnant for are recommendations dosage All 7 days ifnoresponse after repeated may be Dose asingledose as 15min at over least 4 mgIV response in3-7days response ifno repeated may be Dose 4hr over 90 mgIV ofinfusion: rate Max 2-4 days over doses ordivided dose single as given be can Dose 90 mgIV >4mmol/L: Ca Serum 60-90 mgIV 3.5-4mmol/L: Ca Serum 30-60 mgIV 3-3.5mmol/L: Ca Serum 15-30 mgIV <3mmol/L: Ca Serum ©inj IV slow by given 2-4 doses in divided 5-10 iu/kg/day IV hrly or 5-10 IU Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing /kg IV over 6hr24 over /kg IV Dosage Dosage BISPHOSPHONATES (CONT’D) Dosage Guidelines Hypercalcemia (8of9) CALCITONIN

B134 MIMS • • Instructions Special • Reactions Adverse • s • t c ffe E • • Instructions Special • Reactions Adverse • s • t c ffe E • Reactions Adverse • therapy phosphate &Mg during Ca, Monitor renal function, impairmentrenal function inpatients foruse Not recommended w/severe eff rarely pain &chest rash ects, impairment quickly,function too ifadministered GI fl renal disturbances, electrolyte u-like symptoms, & fever including reactions thrombophlebitis, Local effHypocalcemic for30-40days last ects single dose 4-7days usuallyoccurs within of Normocalcemia therapy &phosphate during Ca Monitor electrolytes, impairment orrenal disease Use w/caution inpatients w/CV eff eff rarely CNS ects, (eg agitation, confusion) ects impairment quickly,function too ifadministered GI fl renal disturbances, electrolyte u-like symptoms, & fever including reactions thrombophlebitis, Local effHypocalcemic foramth last ects 1wkofsingledose within administration usuallyoccurs &normocalcemia 1-2days of todecrease starts Ca Serum abdominal pain),flabdominal ushing Transient GIeff inj after (N/V,ects diarrhea, hypercalcemic crisis administration in anacute ispreferred IV Remarks Remarks © MIMS 2019 HYPERCALCEMIA Cinacalcet acid Ethacrynic 200-300mgIV Hydrocortisone Denosumab Denosumab Furosemide 40-100mgPO Prednisolone a as 4-48mgPO Methylprednisolone Drug Drug Drug Products listed above may not be mentioned in the disease management chart but have been have but chart management disease the in mentioned be not may above listed Products placed here based on indications listed in regional manufacturers’ product information. product manufacturers’ regional in listed indications on based here placed & non-elderly adults w/ normal renal & hepatic function unless otherwise stated. otherwise unless function &hepatic renal w/ normal adults & non-elderly All dosage recommendations are for non-pregnant & non-breastfeeding women, women, &non-breastfeeding non-pregnant for are recommendations dosage All © 30 mg PO 12-24 hrly 30 mgPO dose: Initial 1-2hr every 40 mgIV 24 hrly x 3-5 days 4 wk mg SC24hrly every en onday 29:120 days 1,8,&15 120 mgSC24hrly on dose: Initial 1-2hr every 100 mgIV 24 hrly x 3-5 days doses divided orin single dose Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing Please see the end of this section for the reference list. reference the for section this of end the see Please Dosage Dosage Dosage CORTICOSTEROID HORMONES Dosage Guidelines Hypercalcemia (9of9) LOOP DIURETICS OTHER AGENT • • Instructions Special • Reactions Adverse • • Reactions Adverse • • Instructions Special • Reactions Adverse • • • • Instructions Special • Reactions Adverse B135 dose change & regularly during maintenance change during ®ularly dose therapy toinitiating prior therapy levels or calcium serum Assess disorder seizure of hepatic impairment, orhistory moderate tosevere disease, Use w/ caution inpatients w/cardiovascular ofconsciousness loss ortemporary level decreased QT prolonged interval, GIdisturbances, Hypocalcemia, May exacerbate extracellular volumedepletion edema toavoid Supplement pulmonary isnecessary - K &Mg depletion tuberculosis herpes, of psychosis, recent ulcer, immunization, peptic history osteoporosis, infection, in patients fungal Contraindicated w/systemic Take w/food imbalances electrolyte impaired woundhealing, toinfection, susceptibility increased muscle painorweakness, wasting, Adrenocortical insuffi muscle ciency, osteoporosis, impairment Use renal w/caution inpatients &hepatic w/severe inpatientsContraindicated w/hypocalcemia therapyDenosumab &VitCa Dsupplementation whileon isrecommended Administer into thigh, arm abdomen orupper hyperhidrosis) hypophosphatemia, hypocalcemia, (dyspnea, musculoskeletal pain);GIeff (diarrhea); Otherect eff ects MIMS effMusculoskeletal ofthe jaw, (osteonecrosis ects Remarks Remarks Remarks © MIMS 2019