Chlorothiazide (Monograph)

Brand name: Diuril
Drug class: Thiazide Diuretics
- Diuretics, Thiazide
VA class: CV701
CAS number: 58-94-6

Medically reviewed by Drugs.com on Mar 15, 2024. Written by ASHP.

Introduction

Thiazide diuretic and antihypertensive agent.

Uses for Chlorothiazide

Hypertension

Used alone or in combination with other antihypertensive agents for all stages of hypertension.^{b 110 1200}

Thiazide diuretics are recommended as one of several preferred agents for the initial management of hypertension according to current evidence-based guidelines; other preferred options include ACE inhibitors, angiotensin II receptor antagonists, and calcium-channel blockers.^{501 502 503 504 1200} While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.^{501 502 504 1200 1213}

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).^{501 502 503 504 515 1200 1201}

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.¹²⁰⁰ (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP.¹²⁰⁰ However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.^{501 503 504 505 506 507 508 515 523 526 530 1200 1201 1207 1209 1222 1223 1229}

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BPs to achieve with drug therapy and/or nonpharmacologic intervention) of <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.¹²⁰⁰ In addition, an SBP goal of <130 mm Hg generally is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg.¹²⁰⁰ These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.^{1200 1202 1210}

Other hypertension guidelines generally have based target BP goals on age and comorbidities.^{501 504 536} Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients^{501 504 536} compared with those recommended by the 2017 ACC/AHA hypertension guideline.¹²⁰⁰

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.^{1222 1223 1224 1229}

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient's BP treatment goal.^{1200 1220}

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors.^{1200 1207} ASCVD risk assessment recommended by ACC/AHA for all adults with hypertension.¹²⁰⁰

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).¹²⁰⁰

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.¹²⁰⁰

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg.¹²⁰⁰ Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.^{502 1200}

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP.¹²⁰⁰ Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.¹²⁰⁰

Black hypertensive patients generally tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists).^{g 109 501 504 1200} However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium channel blocker or thiazide diuretic produces similar BP lowering in black patients as in other racial groups.¹²⁰⁰

Thiazides may be preferred in hypertensive patients with osteoporosis.^{i j} Secondary beneficial effect in hypertensive geriatric patients of reducing the risk of osteoporosis due to effect on calcium homeostasis and bone mineralization.^{i j}

Edema (General)

Management of edema resulting from various causes; diagnose etiology before use.^{b 110 111}

Edema caused by renal disease or by corticosteroids or estrogens may be relatively resistant to treatment.^b

Ineffective in patients with S_cr or BUN concentrations greater than twice normal.^b

May be ineffective in patients with GFR <15–25 mL/minute; even when GFR is 25–50 mL/minute, more potent (e.g., loop) diuretics may be indicated.^b

No substantial difference in clinical effects or toxicity of comparable thiazide or thiazide-like diuretics except metolazone may be more effective in edema with renal impairment.^b

Edema in Heart Failure

Management of edema associated with heart failure.^{b c}

Most experts state that all patients with symptomatic heart failure who have evidence for, or history of, fluid retention generally should receive diuretic therapy in conjunction with moderate sodium restriction, an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., ACE inhibitor, angiotensin II receptor antagonist, angiotensin receptor-neprilysin inhibitor [ARNI]), a β-adrenergic blocking agent (β-blocker), and in selected patients, an aldosterone antagonist.^{524 n}

Loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, torsemide) are diuretics of choice for most patients with heart failure.⁵²⁴

Do not use diuretics as monotherapy in heart failure even if symptoms (e.g., peripheral edema, pulmonary congestion) are well controlled; diuretics alone do not prevent progression of heart failure.^{e f}

Diuretics produce rapid symptomatic benefits, relieving pulmonary and peripheral edema more rapidly (within hours or days) than cardiac glycosides, ACE inhibitors, or β-blockers (in weeks or months).^e

Diuretics should be continued in heart failure and comorbid conditions (e.g., hypertension) where ongoing therapy with the drugs are indicated.⁵²⁴

Edema Secondary to Nephrotic Syndrome

May be useful if the patient fails to respond to corticosteroid therapy.^b

More likely to become refractory to thiazides than edema associated with congestive heart failure, and more potent diuretics may be required.^b

Edema in Pregnancy

Generally responds well to thiazides except when caused by renal disease.^b

Thiazides should not be used for routine therapy in pregnant women with mild edema who are otherwise healthy.^b

Chlorothiazide Dosage and Administration

General

Monitoring and BP Treatment Goals

• Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.¹²⁰⁰

• If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.^{1200 1216}

• Assess patient's renal function and electrolytes 2–4 weeks after initiation of diuretic therapy.¹²⁰⁰ (See Electrolyte Imbalance under Cautions.)

• If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., ACE inhibitor, angiotensin II receptor antagonist, calcium-channel blocker).^{1200 1216} Many patients will require ≥2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved, add a third drug.^{1200 1216 1220}

Administration

Administer orally or IV.^{a 110 111} Manufacturer states that IV preparations not indicated for hypertension management.⁶⁰²

The injection must not be administered subcutaneously or IM, and extravasation of the alkaline solution must be avoided.^{a 111}

Oral Administration

Administer chlorothiazide tablets and suspension orally.^{a 110}

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer chlorothiazide sodium by slow IV injection or by IV infusion; use IV route only when patients unable to take drug orally or in emergency situations.^{a 111}

Must avoid extravasation of the alkaline solution.^{a 111}

Reconstitution

Reconstitute only with sterile water for injection.^a

Add 18 mL of sterile water for injection to 500-mg vial; provides a solution containing about 28 (27.8) mg/mL.^{a 111} Use no less than 18 mL of diluent for initial reconstitution.^{a 111}

Dilution

May administer injection undiluted or may further dilute with sodium chloride, dextrose, or other compatible infusion fluids before administration.^{a 111}

Rate of Administration

Slowly by direct IV injection or by IV infusion.^{a 111}

Dosage

Dosage of chlorothiazide sodium is expressed in terms of chlorothiazide.^{a 111}

IV and oral dosage are identical.^{a 111}

Individualize dosage according to requirements and response.^a

If added to potent hypotensive agent regimen, initially reduce dosage of hypotensive agent to avoid possibility of severe hypotension.^a

For the management of fluid retention associated with heart failure, experts state that diuretics should be administered at a dosage sufficient to achieve optimal volume status and relieve congestion without inducing excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both.⁵²⁴

Pediatric Patients

Hypertension

Oral

Infants <6 months of age: May require up to 30 mg/kg daily given in 2 divided doses.^{110 601}

Children 6 months to 12 years of age: Usually 10–20 mg/kg daily in 1 or 2 divided doses.^{110 601 1150}

Experts recommend initiation of drug at low end of dosage range; may increase dosage every 2–4 weeks until BP controlled, maximum dosage reached, or adverse effects occur.¹¹⁵⁰

Diuresis

Oral

Infants <6 months of age: May require up to 30 mg/kg daily given in 2 divided doses.^{110 601}

Children 6 months to 12 years of age: Usually 10–20 mg/kg daily in 1 or 2 divided doses.^{110 601}

IV

Experience in infants and children is limited, and IV use in this age group generally is not recommended.^{a 111}

Adults

Hypertension

Oral

Initially, 0.5–1 g daily as a single dose or in 2 divided doses.^{600 601}

Adults rarely may require up to 2 g daily in divided doses.^{600 601}

If adequate response is not achieved with monotherapy, add another antihypertensive agent.¹²⁰⁰

Edema

Oral

Usually, 0.5–1 g daily in 1 or 2 doses.¹¹⁰ Occasionally, up to 2 g daily in 1 or 2 doses.^a

After several days or when nonedematous weight is attained, dosage reduction to a lower maintenance level may be possible.^a

Management of fluid retention associated with heart failure: Some experts recommend initiating chlorothiazide at a low dosage (e.g., 250–500 mg once or twice daily) and increasing dosage until urine output increases and weight decreases, generally by 0.5–1 kg daily.⁵²⁴

With an intermittent dosing schedule, excessive response and the resulting undesirable electrolyte imbalance are less likely to occur.^a

IV

Usually, 0.5–1 g daily in 1 or 2 doses.¹¹⁰ Occasionally, up to 2 g daily in 1 or 2 doses.^a

After several days or when nonedematous weight is attained, dosage reduction to a lower maintenance level may be possible.^a

With an intermittent schedule, excessive response and the resulting undesirable electrolyte imbalance are less likely to occur.^{a 111}

For sequential nephron blockade in the management of fluid retention in heart failure, some experts recommend an initial dosage of 0.5–1 g once daily in combination with a loop diuretic.⁵²⁴

Prescribing Limits

Pediatric Patients

Oral

Infants <2 years of age: Maximum of 375 mg daily.^{a 110}

Children ≥2 years of age: 1 g daily.^{a 110}

Adults

Hypertension

Oral

Rarely, up to 2 g daily in divided doses may be required.^{600 601}

Edema

Oral

Maximum recommended by manufacturer: 2 g daily in divided doses.^{a 110}

Management of fluid retention in heart failure: 1 g maximum daily dosage recommended by ACCF/AHA.⁵²⁴

IV

Maximum of 2 g daily in divided doses.^{a 111}

Special Populations

Hepatic Impairment

No specific dosage recommendations for hepatic impairment; caution because of risk of precipitating hepatic coma.^{a 110 111}

Renal Impairment

No specific dosage recommendations for renal impairment; caution because of risk of precipitating azotemia.^{a 110 111}

Geriatric Patients

No specific geriatric dosage recommendations.^{a 110 111}

Cautions for Chlorothiazide

Contraindications

• Anuria.^{b 110 111}

• Known hypersensitivity to hydrochlorothiazide, other thiazides, or any ingredient in the formulation.^b

• Although manufacturers state allergy to other sulfonamide derivatives is a contraindication,^{110 111} evidence to support cross-sensitivity is limited, and history of sensitivity to sulfonamide anti-infectives (“sulfa sensitivity”) should not be considered an absolute contraindication.^{k l m}

Warnings/Precautions

Warnings

Hypotensive Agents

May potentiate effects of other hypotensive agents.^{110 111} Although additive or potentiated antihypertensive effect usually is used to therapeutic advantage, hypotension could occur.^{110 111 b} (See Interactions.)

Lupus Erythematosus

Possible exacerbation or activation of systemic lupus erythematosus.^{110 111}

Lithium

Generally, do not use with lithium salts.^{110 111} (See Interactions.)

Sensitivity Reactions

Hypersensitivity

May occur with or without history of allergy or bronchial asthma.^{110 111}

Sulfonamide cross-sensitivity unlikely. (See Contraindications under Cautions.)

General Precautions

Electrolyte Imbalance

Monitor for fluid or electrolyte imbalance (hyponatremia, hypochloremic alkalosis, hypokalemia).^{b 110 111 1200}

Observe for signs of electrolyte imbalance (e.g., dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, oliguria, muscle pains, cramps, muscular fatigue, hypotension, tachycardia, nausea, vomiting).^{110 111 1200}

Perform periodic serum electrolyte determinations (particularly of potassium, sodium, chloride, and bicarbonate); institute measures to maintain normal serum electrolyte concentrations if necessary.^{1200 b}

Serum and urinary electrolyte measurements are especially important with diabetes mellitus, vomiting, diarrhea, parenteral fluid therapy, or expectations of excessive diuresis.^b

Weekly (or more frequent) electrolyte measurement early in treatment; possible to extend interval between measurements to ≥3 months when electrolyte response has stabilized.^b

Hypokalemia

May occur after brisk diuresis, when cirrhosis is present, or with prolonged therapy; inadequate oral electrolyte intake may contribute.^{110 111}

May cause cardiac arrhythmias, exaggerate cardiac response to cardiac glycoside toxicity (increase ventricular irritability).^{110 111}

Use potassium-sparing diuretics and/or potassium supplementation to avoid or treat hypokalemia.^{110 111}

Hypochloremia

Generally mild, usually does not require specific treatment except in renal or hepatic impairment.^{110 111}

Chloride replacement may be required for metabolic acidosis.¹⁰⁹

Hyponatremia

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate treatment usually is water restriction rather than salt administration except when hyponatremia is life-threatening.^{110 111}

In actual salt depletion, appropriate replacement is treatment of choice.^{110 111}

Gout

Hyperuricemia or, rarely, precipitation of gout may occur; generally avoid or use with caution in patients with history of gout unless patient is receiving uric acid lowering therapy.^{110 111 502 1200}

Hyperglycemia

In diabetic patients, dosage adjustment of insulin or oral hypoglycemics may be required; hyperglycemia may occur and latent diabetes mellitus may become evident.^{110 111}

Sympathectomy

Antihypertensive effect may be enhanced after sympathectomy.^{110 111}

Hypomagnesemia

May increase magnesium urinary excretion, resulting in hypomagnesemia.^{110 111}

Hypercalcemia

May decrease calcium urinary excretion, cause slight intermittent serum calcium increase in absence of known calcium metabolism disorder; marked hypercalcemia may indicate hyperparathyroidism.^{110 111}

Discontinue parathyroid tests.^{110 111}

Hyperlipidemia

May increase cholesterol and triglyceride concentrations.^{110 111 109}

Clinical importance of these changes is unknown.^b Diet low in saturated fat and cholesterol usually compensates.^b

Hypotensive Effects

Orthostatic hypotension occurs rarely.^b

Specific Populations

Pregnancy

Category C.^{110 111}

Diuretics are considered second-line agents for control of chronic hypertension in pregnant women;¹⁴² if initiation of antihypertensive therapy is necessary in a pregnant woman, other antihypertensives (i.e., methyldopa, nifedipine, labetalol) are preferred.^{142 540}

Edema associated with pregnancy generally responds well to thiazides except when caused by renal disease; however, routine use not recommended in pregnant women with mild edema who are otherwise healthy.^{b 110 111}

Diuretics are not recommended for prevention or management of gestational hypertension or preeclampsia.^{141 539 540}

Lactation

Distributed into milk.^{h 110 111 141} Manufacturer states to discontinue nursing or the drug;^{110 111} however, considered to be compatible with breast-feeding.¹⁴¹

Pediatric Use

No controlled studies in children; use is supported by experience and published literature about hypertension treatment in children.¹¹⁰

Experience with IV chlorothiazide sodium in infants and children is limited, and IV use in this age group generally is not recommended.^{a 111}

Geriatric Use

Elderly may be at increased risk of dilutional hyponatremia, especially underweight females with poor oral fluid and electrolyte intake or excessive low-sodium nutritional supplement intake.^b (See Hyponatremia under Cautions.)

Hepatic Impairment

Use with caution in patients with hepatic impairment or progressive liver disease (particularly with associated potassium deficiency); electrolyte imbalance may precipitate hepatic coma.^{b 110 111}

Discontinue immediately if signs of impending hepatic coma appear.^b

Renal Impairment

Use with caution in severe renal impairment; thiazides decrease GFR and may precipitate azotemia.^{b 110 111} Effects may be cumulative in impaired renal function.^{b 110 111}

Consider interruption or discontinuance if progressive renal impairment (rising nonprotein nitrogen, BUN, or S_cr) occurs.^{110 111}

Common Adverse Effects

Potassium depletion, hyperuricemia (usually asymptomatic; rarely leading to gout).^b Hypochloremic alkalosis in patients at risk (e.g., hypokalemic patients).^b Hyperglycemia and glycosuria in diabetics.^b

Drug Interactions

Specific Drugs and Laboratory Tests

Chlorothiazide Pharmacokinetics

Absorption

Bioavailability

Incompletely and variably absorbed from the GI tract.^a

Absorption from the GI tract appears to be site specific and saturable.^a Several studies indicate that about 50 mg is absorbed following oral administration of a single 250-mg tablet, a single 500-mg tablet, or two 250-mg tablets to fasting healthy individuals.^a

Onset

Diuretic effect (oral): within 2 hours; peak effect in 3–6 hours.^{b 109}

Diuretic effect (IV): within 15 minutes; peak effect in 30 minutes.^b

Hypotensive effect (oral): generally 3–4 days.^b

Duration

Diuretic effect: 6–12 hours.^b

Food

Concomitant administration with food appears to increase the extent of absorption.^a

Distribution

Extent

Distributed in the extracellular space.^{a b}

Readily crosses the placenta.^{a b 141}

Distributed into breast milk.^{a h 141}

Elimination

Metabolism

Not metabolized.^a

Elimination Route

Excreted unchanged in urine;^a about 95% of an IV dose is eliminated in 5 hours and about 20 or 10% of a 250- or 500-mg oral dose, respectively, is eliminated in 48–72 hours.^a

Half-life

45–120 minutes.^a

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 20–25°C.⁶⁰¹

Suspension

Tight containers at 15–30°C; avoid freezing.⁶⁰⁰

Parenteral

Powder for Injection

20–25°C.⁶⁰²

Compatibility

Parenteral

Solution CompatibilityHID

Drug CompatibilityHID

Actions

• Exact mechanism of diuretic action is unclear; may act by altering metabolism of the tubular cells.^b

• Enhances excretion of sodium, chloride, and water by interfering with the transport of sodium ions across the renal tubular epithelium.^b

• Primary site of diuretic action appears to be the cortical diluting segment of the nephron.^b

• GFR decreases, but unclear whether secondary to a direct effect on renal vasculature or to the decrease in intravascular fluid volume or an increase in tubular pressure caused by the inhibition of sodium and water reabsorption.^b The fall in GFR is not important in the mechanism of action.^b

• Enhances urinary excretion of potassium secondary to increased amount of sodium at distal tubular site of sodium-potassium exchange.^b

• Increases urinary bicarbonate excretion (although to a lesser extent than chloride excretion) but change in urinary pH is usually minimal; diuretic efficacy is not affected by the acid-base balance of the patient.^b

• Hypocalciuric effect is thought to result from a decrease in extracellular fluid (ECF) volume, although calcium reabsorption in the nephron may be increased; also, slight or intermittent elevations in serum calcium concentration.^b

• Rate of uric acid excretion is decreased, probably because of competitive inhibition of uric acid secretion or a decrease in ECF volume and a secondary increase in uric acid reabsorption.^b

• Hypotensive activity in hypertensive patients; also augments the action of other hypotensive agents.^b Precise mechanism of hypotensive action has not been determined, but postulated that part of this effect is caused by direct arteriolar dilation.^b

Advice to Patients

• Advise patient of signs of electrolyte imbalance (e.g., dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, oliguria, or muscle pains or cramps, muscular fatigue, hypotension, tachycardia, GI disturbances such as nausea and vomiting).^b

• Advise patients of importance of compliance with scheduled determinations of serum electrolyte concentrations (particularly potassium, sodium, chloride, and bicarbonate).^b

• Advise hypertensive patients of importance of continuing lifestyle/behavioral modifications that include weight reduction (for those who are overweight or obese), dietary changes to include foods that are rich in potassium and calcium and moderately restricted in sodium (adoption of the Dietary Approaches to Stop Hypertension [DASH] eating plan), increased physical activity, smoking cessation, and moderation of alcohol intake.¹²⁰⁰

  Advise that lifestyle/behavioral modifications reduce BP, enhance antihypertensive drug efficacy, and decrease cardiovascular risk and remain an indispensable part of the management of hypertension.¹²⁰⁰

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Frequently asked questions

• Should you use a diuretic with diazoxide?

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