VA Class:CV701

AHFS Class:

• Thiazide-like Diuretics 40:28.24

Generic Name(s):

• metOLazone

Metolazone, which is structurally and pharmacologically similar to thiazides, is a diuretic and antihypertensive agent.

Metolazone shares the uses of the thiazide diuretics; however, there is some evidence that metolazone may be more effective than other thiazide-like diuretics in the management of edema in patients with impaired renal function.

Edema

Metolazone is used in the management of edema associated with heart failure and renal diseases (e.g., nephrotic syndrome, impaired renal function).

Hypertension

Metolazone has been used concomitantly with a loop diuretic to manage hypertension and/or induce diuresis in patients who did not respond to either diuretic alone (e.g., in those with advanced renal insufficiency), and metolazone alone may be effective in some patients who are unresponsive to a loop diuretic.

For further information on the role of diuretics in antihypertensive therapy and information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.

Other Uses

Studies have not been performed to determine if metolazone is effective in the treatment of diabetes insipidus or renal tubular acidosis or in the prophylaxis of renal calculus formation associated with hypercalciuria.

Administration

Metolazone is administered orally.

Dosage

Dosage of metolazone depends on the specific formulation used and condition being treated and should be individualized according to the patient's requirements and response. Mykrox® tablets (no longer commercially available in the US) were more rapidly and extensively absorbed than other metolazone formulations and were not therapeutically equivalent to Zaroxolyn® or other formulations of the drug that share the latter's slower and incomplete absorption. Mykrox® and bioequivalent formulations should not be interchanged with Zaroxolyn® and bioequivalent formulations . If metolazone is added to the regimen of a patient stabilized on a potent hypotensive agent, the dosage of the hypotensive agent should initially be reduced to avoid the possibility of severe hypotension.

Edema

For the management of edema associated with heart failure or renal disease, the usual initial adult dosage of metolazone (as Zaroxolyn^® or another bioequivalent formulation) is 5-10 mg once daily in the morning. Metolazone dosage (as Zaroxolyn^® or another bioequivalent formulation) of up to 20 mg once daily may be required in some patients.109 After several days or when nonedematous weight is attained, reduction of dosage to a lower maintenance level may be possible.109 Metolazone has been administered every other day after the response of the patient was stabilized.

For the management of fluid retention (e.g., edema) associated with heart failure, some experts recommend initiating metolazone (as Zaroxolyn^® or another bioequivalent formulation) at a low dosage (e.g., 2.5 mg once daily) and increasing the dosage (maximum of 20 mg daily) until urine output increases and weight decreases, generally by 0.5-1 kg daily.524 When metolazone (as Zaroxolyn^® or another bioequivalent formulation) is used for sequential nephron blockade in the management of fluid retention in heart failure, some experts recommend an initial dosage of 2.5-10 mg once daily in combination with a loop diuretic.524 Experts state that diuretics should be administered at a dosage sufficient to achieve optimal volume status and relieve congestion without inducing an excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both.524

Hypertension

For the management of hypertension using Zaroxolyn^® or another bioequivalent formulation, an initial adult dosage of 1.25-2.5 mg once daily in the morning has been suggested. Some experts recommend a metolazone dosage (using Zaroxolyn^® or another bioequivalent formulation) of 2.5-5 mg daily.1200

Monitoring and Blood Pressure Treatment Goals

The patient's renal function and electrolytes should be assessed 2-4 weeks after initiation of diuretic therapy.1200 Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved with metolazone monotherapy, another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocker) may be added; if goal blood pressure is still not achieved, a third drug may be added.1200,1216 (See Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.) In patients who develop unacceptable adverse effects, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200,1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.501,503,504,505,506,507,508,515,523,526,530,1200,1201,1207,1209,1222,1223,1229 A 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a blood pressure goal of less than 130/80 mmHg in all adults, regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200,1207 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

Adverse Effects

Adverse reactions that have been reported with metolazone, but not with thiazides, include abdominal bloating, palpitation, chest pain, and chills. In a study on the use of metolazone in patients with ascites caused by liver disease, metolazone appeared to produce a greater incidence of electrolyte disturbances and encephalopathy, but a lower incidence of azotemia, than did the thiazides.

Precautions and Contraindications

Although experience with metolazone is limited, the drug appears to share the toxic potentials of the thiazides, and the usual precautions of thiazide administration should be observed. (See Cautions in the Thiazides General Statement 40:28.20.)

Concurrent administration of metolazone and furosemide may occasionally cause excessive volume and electrolyte depletion, and caution should be used when administering these drugs together.

In addition to sharing the contraindications of the thiazide diuretics, metolazone is contraindicated in patients with hepatic coma or pre-coma and in patients with known allergy or hypersensitivity to metolazone.

Pediatric Precautions

Safety and efficacy of metolazone in children have not been established. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Pharmacology

Metolazone shares the pharmacologic actions of the thiazide diuretics. In contrast to the thiazides, metolazone does not substantially decrease the glomerular filtration rate (GFR) or the renal plasma flow and may produce diuresis in patients with a GFR of less than 20 mL/minute. It has been hypothesized that metolazone may alter renal vascular resistance at the time of maximal diuresis by an unknown mechanism.

Pharmacokinetics

Absorption

The rate and extent of absorption of commercially available metolazone tablets vary depending on the preparation. Mykrox^® 0.5-mg tablets (no longer commercially available in the US) are more rapidly and extensively absorbed than Zaroxolyn^® tablets and other formulations of metolazone with dissolution and absorption characteristics similar to the latter. The rate and extent of absorption of metolazone from Mykrox^® tablets reportedly are equivalent to those of an oral solution of the drug. Following oral administration of Mykrox^®, peak blood metolazone concentrations are attained within 2-4 hours. Blood concentrations of the drug are proportional to dose at Mykrox^® doses of 0.5-2 mg, and steady-state blood concentrations are usually attained within 4-5 days. Zaroxolyn^® and other similar metolazone formulations are slowly and incompletely absorbed from the GI tract, with peak blood concentrations occurring about 8 hours after administration and absorption continuing for an additional 12 hours. An average of 65% of a dose of such a metolazone formulation has been reported to be absorbed following oral administration in healthy individuals, and an average of about 40% of a dose of such a formulation is absorbed in patients with cardiac disease.

Distribution

Metolazone has a steady-state apparent volume of distribution of about 113 L. About 50-70% of the drug in the blood is bound to erythrocytes, and up to 33% is bound to plasma proteins. Only 2-5% of the drug in the circulation is unbound. Metolazone crosses the placenta and is distributed into milk.

Elimination

Plasma concentrations of metolazone decrease in a biphasic manner. The elimination half-life of the drug has been reported to be approximately 14 hours.

Metolazone is not metabolized to a substantial extent. From 70-95% of the drug is excreted unchanged in urine by glomerular filtration and active tubular secretion. The rate of clearance of metolazone is proportional to the creatinine clearance. The remainder of the drug is eliminated by nonrenal routes, mainly in bile, and is reported to undergo enterohepatic recycling.

Chemistry and Stability

Chemistry

Metolazone is a quinazoline-derivative diuretic. The drug is structurally and pharmacologically similar to quinethazone and the thiazides. Metolazone occurs as a white powder, is practically insoluble in water and sparingly soluble in alcohol, and has a pK_a of 9.7.

Stability

Commercially available metolazone tablets should be stored in tight, light-resistant containers at room temperature.

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, laboratory tests interferences, and dosage and administration of metolazone, see the Thiazides General Statement 40:28.20.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

103. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension . 2000; 35:1021-4. [PubMed 10818056]

104. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension . 2000; 35:1019-20. [PubMed 10818055]

105. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis . 2000; 36:646-61. [PubMed 10977801]

106. Associated Press (American Diabetes Association). Diabetics urged: drop blood pressure. Chicago, IL; 2000 Aug 29. Press Release from web site. [Web]

107. Appel LJ. The verdict from ALLHAT—thiazide diuretics are the preferred initial therapy for hypertension. JAMA . 2002; 288:3039-42. [PubMed 12479770]

108. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA . 2002; 288:2981-97. [PubMed 12479763]

109. Celltech Pharmaceuticals Inc. Zaroxolyn^® (metolazone) tablets prescribing information. Rochester, NY; 2002 Jun.

110. Celltech Pharmaceuticals Inc., Mykrox^® (metolazone) tablets prescribing information (dated 2001 May). From the Physicians' desk reference website. [Web]

112. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care . 2003; 26(Suppl 1):S80-2.

141. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:255-8.

142. ACOG task force on hypertension in pregnancy: hypertension in pregnancy. Washington, DC: American College of Obstetricians and Gynecologists; 2013.

218. National Kidney Foundation Guideline. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis . 2002; 39(Suppl 2):S1-246.

501. James PA, Oparil S, Carter BL et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA . 2014; 311:507-20. [PubMed 24352797]

502. Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens . 2013; 31:1281-357. [PubMed 23817082]

503. Go AS, Bauman MA, Coleman King SM et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension . 2014; 63:878-85. [PubMed 24243703]

504. Weber MA, Schiffrin EL, White WB et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) . 2014; 16:14-26. [PubMed 24341872]

505. Wright JT, Fine LJ, Lackland DT et al. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med . 2014; 160:499-503. [PubMed 24424788]

506. Mitka M. Groups spar over new hypertension guidelines. JAMA . 2014; 311:663-4. [PubMed 24549531]

507. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: what are the right goals and purposes?. JAMA . 2014; 311:474-6. [PubMed 24352710]

508. Bauchner H, Fontanarosa PB, Golub RM. Updated guidelines for management of high blood pressure: recommendations, review, and responsibility. JAMA . 2014; 311:477-8. [PubMed 24352759]

511. JATOS Study Group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertens Res . 2008; 31:2115-27. [PubMed 19139601]

515. Thomas G, Shishehbor M, Brill D et al. New hypertension guidelines: one size fits most?. Cleve Clin J Med . 2014; 81:178-88. [PubMed 24591473]

523. Fihn SD, Gardin JM, Abrams J et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation . 2012; 126:e354-471.

524. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation . 2013; 128:e240-327.

526. Kernan WN, Ovbiagele B, Black HR et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke . 2014; :. [PubMed 24788967]

530. Myers MG, Tobe SW. A Canadian perspective on the Eighth Joint National Committee (JNC 8) hypertension guidelines. J Clin Hypertens (Greenwich) . 2014; 16:246-8. [PubMed 24641124]

535. Taler SJ, Agarwal R, Bakris GL et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD. Am J Kidney Dis . 2013; 62:201-13. [PubMed 23684145][PubMedCentral]

536. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl . 2012; 2:337-414.

539. Churchill D, Beevers GD, Meher S et al. Diuretics for preventing pre-eclampsia. Cochrane Database Syst Rev . 2007; :CD004451.

540. Magee LA, Pels A, Helewa M et al., for the Canadian Hypertensive Disorders of Pregnancy (HDP) Working Group. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. Pregnancy Hypertens . 2014; 4:105-45. [PubMed 26104418]

541. Perk J, De Backer G, Gohlke H et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J . 2012; 33:1635-701. [PubMed 22555213]

1200. 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:el13-e115. [PubMed 29133356]

1201. Bakris G, Sorrentino M. Redefining hypertension - assessing the new blood-pressure guidelines. N Engl J Med . 2018; 378:497-499. [PubMed 29341841]

1202. Carey RM, Whelton PK, 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association hypertension guideline. Ann Intern Med . 2018; 168:351-358. [PubMed 29357392]

1207. Burnier M, Oparil S, Narkiewicz K et al. New 2017 American Heart Association and American College of Cardiology guideline for hypertension in the adults: major paradigm shifts, but will they help to fight against the hypertension disease burden?. Blood Press . 2018; 27:62-65. [PubMed 29447001]

1209. Qaseem A, Wilt TJ, Rich R et al. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline From the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med . 2017; 166:430-437. [PubMed 28135725]

1210. SPRINT Research Group, Wright JT, Williamson JD et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med . 2015; 373:2103-16. [PubMed 26551272]

1213. Reboussin DM, Allen NB, Griswold ME et al. Systematic review for the 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. J Am Coll Cardiol . 2017; [PubMed 29146534]

1216. Taler SJ. Initial Treatment of Hypertension. N Engl J Med . 2018; 378:636-644. [PubMed 29443671]

1220. Cifu AS, Davis AM. Prevention, detection, evaluation, and management of high blood pressure in adults. JAMA . 2017; 318:2132-2134. [PubMed 29159416]

1222. Bell KJL, Doust J, Glasziou P. Incremental benefits and harms of the 2017 American College of Cardiology/American Heart Association high blood pressure guideline. JAMA Intern Med . 2018; 178:755-7. [PubMed 29710197]

1223. LeFevre M. ACC/AHA hypertension guideline: What is new? What do we do?. Am Fam Physician . 2018; 97(6):372-3. [PubMed 29671534]

1224. Brett AS. New hypertension guideline is released. From NEJM Journal Watch website. Accessed 2018 Jun 18. [Web]

1229. Ioannidis JPA. Diagnosis and treatment of hypertension in the 2017 ACC/AHA guidelines and in the real world. JAMA . 2018; 319(2):115-6. [PubMed 29242891]