Spironolactone

Class: Mineralocorticoid (Aldosterone) Receptor Antagonists
VA Class: CV704
CAS Number: 52-01-7
Brands: Aldactone, Aldactazide

• 
  

  Tumorigenic in chronic toxicity studies in rats.^{256 265} Use for FDA-approved indications; avoid unnecessary use.^{256 265}

  
  

• 
  

  Spironolactone/hydrochlorothiazide fixed combination not indicated for initial therapy of edema or hypertension.²⁵⁶ Individualize dosage.²⁵⁶ If the fixed combination represents the dosage so determined, its use may be more convenient in patient management.²⁵⁶ The treatment of hypertension and edema is not static but must be reevaluated as conditions in each patient warrant.²⁵⁶ (See Dosage and Administration.)

  
  

Introduction

Aldosterone antagonist; a potassium-sparing diuretic.^{256 265}

Uses for Spironolactone

Edema

Management of edema associated with excessive aldosterone including cirrhosis of the liver and nephrotic syndrome.²⁵⁶

Used as an adjunct to thiazide therapy when diuresis is inadequate or reduction of potassium excretion is necessary.^a

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents);^{256 262 265} used for patients who cannot be treated adequately with other agents or for whom other agents are considered inappropriate.²⁶⁵

One of several initial preferred therapies in hypertensive patients with heart failure and in those with ischemic heart disease (e.g., MI).²⁶²

Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.²⁶²

CHF

Management of edema and sodium retention in CHF in patients only partially responsive to, or intolerant of, other therapeutic measures.²⁶⁵

Has been used in conjunction with ACE inhibitors, loop diuretics, and occasionally cardiac glycosides in patients with severe CHF whose condition was inadequately controlled by an ACE inhibitor and a loop diuretic.^{215 216 217 226 247}

Consider adding spironolactone to standard therapy in patients with severe (i.e., NYHA class IV) CHF.^{246 247}

Safety and efficacy in mild or moderate CHF not determined.^{246 247}

Primary Aldosteronism

Diagnosis of primary aldosteronism by therapeutic trial;²⁶⁵ test results may be equivocal and additional diagnostic studies often required.^a

Short-term preoperative treatment of primary aldosteronism.²⁶⁵

Long-term maintenance therapy in patients with discrete aldosterone-producing adrenal adenomas who cannot undergo adrenalectomy or who decline surgery.²⁶⁵

Long-term maintenance therapy for patients with bilateral micronodular or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism).²⁶⁵

Hypokalemia

Treatment of hypokalemia when oral potassium supplements or other measures are inappropriate or inadequate.^{265 a}

Prophylaxis of hypokalemia in patients taking digitalis when other measures are inappropriate or inadequate.²⁶⁵

Precocious Puberty

Management of certain forms of gonadotropin releasing hormone (GnRH)-independent (peripheral) precocious puberty† (e.g., familial male precocious puberty [testotoxicosis]).^{203 204 205 206 207 208 211 213}

Hirsutism

Treatment of hirsutism† in women with polycystic ovary syndrome or idiopathic hirsutism.^a

Spironolactone Dosage and Administration

Administration

Administer orally.^{256 265}

Oral Administration

Administer as single or divided doses; 2 doses daily may be adequate.^{262 265 a}

For administration in children†, tablets may be pulverized and administered as an oral suspension in cherry syrup.^a

When used with a thiazide diuretic in edema associated with cirrhosis of the liver, administer spironolactone for 2–3 days prior to the thiazide diuretic in order to prevent potassium depletion and precipitation of hepatic coma.^a

Dosage

Pediatric Patients

Edema†

Oral

3.3 mg/kg (up to 100 mg) daily as a single dose or in divided doses.^a

Alternatively, initial dosage of 60 mg/m² daily in divided doses.^a

Hypertension†

Oral

Initially, 1 mg/kg daily as a single dose or in 2 divided doses.²⁶⁹ Increase dosage as necessary up to a maximum of 3.3 mg/kg (up to 100 mg) daily as a single dose or in 2 divided doses.²⁶⁹

Primary Aldosteronism†

Diagnosis

Oral

125–375 mg/m² in divided doses over 24 hours.^a

If serum potassium concentration increases during therapy but decreases when the drug is discontinued, a presumptive diagnosis of primary aldosteronism should be considered.²⁶⁵

Adults

Edema

Oral

Initially, 100 mg daily.²⁶⁵ Range: 25–200 mg daily.²⁶⁵

As monotherapy, administer usual initial dosage for ≥5 days; if response is satisfactory, titrate dosage to optimal dosage.²⁶⁵

If response is not satisfactory after initial 5 days of therapy, add a thiazide or loop diuretic.²⁶⁵ Do not adjust spironolactone dosage during combined diuretic therapy.²⁶⁵

Spironolactone in combination with hydrochlorothiazide: spironolactone 100 mg daily and hydrochlorothiazide 100 mg daily as a single dose or in divided doses.²⁵⁶ Range: spironolactone 25–200 mg daily and hydrochlorothiazide 25–200 mg daily as a single dose or in divided doses.²⁵⁶

Initial use of fixed-combination preparations is not recommended; adjust by administering each drug separately, then use the fixed combination if the optimum maintenance dosage corresponds to the ratio of drugs in the combination preparation.²⁵⁶ Administer separately for subsequent dosage adjustment.²⁵⁶

Hypertension

Lower dosage and combination therapy recommended by JNC 7; higher spironolactone dosage may result in intolerable adverse effects.²⁶²

Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.^{214 262}

Adjust dosage at approximately monthly intervals.^{214 262}

Monotherapy

Oral

Usual initial dosage: 50–100 mg daily as a single dose or in divided doses.²⁶⁵ Full hypotensive response may require 2 weeks.²⁶⁵

Usual dosage recommended by JNC 7: 25–50 mg daily.²⁶²

Spironolactone/Hydrochlorothiazide Combination Therapy

Oral

Spironolactone 50–100 mg daily and hydrochlorothiazide 50–100 mg daily as a single dose or in divided doses.²⁵⁶

Initial use of fixed-combination sprionolactone/hydrochlorothiazide preparations is not recommended; adjust by administering each drug separately, then use the fixed combination if the optimum maintenance dosage corresponds to the ratio of drugs in the combination preparation.²⁵⁶ Administer separately for subsequent dosage adjustment.²⁵⁶

CHF

Oral

Initially, 12.5–25 mg daily used in patients receiving an ACE inhibitor and a loop diuretic with or without a cardiac glycoside.^{215 216 246 247}

Increase to 50 mg daily after 8 weeks in patients who exhibit signs and symptoms of progressive heart failure and have serum potassium concentrations <5.5 mEq/L.²¹⁵

Decrease to 25 mg every other day if hyperkalemia occurs.^{215 216}

Primary Aldosteronism

Diagnosis

Oral

400 mg daily for 3–4 weeks.²⁶⁵ Correction of hypokalemia and hypertension provides presumptive evidence for the diagnosis of primary aldosteronism.²⁶⁵

Alternatively, 400 mg daily for 4 days.²⁶⁵ If serum potassium concentration increases during spironolactone therapy but decreases when the drug is discontinued, consider presumptive diagnosis of primary aldosteronism.²⁶⁵

Medical Therapy Prior to Adrenalectomy

Oral

Patients with a definitive diagnosis: 100–400 mg daily before surgery.²⁶⁵

Treatment Of Primary Aldosteronism

Oral

Initially, 400 mg daily.²⁶⁵

Maintenance dosage: 100–300 mg daily.²⁶⁵ Use lowest effective dosage for long-term maintenance therapy.²⁶⁵

Hypokalemia

Oral

25–100 mg daily.²⁶⁵

Hirsutism†

Oral

50–200 mg daily.^a Regression of hirsutism evident within 2 months, maximal within 6 months, and has been maintained for ≥16 months with continued therapy.^a

Prescribing Limits

Pediatric Patients

Hypertension†

Oral

Maximum 3.3 mg/kg (up to 100 mg) daily.²⁶⁹

Cautions for Spironolactone

Contraindications

• 
  

  Anuria.²⁶⁵

  
  


• 
  

  Acute renal insufficiency²⁶⁵

  
  


• 
  

  Substantial impairment of renal excretory function.²⁶⁵

  
  


• 
  

  Hyperkalemia.²⁶⁵

  
  


• 
  

  Known hypersensitivity to spironolactone or any ingredient in the formulation.²⁶⁵

  
  

Warnings/Precautions

Warnings

Hyperkalemia

Avoid concurrent use of potassium supplements.^{256 265} (See Specific Drugs, Foods, and Laboratory Tests under Interactions.)

Hyperkalemia reported in patients with excess potassium intake and in those with renal insufficiency; hyperkalemia may cause potentially fatal cardiac irregularities.²⁵⁶

If hyperkalemia suspected (paresthesia, muscle weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock), obtain an ECG and monitor serum potassium concentrations.²⁵⁶

If hyperkalemia occurs, immediately discontinue and treat as indicated with parenteral calcium chloride, sodium bicarbonate, and/or oral or parenteral glucose with a rapid acting insulin preparation.²⁵⁶ Consider cationic exchange resins (e.g., sodium polystyrene sulfonate).²⁵⁶ Persistent hyperkalemia may require dialysis.²⁵⁶

Concomitant ACE Inhibitor Therapy

Combined therapy with spironolactone and an ACE inhibitor has been considered relatively contraindicated because of the potential for developing severe hyperkalemia and inhibition of aldosterone formation;^{215 217 218 222} however, clinical studies in patients with moderate or severe CHF indicate addition of low-dose (25–50 mg daily) spironolactone to standard therapy (e.g., an ACE inhibitor and a loop diuretic with or without a cardiac glycoside) decreases mortality and hospitalization.^{218 219 246 247 251 252 253 254}

Tumorigenic Effects

Tumorigenic in animals; proliferative effects observed in liver and endocrine organs.^{256 265} (See Boxed Warning.)

Sensitivity Reactions

Anaphylaxis

Anaphylaxis reported.^{256 265}

Major Toxicities

Fluid and Electrolyte Imbalance

Observe for signs of fluid and electrolyte imbalance (e.g., dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, vomiting).²⁵⁶

Monitor serum and urine electrolyte concentrations periodically, especially if the patient is vomiting excessively or receiving parenteral fluid therapy.^{256 265}

Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function.²⁵⁶ (See Hepatic Impairment under Cautions.)

General Precautions

Dilutional Hyponatremia

Dilutional hyponatremia (dry mouth, thirst, lethargy, and drowsiness) reported; diagnosis confirmed by a low serum sodium concentration.²⁵⁶

Increased risk when spironolactone combined with other diuretics, in edematous patients during hot weather, and in patients with advanced cirrhosis.^{256 a}

Gynecomastia

Gynecomastia reported; appears related to dose and duration of therapy.²⁵⁶ Generally reversible upon discontinuance.²⁵⁶

Use of Fixed Combinations

When spirolactone is used in fixed combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with hydrochlorothiazide.²⁵⁶

Specific Populations

Pregnancy

Category C.²⁶⁵

Lactation

Metabolite distributed into milk.²⁶⁵ Discontinue nursing or the drug.²⁶⁵

Pediatric Use

Safety and efficacy not fully established.²⁶⁵

Geriatric Use

Monitor serum and urine electrolyte concentrations.²⁶⁵

Hepatic Impairment

Use with caution in patients with impaired hepatic function; minor alterations of fluid and electrolyte balance may precipitate hepatic coma.²⁶⁵

Monitor serum and urine electrolyte concentrations.^{256 265}

Reversible hyperchloremic metabolic acidosis (usually in association with hyperkalemia) reported in patients with decompensated hepatic cirrhosis, even in the presence of normal renal function.²⁶⁵

Renal Impairment

Hyperkalemia reported in patients with impaired renal function.²⁶⁵ (See Contraindications under Cautions.)

Monitor serum and urine electrolyte concentrations periodically.^{256 265}

Transient elevations of BUN reported.²⁶⁵

Common Adverse Effects

Hyperkalemia, hyponatremia, anorexia, nausea, vomiting, diarrhea, abdominal cramping, gastritis, gastric bleeding, ulceration, headache, drowsiness, lethargy, ataxia, mental confusion, fever, rash, anaphylaxis, vasculitis, urticaria, gynecomastia, decreased libido, relative impotence in males, menstrual irregularities, amenorrhea, postmenopausal bleeding, increased BUN concentrations.^{256 265 a}

Interactions for Spironolactone

Specific Drugs, Foods, and Laboratory Tests

Drug, Food, or Test	Interaction	Comments
ACE inhibitor	Increased risk of hyperkalemia265	Monitor serum potassium frequently265 (See CHF under Uses and also under Dosage and Administration)
Alcohol	Potentiation of orthostatic hypotension265
Antihypertensive and hypotensive agents	Additive antihypertensive effectsa	Reduce dosage of antihypertensive agent, especially ganglionic blocking agents, by at least 50% when spirolactone initiateda
Barbiturates	Potentiation of orthostatic hypotension265
Corticosteroids/ACTH	Possible additive electrolyte depletion, especially potassium265	Monitor serum electrolytes265
Digoxin	Increased serum concentrations of digoxin; possible toxicity265	Monitor for digitalis toxicity; adjust digoxin dosage (maintenance and digitalization)265
Diuretics, potassium-sparing (e.g. amiloride, triamterene)	Increased risk of hyperkalemiaa	Concomitant use contraindicateda
Lithium	Reduced renal clearance of lithium; increased risk of lithium toxicity 265	Concomitant use generally contraindicated; if concomitant therapy is necessary, monitor serum lithium concentrations closely and adjust dosage 265
Nondepolarizing neuromuscular blocking agents (e.g., tubocurarine chloride)	Potential increase in neuromuscular blockade265
NSAIAs (e.g., indomethacin, aspirin)	Possible decreased diuretic, natriuretic, and antihypertensive effect; increased risk of hyperkalemia265	Use with caution, monitor for diuretic effects265 a Monitor for hyperkalemia265
Opiate agonists	Potentiation for orthostatic hypotension265
Potassium supplements and/or foods containing potassium (e.g., salt substitutes, low-salt milk)	Increased risk of hyperkalemia 265	Concomitant use generally not recommended265
Test, aldosterone (urinary)	Most methods appear unaffected; metabolites may interfere with radioimmunoassay proceduresa
Test, digoxin (serum)	Possible false elevations with radioimmunoassay procedures; possibly assay specific265	Clinical relevance not fully known265
Tests, steroids Cortisol (17-hydroxycorticosteroids, plasma and urinary) 17-hydroxycorticosteroids (urinary, Porter-Silber technique) 17-ketosteroids, 17-ketogenic steroids, (urinary, Klendshoj, Feldstein and Sprague technique)	Spironolactone metabolites fluoresce; may interfere with fluorometric analysisa	Clinical relevance not fully known265
Vasopressors (e.g. norepinephrine)	Possible decreased vascular response265	Use anesthesia (regional or general) with caution265

Spironolactone Pharmacokinetics

Absorption

Well absorbed following oral administration; peak serum concentrations of spironolactone usually attained within 1–2 hours;^{200 201} peak serum concentrations of the principal metabolites^{200 201} usually attained within 2–4 hours.^a

Bioavailability

>90%.^a

Onset

Gradual; maximum diuretic effect reached on third day.^a

Spironolactone in fixed combination with hydrochlorothiazide: diuresis usually occurs on the first day.^a

Duration

Diuresis persists for 2–3 days after discontinuance.^a

Food

Food increases peak serum concentrations and AUC; clinical importance not known.²⁰⁰

Distribution

Extent

Spironolactone and its metabolites crosses the placenta.

Canrenone, a major active metabolite, is distributed into milk.^{256 a}

Plasma Protein Binding

Spironolactone and canrenone: >90%.²⁶⁵

Elimination

Metabolism

Rapidly and extensively metabolized; canrenone and/or 7α-thiomethylspironolactone appear to be major active metabolites.^{200 201 256}

Undergoes hepatic deacetylation, thiomethylation, and hydroxylation.^{200 201}

Elimination Route

Excreted principally in urine as metabolites and to a lesser extent in bile.²⁶⁵

Half-life

Spironolactone: 1.4 hours.²⁶⁵

Metabolites: 13.8–16.5 hours.²⁶⁵

Stability

Storage

Oral

Tablets

<25°C.^{256 265}

Suspension

Extemporaneously prepared oral suspensions in cherry syrup reported to be stable for 1 month at 2–8°C.^a

ActionsActions

• 
  

  Synthetic steroid mineralocorticoid receptor antagonist (aldosterone antagonist).^{215 256 265 266}

  
  


• 
  

  Exhibits magnesium- and potassium-sparing,^{224 230 233} natriuretic,^{232 247} diuretic,^{224 232} and hypotensive^{215 224 225 227} effects by competitively inhibiting the physiologic effects of the adrenocorticortical hormone aldosterone on the distal renal tubules, myocardium,^{225 226 228 232} and vasculature.^{232 233 265}

  
  


• 
  

  Generally does not cause potassium depletion or affect glucose metabolism or uric acid excretion.²⁶⁵

  
  


• 
  

  Androgen and progesterone receptor antagonist.^{206 208 209 210 211 215 256 265 266 267 268}

  
  

Advice to Patients

• 
  

  Importance of advising patient to avoid excessive ingestion of potassium supplements, potassium-rich foods, or salt substitutes.²⁵⁶

  
  

• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.²⁶⁵

  
  

• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as concomitant illnesses.²⁶⁵

  
  

• 
  

  Importance of informing patients of other important precautionary information.²⁶⁵ (See Cautions.)

  
  

Preparations

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

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

Spironolactone

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	25 mg*	Aldactone (with povidone)	Pfizer
			Spironolactone Tablets	Mutual, Mylan, Sandoz, UDL, United Research
		50 mg*	Aldactone (with povidone; scored)	Pfizer
			Spironolactone Tablets	Mutual, Mylan, Purepac, United Research
		100 mg*	Aldactone (with povidone; scored)	Pfizer
			Spironolactone Tablets	Mutual, Mylan, Purepac, United Research

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

Spironolactone and Hydrochlorothiazide

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	25 mg Spironolactone and Hydrochlorothiazide 25 mg*	Aldactazide (with povidone)	Pfizer
			Spironolactone and Hydrochlorothiazide Tablets	Mutual, Mylan, United Research
		50 mg Spironolactone and Hydrochlorothiazide 50 mg	Aldactazide (with povidone; scored)	Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Aldactazide 25-25MG Tablets (PFIZER U.S.): 30/$40.99 or 90/$98.97

Aldactazide 50-50MG Tablets (PFIZER U.S.): 30/$64.99 or 90/$176.97

Aldactone 100MG Tablets (PFIZER U.S.): 30/$89.99 or 90/$249.98

Aldactone 25MG Tablets (PFIZER U.S.): 30/$39.99 or 90/$96.97

Aldactone 50MG Tablets (PFIZER U.S.): 30/$61.99 or 90/$160.96

Spironolactone 100MG Tablets (ACTAVIS ELIZABETH): 30/$34.99 or 90/$81.97

Spironolactone 25MG Tablets (ACTAVIS ELIZABETH): 30/$15.99 or 60/$22.98

Spironolactone 50MG Tablets (QUALITEST): 30/$21.99 or 90/$46.97

Spironolactone-HCTZ 25-25MG Tablets (MYLAN): 30/$16.99 or 60/$22.98

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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

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232. Struthers AD. Why does spironolactone improve mortality over and above an ACE inhibitor in congestive heart failure? Br J Clin Pharmacol. 1999; 47:479-82.

233. Barr CS, Lang CC, Hanson J et al. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1995; 76:1259-65. [IDIS 360040] [PubMed 7503007]

234. Francis GS, Chu C. Compensatory and maladaptive responses to cardiac dysfunction. Curr Opin Cardiol. 1995; 10:260-7. [PubMed 7612975]

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236. Wang W. Chronic administration of aldosterone depresses baroreceptor reflex function in the dog. Hypertension. 1994;24:571-5.

237. Wang W, McClain JM, Zucker IH. Aldosterone reduces baroreceptor discharge in the dog. Hypertension. 1992;19:270-7.

238. Jacobs DS, DeMott, Grady HS et al, ed. Laboratory test handbook. 4th ed. Hudson: Lexi-Comp, Inc; 1996:67-8.

239. Packer M, Gottlieb SS, Blum MA. Immediate and long-term pathophysiologic mechanisms underlying the genesis of sudden cardiac death in patients with congestive heart failure. Am J Med. 1987; 82(Suppl 3A):4-9. [PubMed 2882674]

240. Packer M, Lee WH, Kessler PD et al. Role of neurohormonal mechanisms in determining survival in patients with severe chronic heart failure. Circulation. 1987; 75(Suppl IV):IV-80-IV-92.

241. Whang R. Magnesium deficiency: pathogenesis, prevalence, and clinical implications. Am J Med. 1987; 82(suppl 3A):24-9. [PubMed 3565424]

242. Hollifield JW. Magnesium depletion, diuretics, and arrhythmias. Am J Med. 1987; 82(Suppl 3A):30-7. [IDIS 227096] [PubMed 2436474]

243. Sueta CA, Clarke SW, Dunlap SH et al. Effect of acute magnesium administration on the frequency of ventricular arrhythmia in patients with heart failure. Circulation. 1994; 89:660-6. [IDIS 325472] [PubMed 7508827]

244. Bashir Y, Sneddon JF, Staunton HA et al. Effects of long-term oral magnesium chloride replacement in congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1993; 72:1156-62. [IDIS 322178] [PubMed 8237806]

245. Eichhorn EJ, Tandon PK, DiBianco R et al. Clinical and prognostic significance of serum magnesium concentration in chronic congestive heart failure: The PROMISE Study. J Am Coll Cardiol. 1993; 21:634-40. [PubMed 8436744]

246. Anon. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Part II. Management of heart failure: approaches to the prevention of heart failure. Am J Cardiol. 1999; 83:9-38A.

247. Anon. Spironolactone for heart failure. Med Lett Drugs Ther. 1999; 41:81-2. [PubMed 10505071]

248. Juillerat L, Nussberger J, Menard J et al. Determinants of angiotensin II generation during converting enzyme inhibition. Hypertension. 1990; 16:564-72. [PubMed 2172161]

249. Pitt B. “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther. 1995; 9:145-9. [PubMed 7786835]

250. Richards AM. Aldosterone antagonism in heart failure. Lancet. 1999; 354:789-90. [PubMed 10485716]

251. Johnston CI, Jackson BJ, Larmour I et al. Plasma enalapril levels and hormonal effects after short- and long-term administration in essential hypertension. Br J Clin Pharmacol. 1984; 18:233-9S.

252. Sanchez RA, Marco E, Gilbert HB et al. Natriuretic effect and changes in renal haemodynamics induced by enalapril in essential hypertension. Drugs. 1985; 30(Suppl 1):49-58. [IDIS 203564] [PubMed 2994987]

253. Hodsman GP, Brown JJ, Cumming AMM et al. Enalapril in the treatment of hypertension with renal artery stenosis. BMJ. 1983; 287:1413-7. [IDIS 178988] [PubMed 6315126]

254. Rocha R, Chander PN, Khann K et al. Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. Hypertension. 1998; 31(Part 2):451-8. [PubMed 9453344]

255. Brilla CG, Pick R, Tan LB et al. Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res. 1990; 67:1355-64. [PubMed 1700933]

256. Searle. Aldactazide (spironolactone with hydrochlorothiazide) tablets prescribing information. Chicago, IL; 2003 Jul.

257. Digoxin interactions: spironolactone (Aldactone). In: Hansten PD, Horn JR. Drug interactions Analysis and Management. Vancouver, WA: Applied Therapeutics, Inc; 1997:240.

258. Merck. Midamor (amiloride HCl) tablets prescribing information (dated 1996 Aug). In: Physicians’ desk reference. 54th ed. Montvale, NJ: Medical Economics Company Inc; 2000:1837-8.

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

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

261. 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. [IDIS 452007] [PubMed 10977801]

262. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) Express. Bethesda, MD: May 14 2003. From NIH website. (). (Also published in JAMA. 2003; 289.

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

264. Guidelines Committee. 2003 European Society of Hypertension–European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertension. 2003; 21:1011-53.

265. Searle. Aldactone (spirono lactone) tablets prescribing information. Chicago, IL; 2003 Jul.

266. Zillich AJ, Carter BL. Eplerenone-a novel selective aldosterone blocker. Ann Pharmacother. 2002; 36:1567-76. [IDIS 487932] [PubMed 12243608]

267. Fernandez MD, Carter GD, Palmer TN. The interaction of canrenone with oestrogen and progesterone receptors in human uterine cytosol. Br J Clin Pharmacol. 1983; 15:95-101. [PubMed 6849751]

268. Nirde P, Terouanne B, Gallais N et al. Antimineralocorticoid 11B-substituted spirolactones exhibit androgen receptor agonistic activity: A structure function study. Mol Pharmacol. 2001; 59:1307-13. [PubMed 11306716]

269. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adoles

Januvia

Generic Name: Sitagliptin Phosphate
Class: Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
VA Class: HS502
Chemical Name: 7 - [(3R) - 3 - amino - 1 - oxo - 4 - (2,4,5 - trifluorophenyl)butyl] - 5,6,7,8 - tetrahydro - 3 - (trifluoromethyl) - 1,2,4 - triazolo[4,3 - a]pyrazine phosphate monohydrate
Molecular Formula: C₁₆H₁₅F₆N₅O•H₃O₄P•H₂O
CAS Number: 654671-77-9

Special Alerts:

[Posted 09/25/2009] FDA notified healthcare professionals and patients of revisions to the prescribing information for sitagliptin (Januvia) and sitagliptin/metformin (Janumet) to include information on reported cases of acute pancreatitis in patients using these products. Eighty-eight post-marketing cases of acute pancreatitis, including two cases of hemorrhagic or necrotizing pancreatitis in patients using sitagliptin, were reported to the Agency between October 2006 and February 2009. It is recommended that healthcare professionals monitor patients carefully for the development of pancreatitis after initiation or dose increases of sitagliptin or sitagliptin/metformin. Sitagliptin has not been studied in patients with a history of pancreatitis. Therefore, it is not known whether these patients are at an increased risk for developing pancreatitis and the medication should be used with caution and with appropriate monitoring in patients with a history of pancreatitis. Considerations for healthcare professionals, information for patients, and a Data Summary are provided. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for sitagliptin to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Antidiabetic agent; dipeptidyl peptidase-4 (DPP-4) inhibitor.^{1 9 11}

Uses for Januvia

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise for management of type 2 diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet and exercise alone.^{1 3 4 9}

Used in combination with metformin hydrochloride as initial therapy for management of patients with type 2 diabetes mellitus whose hyperglycemia cannot be controlled by diet and exercise alone.^{1 11 21}

Used in combination with metformin, a sulfonylurea, or a thiazolidinedione (e.g., a peroxisome proliferator-activated receptor-_γ [PPAR-_γ] agonist) as second-line therapy for management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and metformin, sulfonylurea, or thiazolidinedione monotherapy.^{1 2 5 9 11 22 24} Patients initially receiving an oral antidiabetic agent will eventually require multiple oral antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control because of declining β₂-cell function with disease progression.^{15 16 17 18 19}

Used in combination with metformin and a sulfonylurea as second-line therapy for management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and combined therapy with a sulfonylurea and metformin.^{1 22}

Fixed combination with metformin used as second-line therapy in patients who do not achieve adequate glycemic control despite diet, exercise, and monotherapy with sitagliptin or metformin.^{1 11} Fixed combination with metformin also used in those already receiving therapy with sitagliptin and metformin as separate components.¹¹ Safety and efficacy of switching to sitagliptin/metformin fixed combination from antidiabetic agents other than sitagliptin or metformin not established.¹¹

Safety and efficacy of sitagliptin in combination with insulin not established.^{1 6 11}

Not indicated for type 1 diabetes mellitus or diabetic ketoacidosis; insulin is required in these conditions.^{1 6 10 11 13 20 21}

Januvia Dosage and Administration

General

• 
  

  Individualize dosage of sitagliptin/metformin hydrochloride in fixed combination based on patient's current antidiabetic regimen, clinical response, and tolerability.¹¹ Undertake any change in therapy with care and appropriate monitoring because changes in glycemic control can occur.¹¹

  
  

Administration

Oral Administration

Sitagliptin monotherapy: Administer orally once daily with or without food.^{1 6 10} If a dose is missed, take missed dose as soon as it is remembered followed by resumption of regular schedule.⁶ If the missed dose is remembered at time of next dose, skip missed dose and resume the regular schedule.⁶ Do not double dose to replace missed dose.⁶

Sitagliptin/metformin hydrochloride fixed combination: Administer twice daily with meals, increasing dosage gradually to minimize GI adverse effects of metformin hydrochloride component.^{11 13} If a dose is missed, take missed dose with a meal²³ as soon as it is remembered followed by resumption of regular schedule.¹³ If missed dose is remembered at time of next dose, skip missed dose and resume regular schedule.¹³ Do not double dose to replace missed dose.¹³

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as sitagliptin phosphate (as the monohydrate); dosage expressed in terms of sitagliptin.¹

Adults

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Diabetes Mellitus

Previously Untreated Patients

Oral

Monotherapy: 100 mg once daily.^{1 10}

Combination therapy with metformin hydrochloride (as separate components): 100 mg of sitagliptin once daily.^{1 21 23}

Patients Transferred to Combination Therapy with Certain Other Antidiabetic Agents Given as Separate Components

Oral

Combination therapy with metformin hydrochloride: 100 mg of sitagliptin once daily.^{1 5 10 24} May continue current dosage of metformin hydrochloride at initiation of sitagliptin.¹ For additional therapy, see Diabetes Mellitus under Uses.

Combination therapy with a sulfonylurea: 100 mg of sitagliptin once daily.^{1 22} Dosage of concomitant sulfonylurea may need to be reduced to decrease risk of hypoglycemia.^{1 6} For additional therapy, see Diabetes Mellitus under Uses.

Combination therapy with metformin hydrochloride and a sulfonylurea: 100 mg of sitagliptin once daily.^{1 22} Dosage of concomitant sulfonylurea may need to be reduced to decrease risk of hypoglycemia.^{1 6} For additional therapy, see Diabetes Mellitus under Uses.

Combination therapy with a thiazolidinedione: 100 mg of sitagliptin once daily.^{1 2 10} May continue current dosage of thiazolidinedione at initiation of sitagliptin.¹ For additional therapy, see Diabetes Mellitus under Uses.

Sitagliptin/Metformin Hydrochloride Fixed-combination Therapy

Oral

Patients inadequately controlled on monotherapy with metformin hydrochloride: Initially, 50 mg of sitagliptin and 500 mg of metformin hydrochloride or 50 mg of sitagliptin and 1 g of metformin hydrochloride twice daily as the fixed combination, depending on the patient's existing dosage of metformin hydrochloride.^{11 23} Select the tablet strength of the fixed combination that most closely provides the patient's existing dosage of metformin hydrochloride.^{11 23}

Patients inadequately controlled on metformin hydrochloride 850 mg twice daily: 50 mg of sitagliptin and 1 g of metformin hydrochloride twice daily as the fixed combination.¹¹

Efficacy and safety of transferring patients inadequately controlled on metformin hydrochloride dosage >2 g daily to sitagliptin in fixed combination with metformin hydrochloride not established.²³

Patients inadequately controlled on sitagliptin monotherapy: Initially, 50 mg of sitagliptin and 500 mg of metformin hydrochloride as the fixed combination twice daily.¹¹ If additional glycemic control is needed, increase dosage of the metformin hydrochloride component by administering 50 mg of sitagliptin and 1 g of metformin hydrochloride as the fixed combination twice daily.^{11 23}

For replacement of therapy with the drugs given concurrently as separate tablets, dosage of the fixed combination is based on the patient's current dosages of sitagliptin and metformin hydrochloride.¹¹ Select the tablet strength of the fixed combination that most closely provides patient's existing dosages of sitagliptin and metformin hydrochloride.^{11 23}

Prescribing Limits

Adults

Diabetes Mellitus

Oral

Sitagliptin monotherapy: Maximum 100 mg daily.²³

Fixed combination with metformin hydrochloride: Maximum 100 mg of sitagliptin and 2 g of metformin hydrochloride daily (in divided doses).^{11 23}

Special Populations

Hepatic Impairment

No dosage adjustments necessary in patients with mild to moderate hepatic impairment (Child-Pugh score ≤9).^{1 10 23} Efficacy and safety not established in patients with severe hepatic impairment (Child-Pugh score >9).^{1 10}

Renal Impairment

Sitagliptin Monotherapy

Oral

Moderate renal impairment (Cl_cr of 30 to <50 mL/minute, corresponding to S_cr of >1.7–3 mg/dL in men or >1.5–2.5 mg/dL in women): 50 mg once daily.^{1 23 26}

Severe renal impairment (Cl_cr <30 mL/minute, corresponding to S_cr of >3 mg/dL in men or >2.5 mg/dL in women): 25 mg once daily.^{1 26}

End-stage renal disease requiring hemodialysis or peritoneal dialysis: 25 mg once daily.^{1 26}

May administer without regard to timing of hemodialysis.^{1 10 26} (See Absorption: Special Populations, under Pharmacokinetics.)

Sitagliptin/Metformin Hydrochloride Fixed-combination Therapy

Oral

Patients with renal impairment receiving reduced dosages of sitagliptin should not be switched to the fixed combination of sitagliptin and metformin hydrochloride.¹¹ (See Renal Impairment under Cautions.)

Geriatric Patients

Sitagliptin monotherapy: Select dosage with caution because of age-related decreases in renal function.^{1 11} (See Geriatric Use and also see Renal Impairment under Cautions.)

Sitagliptin in fixed combination with metformin hydrochloride: Select dosage with caution because of age-related decreases in renal function.¹¹ (See Geriatric Use and also see Renal Impairment under Cautions.) Carefully titrate dosage to minimum dosage necessary for adequate glycemic control.¹¹

Cautions for Januvia

Contraindications

• 
  

  Known serious hypersensitivity (e.g., anaphylaxis, angioedema) to sitagliptin or any ingredient in formulation.^{1 11}

  
  

Warnings/Precautions

Use of Fixed Combinations

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

When used in fixed combination with metformin hydrochloride, consider the cautions, precautions, and contraindications associated with metformin hydrochloride.¹¹

Loss of Glycemic Control

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Possible loss of glycemic control during periods of stress (e.g., fever, trauma, infection, surgery).^{1 6 11} (See Advice to Patients.)

Temporary discontinuance of sitagliptin and administration of insulin may be required.¹¹ May reinstitute therapy after acute episode of hyperglycemia resolved.¹¹

Sensitivity Reactions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Risk of hypersensitivity reactions (e.g., anaphylaxis, angioedema, exfoliative dermatitis, Stevens-Johnson syndrome).^{1 11} Onset usually within first 3 months of treatment initiation, but may occur after first dose.^{1 11} (See Contraindications under Cautions.)

If hypersensitivity reactions occur, discontinue drug, assess other potential causes for event, and institute alternative antidiabetic therapy.^{1 11} (See Advice to Patients.)

Concomitant Antidiabetic Therapy

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

In clinical studies, rates of hypoglycemia in patients receiving sitagliptin in combination with metformin or pioglitazone were similar to placebo.^{1 11 21}

In a long-term (52-week) clinical noninferiority study, rates of hypoglycemia with sitagliptin/metformin combination therapy were lower than those observed with glipizide/metformin combination therapy.^{1 24} However, in a 24-week clinical study, rates of hypoglycemia in patients receiving sitagliptin and glimepiride with or without metformin were greater than those in patients receiving glimepiride and metformin.²² For dosage adjustments, see Patients Transferred to Combination Therapy with Certain Other Antidiabetic Agents Given as Separate Components, under Dosage and Administration.

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Safety of sitagliptin in combination with insulin not established.^{1 6 11}

Specific Populations

Pregnancy

Category B.^{1 11} Pregnancy registry at 800-986-8999.^{1 11 13}

Lactation

Distributed into milk in rats; not known whether distributed into human milk.^{1 6 11} Use caution.^{1 11}

Pediatric Use

Safety and efficacy of sitagliptin alone or in fixed combination with metformin not established in children <18 years of age.^{1 6 11 13 23}

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹

Substantially eliminated by kidneys; assess renal function prior to initiation of therapy and periodically thereafter because geriatric patients more likely to have decreased renal function.¹

Renal Impairment

Substantially eliminated by kidneys; assess renal function prior to initiation of therapy and periodically thereafter.¹

Common Adverse Effects

Upper respiratory tract infection,^{1 10} nasopharyngitis,^{1 3 4 10} headache.^{1 6 10}

Interactions for Januvia

Metabolized to a limited extent by CYP isoenzymes 3A4 and 2C8 to inactive metabolites.^{1 10 12}

Drugs Metabolized by Hepatic Microsomal Enzymes

Does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro or induce CYP3A4.^{1 11} Pharmacokinetic interactions with drugs metabolized by these isoenzymes unlikely.¹

Inhibitors of p-Glycoprotein Transport System

Substrate of p-glycoprotein transport system.^{1 12} Potential pharmacokinetic interaction (increased absorption and renal clearance of sitagliptin) with p-glycoprotein inhibitors.^{1 12 23}

With wide safety margin of sitagliptin, clinically important pharmacokinetic interactions with p-glycoprotein inhibitors unlikely.^{1 12 23} Does not appear to inhibit p-glycoprotein transport system.^{1 12}

Drugs Secreted by Renal Tubular Cationic Transport

Substrate of organic anion transport system; pharmacokinetic interaction unlikely with substrates of organic cationic transport system.¹

Protein-bound Drugs

Pharmacokinetic interaction unlikely.¹

Specific Drugs

Drug	Interaction	Comments
Cyclosporine	Increased absorption and plasma concentrations of sitagliptin1 12	Not considered clinically important1 12
Digoxin	Slight increase in plasma concentrations and AUC of digoxin 1 23	Not considered clinically important; no dosage adjustment needed1 23
Hormonal contraceptives, oral	No clinically meaningful effect on pharmacokinetics of norethindrone or ethinyl estradiol1
Metformin	Potential additive effect on active GLP-1 concentrations1 11 21 22 Pharmacokinetic interactions unlikely1 10 11 27	Relevance of these effects to glycemic control in patients with type 2 diabetes mellitus unclear11 23
Simvastatin	Pharmacokinetic interactions unlikely1
Sulfonylureas	Minimal additional risk of hypoglycemia when sitagliptin added to glimepiride therapy (limited data)1 22 Pharmacokinetic interactions unlikely1 23	Reduced dosage of sulfonylurea may be required to reduce risk of hypoglycemia1 23
Thiazolidinediones	Pharmacokinetic interactions unlikely1
Warfarin	Pharmacokinetic interactions unlikely1

Januvia Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability 87%.^{1 23}

Rapidly absorbed following oral administration; at steady state (within 3 days of therapy initiation), peak plasma concentrations generally attained ≤3 hours following administration of recommended doses.^{1 23 25}

Fixed-combination tablet containing sitagliptin 50 mg and metformin hydrochloride 500 mg or 1 g (Janumet) bioequivalent to one 50-mg tablet of sitagliptin and one 500-mg or 1-g tablet of metformin hydrochloride, respectively, given simultaneously.¹¹

Onset

Reduction in postprandial plasma glucose excursion: Approximately 60 minutes.^{4 7 23}

Duration

Approximately 80% inhibition of DPP-4 activity persists for 12 or 24 hours following administration of ≥50 or ≥100 mg, respectively, of sitagliptin.^{1 9 23 25}

Food

Food does not appear to affect absorption.¹

Special Populations

Renal impairment results in increased plasma AUC.¹ Removed modestly by hemodialysis; time to peak plasma drug concentration increased in a limited number of patients with end-stage renal disease requiring hemodialysis.^{1 26}

Moderate hepatic impairment results in increased peak plasma concentrations and AUC; not considered clinically important.^{1 23}

In geriatric patients, modest increases in plasma concentrations compared with younger adults.^{1 11}

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.^{1 11}

Plasma Protein Binding

38%.¹

Elimination

Metabolism

Metabolized to a limited extent by CYP isoenzymes 3A4 and 2C8 to inactive metabolites.^{1 12}

Elimination Route

Eliminated principally by kidneys via active tubular secretion.^{1 25 26} Excreted in urine (87%) mainly as unchanged drug and in feces (13%).^{1 10}

Half-life

12.4 hours.¹

Special Populations

Renal impairment results in increased terminal elimination half-life.²⁶

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).^{1 11 13}

Actions

• 
  

  Inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme that inactivates incretin hormones glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).^{1 7 8 9 11 21 24}

  
  


• 
  

  Inhibits DPP-4 selectively with no effect on DPP-8 or DDP-9 in vitro at concentrations approximating those from therapeutic dosage.^{1 11}

  
  


• 
  

  Increases circulating concentrations of GIP and GLP-1 in a glucose-dependent manner.^{1 2 3 7 8 9 10 21} Coadministration of sitagliptin and metformin has an additive effect on active GLP-1 concentrations.^{1 11 21}

  
  


• 
  

  GIP and GLP-1 stimulate insulin synthesis and release from pancreatic β-cells in a glucose-dependent manner (i.e., when glucose concentrations are normal or elevated) by intracellular signaling pathways involving cyclic 3′,5′-adenosine monophosphate (cAMP).^{1 8 21 24}

  
  


• 
  

  GLP-1 also decreases glucagon secretion from pancreatic α-cells in a glucose-dependent manner, leading to reduced hepatic glucose production.^{1 2 3 7 21 24}

  
  


• 
  

  Lowers fasting plasma glucose concentrations and reduces glucose excursions following glucose load or meal in patients with type 2 diabetes mellitus.^{1 4 7 11}

  
  


• 
  

  Sitagliptin usually not associated with hypoglycemia or substantial changes in body weight.^{1 3 4 5 8 9}

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Inform patients of potential risks and advantages of sitagliptin-containing therapy and of alternative therapies.^{1 11}

  
  


• 
  

  Importance of patient reading patient information leaflet before initiating therapy and each time drug is dispensed.^{1 6 13}

  
  


• 
  

  Importance of instructing patients regarding self-monitoring of blood glucose, periodic HbA_1c monitoring, adherence to meal planning, regular physical exercise, and management of hypoglycemia and hyperglycemia.^{1 6 11 13}

  
  


• 
  

  Discuss potential for alterations in dosage requirements in special situations (e.g., fever, trauma, infection, surgery, changes in renal function); importance of informing clinician promptly if such situations occur.^{1 6 13} (See Loss of Glycemic Control under Cautions.)

  
  


• 
  

  Risk of allergic reactions (e.g., rash; hives; swelling of face, lips, tongue, throat that may cause difficulty in breathing or swallowing).^{1 6 11} If such reactions occur, importance of discontinuing sitagliptin and informing clinicians promptly.^{1 6 11 13} (See Sensitivity Reactions under Cautions.)

  
  


• 
  

  Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 6 13}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., allergies, kidney problems).^{6 13}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{1 6 13} (See Cautions.)

  
  

Preparations

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

Sitagliptin Phosphate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	25 mg (of sitagliptin)	Januvia	Merck
		50 mg (of sitagliptin)	Januvia	Merck
		100 mg (of sitagliptin)	Januvia	Merck

Sitagliptin Phosphate Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	50 mg (of sitagliptin) with Metformin Hydrochloride 500 mg	Janumet (with povidone)	Merck
		50 mg (of sitagliptin) with Metformin Hydrochloride 1 g	Janumet (with povidone)	Merck

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Janumet 50-1000MG Tablets (MERCK SHARP & DOHME): 60/$216.00 or 180/$618.99

Janumet 50-500MG Tablets (MERCK SHARP & DOHME): 60/$217.00 or 180/$629.95

Januvia 100MG Tablets (MERCK SHARP & DOHME): 30/$216.00 or 90/$619.94

Januvia 25MG Tablets (MERCK SHARP & DOHME): 90/$645.98 or 270/$1,825.92

Januvia 50MG Tablets (MERCK SHARP & DOHME): 30/$220.99 or 90/$635.94

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Merck. Januvia (sitagliptin) tablets prescribing information. Whitehouse Station, NJ; 2007 Oct.

2. Rosenstock J, Brazg R, Andryuk PJ et al. Efficacy and safety of dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006; 28:1556-68. [PubMed 17157112]

3. Raz I, Hanefeld M, Xu L et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006; 49:2564-71. [PubMed 17001471]

4. Aschner P, Kipnes MS, Lunceford JK et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006; 29:2632-7. [PubMed 17130196]

5. Charbonnel B, Karasik A, Liu J et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006; 29:2638-43. [PubMed 17130197]

6. Merck. Januvia (sitagliptin phosphate) tablets patient information. Whitehouse Station, NJ; 2007 Oct.

7. Herman GA, Bergman A, Stevens C et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006; 91:4612-9. [PubMed 16912128]

8. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhbitors in type 2 diabetes. Lancet. 2006; 368:1696-705. [PubMed 17098089]

9. Anon. Sitagliptin (Januvia) for type 2 diabetes. Med Lett Drugs Ther. 2007; 49:1-3.

10. Merck. Product information form for AHFS drug information: Januvia (sitagliptin phosphate) tablets. Whitehouse Station, NJ; 2006.

11. Merck. Janumet (sitagliptin/metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2008 Jan.

12. Krishna R, Bergman A, Larson P et al. Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects. J Clin Pharmacol. 2007; 47:165-74. [PubMed 17244767]

13. Merck. Janumet (sitagliptin phosphate) tablets patient information. Whitehouse Station, NJ; 2008 Jan.

14. Nathan DM, Buse JB, Davidson MB et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006; 29:1963-72. [PubMed 16873813]

15. Hirsch IB, Bergenstal RM, Parkin CG et al. A real-world approach to insulin therapy in primary care practice. Clin Diabetes. 2005; 23(2):78-86.

16. Buse J. Combining insulin and oral agents. Am J Med. 2000; 108(Suppl 6A):23S-32S. [IDIS 446200] [PubMed 10764847]

17. Florence JA, Yeager BF. Treatment of type 2 diabetes mellitus. Am Fam Physician. 1999; 59:2835-44. [IDIS 428714] [PubMed 10348076]

18. Bastyr EJ, Johnson ME, Trautman ME et al. Insulin lispro in the treatment of patients with type 2 diabetes mellitus after oral agent failure. Clin Ther. 1999; 21:1703-4. [IDIS 438022] [PubMed 10566566]

19. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999; 131:281-303. [IDIS 430576] [PubMed 10454950]

20. American Diabetes Association. Hyperglycemic crises in patients with diabetes mellitus. Diabetes Care. 2004; 27(Suppl 1):S94-102.

21. Goldstein BJ, Feinglos MN, Lunceford JK et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007; 30:1979-87. [PubMed 17485570]

22. Hermansen K, Kipnes M, Luo E et al. Efficacy and safety of the didpeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007; 9:733-45. [PubMed 17593236]

23. Merck, North Wales, PA: personal communication.

24. Nauck MA, Meininger G, Sheng G et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007; 9:194-205. [PubMed 17300595]

25. Bergman A, Stevens C, Zhou YY et al. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a didpeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther. 2006; 28:55-72. [PubMed 16490580]

26. Bergman AJ, Cote J, Yi B et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care. 2007; 30:1862-4. [PubMed 17468348]

27. Herman GA, Bergman A, Yi B et al. Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes. Curr Med Res Opin. 2006; 22:1939-47. [PubMed 17022853]

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• Diabetes, Type 2

Promazine Hydrochloride 25mg / 5ml Oral Syrup

1. Name Of The Medicinal Product

Promazine Hydrochloride 25mg/5ml Oral Syrup

2. Qualitative And Quantitative Composition

Promazine Hydrochloride 25mg/5ml

3. Pharmaceutical Form

Oral Syrup

4. Clinical Particulars

4.1 Therapeutic Indications

1. As an adjunct to short-term management of moderate to severe psychomotor agitation

2. Agitation and restlessness in the elderly

4.2 Posology And Method Of Administration

For oral administration only.

Dosage varies with the individual and the purpose for which the drug is used, so the following dosages are only for general guidance with regard to possible effectiveness and good tolerance.

Initial dosages should be low, with increments at frequent, regular intervals until the desired response is obtained. Dosage intervals are usually six to eight hours, but in some patients the 24 hour requirement may be conveniently administered in a single bedtime dose.

The commencement and increase of dosage should be performed under close supervision.

Psychomotor Agitation

Adults: 100mg to 200mg, four times daily.

Elderly: Half the normal starting dose may be sufficient for a therapeutic response.

Agitation and Restlessness

Elderly: 25mg initially, increasing, if necessary, up to 50mg, four times a day.

Children: Promazine is not recommended for children

4.3 Contraindications

Use in patients hypersensitive to the active ingredient or other phenothiazines.

Use in patients in coma or CNS depression

Use in patients with bone marrow depression

Use in patients with phaeochromocytoma

Use during lactation

Do not use during pregnancy, especially during the first three months, unless there are compelling reasons.

4.4 Special Warnings And Precautions For Use

1. Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia have been described after abrupt cessation of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore, gradual withdrawal is advisable.

2. Phenothiazine should only be used with great caution in patients with a history of jaundice or with existent liver dysfunction, or blood dyscrasias, (perform blood counts if unexplained infection or fever occurs) coronary insufficiency or cardiac disease.

3. Respiratory depression may occur in patients with severe respiratory disease.

4. Promazine should be used with caution in patients with renal failure.

5. Patients receiving phenothiazines over a prolonged period require regular and careful surveillance with particular attention to potential for inducing eye changes (corneal and lens opacities and purplish pigmentation of the skin, cornea, conjunctiva and retina), effects on haemopoiesis, liver dysfunction, myocardial conduction effects, particularly if other concurrently administered drugs also have potential effects on these systems.

6. Use of phenothiazines at high (relative or absolute) doses may induce extrapyramidal side effects, dyskinesia, akathisia, dystonia. These are likely to be particularly severe in children. Caution should be exercised in patients with Parkinson's disease. Anti-parkinson agents should not be prescribed routinely because of the risk of aggravating anticholinergic side effects of Promazine, of precipitating toxic-confusional states or of impairing its therapeutic efficacy. They should be given only as required.

7. Prolonged administration of phenothiazines may result in persistent or tardive dyskinesias particularly in the elderly. The risk of tardive dyskinesia and the likelihood of irreversibility are believed to increase as the duration of therapy and total cumulative dose increase. Neuroleptic therapy should be withdrawn if dyskinesia develops.

8. Care should be exercised if Promazine is used for the treatment of patients with cerebral arteriosclerosis, coronary heart disease or other conditions in which a fall in blood pressure might be undesirable.

9. Caution should be observed with patients suffering from epilepsy or conditions predisposing to epilepsy.

10. Personal or family history of narrow angle glaucoma.

11. Phenothiazines may impair body temperature regulation. Caution should be observed in very hot or very cold weather.

12. Hypothyroidism.

13. Myasthenia gravis.

14. Phaeochromocytoma.

15. Prostatic hypertrophy.

16. Antipsychotic drugs may increase prolactin secretion.

17. An approximately 3-fold increased risk of cerebrovascular adverse events have been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. Promazine should be used with caution in patients with risk factors for stroke.

18. As with other drugs belonging to the therapeutic class of antipsychotics, promazine may cause QT prolongation. Persistently prolonged QT intervals may increase the risk of malignant arrhythmias. Therefore, promazine should be used with caution in susceptible individuals (with hypoklaemia, hypomagnesia or genetic predisposition) and in patients with a history of cardiovascular disorders, e.g. QT prolongation, significant bradycardia (<50 beats per minute), a recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia. Concomitant treatment with other antipsychotics should be avoided (See section 4.5).

19. Concomitant use of promazine with other neuroleptics should be avoided.

20. Photosensitisation may occur, particularly at higher doses. Patients should be advised to avoid direct sunlight.

21. The elderly are particularly susceptible to the side effects of promazine, particularly hypotension, sedation and temperature regulation effects.

22. Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Promazine and preventive measures undertaken.

Increased Mortality in Elderly people with Dementia

Data from two large observational studies showed that elderly people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.

Promazine is not licensed for the treatment of dementia-related behavioural disturbances.

Excipients in the Formulation

This product contains hydroxybenzoate esters. These are known to cause urticaria, delayed type reactions such as contact dermatitis and rarely an immediate reaction with urticaria and bronchospasm.

Promazine Syrup contains liquid glucose. Patients with rare glucose-galactose malabsorption should not take this medicine.

Promazine Syrup contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The concomitant administration of this product with other medication such as central nervous system depressants (including alcohol and anaesthetics) or antihypertensives, opioids, anticholinergic or dopaminergic drugs may result in accentuation of their effects, while potentiation of action may also occur with monoamine oxidase inhibitors, antidepressants and analgesics. Promazine may impair the effects of anticonvulsants. Promazine may affect the control of diabetes and possibly antagonises the hypoglycaemic effect of sulfonylureas. Undesirable anticholinergic effects can be enhanced by anti-parkinson or other anticholinergic drugs.

The concomitant administration of this product with myelosuppressive drugs (carbamazepine, co-trimoxazole, chloramphenicol, sulphonamides, pyralizone analgesics (e.g. azapropazone), penicillamine and cytotoxics) increases the risk of toxicity.

Lithium administration will result in an increased risk of extrapyramidal effects and the possibility of neurotoxicity.

Coadministration of phenothiazines with metoclopramide or tetrabenazine increases the risk of extrapyramidal effects.

An increase in plasma concentration of antipsychotic drugs may occur if taken with ritonavir.

There is an increased risk of convulsions when promazine is coadministered with tramadol

Antipsychotic drugs antagonize the pressor effects of sympathomimetics.

The effects of antipsychotic drugs may be enhanced by cimetidene and reduced by memantine.

Antacids and kaolin may reduce absorption of phenothiazines.

Caution should be used when using antipsychotics with reboxetine.

Sotalol administration will result in an increased risk of ventricular arrhythmia.

Concomitant use of promazine with drugs known to prolong the QT interval may increase the risk of ventricular arrhythmias, including torsade de pointes. Therefore concomitant use of these products is not recommended. Examples include certain antiarrhythmics, such as those of Class 1A (such as quinidine, disopyramide and procainamide) and Class III (such as amiodarone, sotalol and dofetilide), certain antimicrobials (sparfloxacin, moxifloxacin, erythromycin IV), tricyclic antidepressants (such as amitriptyline), certain tetracyclic antidepressants (such as maprotiline), other neuroleptics (e.g. phenothiazines, pimozide, sertindole and haloperidol), certain antihistamines (such as terfenadine), cisapride, bretylium and certain antimalarials such as quinine and mefloquine. This list is not comprehensive.

Concurrent use of drugs causing electrolyte imbalance is not recommended. Diuretics, in particular those causing hypokalemia, should be avoided but, if necessary, potassium-sparing diuretics are preferred.

4.6 Pregnancy And Lactation

Do not use during pregnancy, especially during the first three months, unless there are compelling reasons. There is insufficient evidence of the safety of Promazine in human pregnancy nor is there evidence from animal studies that it is free from hazard.

Promazine should not be used during lactation.

4.7 Effects On Ability To Drive And Use Machines

Phenothiazines may impair alertness and induce drowsiness especially at the start of treatment. Alcohol and many other drugs (see section 4.5) may enhance these effects and impair the ability to drive.

Persons taking these drugs should not drive or operate machinery unless the drug has been shown not to interfere with physical or mental ability.

4.8 Undesirable Effects

Promazine is a member of the phenothiazine group of drugs and the size effects associated with that group have been noted.

System Organ Class
Blood and lymphatic system disorders	Sensitivity reactions including agranulocytosis, leucopenia, haemolytic anaemia.
Metabolism and nutrition disorders	Weight gain
Psychiatric disorders	Apathy, confusional state. Some individuals may be susceptible to the drug in low dosage and show paradoxical effects of excitement, agitation or insomnia and other minor side effects.
Nervous system disorders	Drowsiness, dizziness, headache, sedation, epileptic fits, extrapyramidal symptoms (dystonia, tremor, tardive dyskinesia and akathisia), neuroleptic malignant syndrome (hyperthermia, rigidity, autonomic dysfunction, altered consciousness) may occur with any neuroleptic.
Eye disorders	Blurred vision, precipitation of glaucoma, corneal and lens opacities and purplish pigmentation of the skin, cornea, conjunctiva and retina.
Cardiac disorders	Tachycardia, cardiovascular effects include hypotension. Phenothiazines can produce ECG changes with prolongation of QT interval and T-wave changes, ventricular arrhythmias (VF, VT (rare)), sudden unexplained death, cardiac arrest and Torsades de pointes have been reported.
Respiratory, thoracic and mediastinal disorders	Nasal stuffiness
Gastrointestinal disorders	Gastrointestinal disturbances, dry mouth, constipation.
Hepatobiliary disorders	Transient abnormalities of liver function tests may occur without jaundice. Rarely - obstructive jaundice associated with stasis in biliary canaliculi. Treatment should then be withdrawn and not given again.
Skin and subcutaneous tissue disorder	Sensitivity reactions including allergic skin reactions, rashes, photosensitisation and contact sensitization.
Renal and urinary disorders	Urinary hesitancy or retention when due to enlarged prostate.
Reproductive system and breast disorders	Menstrual disturbances, galactorrhoea, gynaecomastia, impotence.
General disorders and administration site conditions	Hypothermia, hyperpyrexia.

The elderly are particularly susceptible to side effects of Promazine, especially to the sedative, hypotensive and temperature regulation effects. This may be dose related.

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs – Frequency unknown

Withdrawal symptoms, including nausea, vomiting, sweating, insomnia, recurrence of psychotic symptoms and involuntary movement disorders have been noted (see Section 4.4).

4.9 Overdose

Ingestion of large amounts of Promazine is followed by deep sleep, with or without a pronounced fall in blood pressure and without particular change in respiration rate, other than the slowing attendant upon sedation. Occasionally an initial period of excitement may precede coma, followed by grand mal seizures.

In the absence of any specific antidote, treatment should be based on ordinary therapeutic principles with special emphasis on the following measures:

a. Gastric lavage;

b. Treat convulsions if present;

c. Correction of acute hypotension if necessary;

d. Counteraction of the effects of an excess of Promazine on the central nervous system;

e. Control and natural recovery of hypothermia.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Promazine has a wide range of activity arising from its depressant actions on the central nervous system and its alpha-adrenergic blocking and weaker anticholinergic activities. It is a dopamine inhibitor; it inhibits prolactin release-inhibitory factor, considered to be dopamine, thus stimulating the release of prolactin. The turnover of dopamine in the brain is also increased.

5.2 Pharmacokinetic Properties

Promazine is readily absorbed from the gastro-intestinal tract but is subject to considerable first-pass metabolism in the gut wall. It is also extensively metabolised in the liver and is excreted in the urine and faeces in the form of numerous active and inactive metabolites; there is evidence of enterohepatic recycling. Owing to the first-pass effect, plasma concentrations following oral administration are much lower than those following intramuscular administration.

Moreover, there is very wide intersubject variation in plasma concentrations of Promazine; no simple correlation has been found between plasma concentrations of Promazine and its metabolites, and their therapeutic effect. Paths of metabolism of Promazine include hydroxylation and conjugation with glucuronic acid, N-oxidation, oxidation of a sulphur atom, and dealkylation. Its duration of therapeutic effect can range from a few days to several weeks or possibly longer.

Promazine is very extensively bound to plasma proteins. It is widely distributed in the body and crosses the blood-brain barrier to achieve higher concentrations in the brain than in the plasma. Promazine and its metabolites also cross the placental barrier and are excreted in milk.

5.3 Preclinical Safety Data

None stated

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene glycol (E1520), methyl hydroxybenzoate (E218), ethyl hydroxybenzoate (E214), propyl hydroxybenzoate (E216), sucrose, liquid glucose, ascorbic acid (E300), green lemon flavour 545489E and purified water.

6.2 Incompatibilities

None known

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Store below 25°C. Protect from light.

6.5 Nature And Contents Of Container

Amber (type III) glass bottle with capacities of 150ml, 200ml and 500ml

1. Aluminium, wadded, roll-on, pilfer proof closure.

2. HDPE, child resistant, tamper evident, EPE wadded closure.

3. HDPE, tamper evident, EPE wadded closure.

6.6 Special Precautions For Disposal And Other Handling

Dispense in amber glass bottles. If a dose of under 5ml is required, the oral syrup should be administered using an oral dosing device.

Administrative Data

7. Marketing Authorisation Holder

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

8. Marketing Authorisation Number(S)

PL 0427/0054

9. Date Of First Authorisation/Renewal Of The Authorisation

5.2.82 / 24.3.95/5.4.02

10. Date Of Revision Of The Text

07.06.2010

PR Otic

Pronunciation: a-SEE-tik AS-id/AN-tee-PYE-reen/BEN-zoe-kane/POL-ee-COHS-an-ol
Generic Name: Acetic Acid/Antipyrine/Benzocaine/U-Polycosanol
Brand Name: PR Otic

PR Otic is used for:

Relieving pain and inflammation in the ear caused by certain ear conditions. It may be used with antibiotics given by mouth to treat certain ear infections. It may also be used to help remove a buildup of earwax.

PR Otic is an antibacterial, analgesic, and anesthetic combination. It works by relieving pressure and reducing inflammation, congestion, pain, and discomfort.

Do NOT use PR Otic if:

• you are allergic to any ingredient in PR Otic or to similar medicines


• your eardrum is perforated or you have discharge from your ear

Contact your doctor or health care provider right away if any of these apply to you.

Before using PR Otic:

Some medical conditions may interact with PR Otic. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances

Some MEDICINES MAY INTERACT with PR Otic. However, no specific interactions with PR Otic are known at this time.

Ask your health care provider if PR Otic may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use PR Otic:

Use PR Otic as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• PR Otic is for topical use in the ear canal only. Do not get PR Otic in the eyes, nose, or mouth. If you get PR Otic in any of these areas, rinse right away with cool water.


• Before using, hold the ear drop container in your hand for 1 or 2 minutes to avoid dizziness that may result from putting cold drops into the ear. To use ear drops, lie down or tilt your head so that the affected ear faces up. For adults, gently pull the earlobe up and back to straighten the ear canal. For children, gently pull the earlobe down and back to straighten the ear canal. Drop the medicine into the ear canal. Keep the ear facing up for several minutes so the medicine can run to the bottom of the ear canal. Moisten a clean cotton plug with PR Otic and gently insert into the ear canal to prevent medicine from leaking out.


• To prevent germs from contaminating the medicine, do not touch the applicator to any surface, including the ear. Do not rinse dropper after use. Keep the container tightly closed.


• If PR Otic is brown or contains particles, do not use it.


• If you miss a dose of PR Otic, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use PR Otic.

Important safety information:

• PR Otic may cause harm if it is swallowed. If you may have taken it by mouth, contact your poison control center or emergency room right away.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using PR Otic while you are pregnant. It is not known if PR Otic is found in breast milk. If you are or will be breast-feeding while you use PR Otic, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of PR Otic:

All medicines may cause side effects, but many people have no, or minor, side effects. When used in small doses, no COMMON side effects have been reported with PR Otic. Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); irritation not present when you began using PR Otic.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch .

See also: PR Otic side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of PR Otic:

Store PR Otic at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Protect from freezing. Keep the container tightly closed. Store away from heat, moisture, and light. Keep PR Otic out of the reach of children and away from pets.

General information:

• If you have any questions about PR Otic, please talk with your doctor, pharmacist, or other health care provider.


• PR Otic is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about PR Otic. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More PR Otic resources

• PR Otic Side Effects (in more detail)
• PR Otic Use in Pregnancy & Breastfeeding
• 0 Reviews for PR Otic - Add your own review/rating

Compare PR Otic with other medications

• Ear Wax Impaction

Hydra-1

Generic Name: carbohydrate and electrolyte combination (Oral route)

Commonly used brand name(s)

In the U.S.

• CeraLyte 70


• Cera Sport


• Hydra-1


• HydraLife


• Pedia-Pop

In Canada

• Gastrolyte

Available Dosage Forms:

• Tablet


• Powder for Suspension


• Solution


• Powder for Solution


• Packet

Uses For Hydra-1

Carbohydrate and electrolytes combination is used to treat or prevent dehydration (the loss of too much water from the body) that may occur with severe diarrhea, especially in babies and young children. Although this medicine does not immediately stop the diarrhea, it replaces the water and some important salts (electrolytes), such as sodium and potassium, that are lost from the body during diarrhea, and helps prevent more serious problems. Some carbohydrate and electrolytes solutions may also be used after surgery when food intake has been stopped.

This medicine is available without a prescription; however, your doctor may have special instructions on the proper use and dose for you or your child.

Before Using Hydra-1

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

This medicine has been tested in children and, in effective doses, appears to be safe and effective in children. This medicine has not been tested in premature infants.

Geriatric

This medicine has been tested and has been shown to be well tolerated by older people.

Pregnancy

Carbohydrate and electrolytes solutions have not been shown to cause birth defects or other problems in humans.

Breast Feeding

This medicine has not been reported to cause problems in nursing babies. Breast-feeding should continue, if possible, during treatment with carbohydrate and electrolytes solution.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking any of these medicines, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using medicines in this class with any of the following medicines is not recommended. Your doctor may decide not to treat you with a medication in this class or change some of the other medicines you take.

• Amantadine


• Atropine


• Belladonna


• Belladonna Alkaloids


• Benztropine


• Biperiden


• Clidinium


• Darifenacin


• Dicyclomine


• Eplerenone


• Glycopyrrolate


• Hyoscyamine


• Methscopolamine


• Oxybutynin


• Procyclidine


• Scopolamine


• Solifenacin


• Tolterodine


• Trihexyphenidyl

Using medicines in this class with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alacepril


• Amiloride


• Benazepril


• Canrenoate


• Captopril


• Cilazapril


• Delapril


• Eltrombopag


• Enalaprilat


• Enalapril Maleate


• Fosinopril


• Imidapril


• Indomethacin


• Licorice


• Lisinopril


• Moexipril


• Pentopril


• Perindopril


• Quinapril


• Ramipril


• Spirapril


• Spironolactone


• Temocapril


• Trandolapril


• Triamterene


• Zofenopril

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of medicines in this class. Make sure you tell your doctor if you have any other medical problems, especially:

• Difficult urination—This condition may prevent the carbohydrate and electrolytes solution from working properly.

• Inability to drink or


• Vomiting (severe and continuing)—Treatment by injection may need to be given to patients with these conditions.

• Intestinal blockage—Carbohydrate and electrolytes solution may be harmful if given to patients with this condition.

Proper Use of carbohydrate and electrolyte combination

This section provides information on the proper use of a number of products that contain carbohydrate and electrolyte combination. It may not be specific to Hydra-1. Please read with care.

For patients using the commercial powder form of this medicine:

• Add 7 ounces of boiled, cooled tap water to the entire contents of one powder packet. Shake or stir the container for 2 or 3 minutes until all the powder is dissolved.


• Do not add more water to the solution after it is mixed.


• Do not boil the solution.


• Make and use a fresh solution each day.

For patients using the freezer pop form of this medicine:

• Pops should be removed from the box before being placed in the freezer. The pops should be frozen before separating.


• The freezer pop can be eaten without freezing, but tastes best when frozen. To eat the frozen pop, cut the top of the wrapper open and push the pop from the bottom of the plastic sleeve.


• To drink as a liquid, cut the top of the wrapper open and pour the unfrozen pop into a cup or glass.

For patients using the powder form of this medicine distributed by the World Health Organization (WHO):

• Add the entire contents of one powder packet to enough drinking water to make one quart (32 ounces) or liter of solution. Shake the container for 2 or 3 minutes until all the powder is dissolved.


• Do not add more water to the solution after it is mixed.


• Do not boil the solution.


• Make and use a fresh solution each day.

Babies and small children should be given the solution slowly, in small amounts, with a spoon, as often as possible, during the first 24 hours of diarrhea.

Take as directed. Do not take it for a longer time than your doctor has recommended. To do so may increase the chance of side effects.

Dosing

The dose medicines in this class will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For dextrose and electrolytes and for rice syrup solids and electrolytes


• For rehydration (to replace the water and some important salts [electrolytes]):
  
  • For oral dosage form (solution):
    
    • Adults and children over 10 years of age—Dose is based on body weight and must be determined by your doctor. At first, the usual dose is 50 to 100 milliliters (mL) per kilogram (kg) (23 to 45 mL per pound) of body weight taken over four to six hours. Your doctor may change the dose depending on your thirst and your response to the treatment.
    
    
    • Children 2 to 10 years of age—Dose is based on body weight and must be determined by your doctor. At first, the usual dose is 50 mL per kg (23 mL per pound) of body weight taken over the first four to six hours. Then, the dose is 100 mL per kg (45 mL per pound) of body weight taken over the next eighteen to twenty-four hours. Your doctor may change the dose depending on your thirst and your response to the treatment. However, the dose is usually not more than 100 mL in any 20-minute period.
    
    
    • Children up to 2 years of age—The dose is based on body weight and must be determined by your doctor. At first, the usual dose is 75 mL per kg (34 mL per pound) of body weight during the first eight hours and 75 mL per kg (34 mL per pound) of body weight during the next sixteen hours. Your doctor may change the dose depending on your thirst and your response to the treatment. However, the dose is usually not more than 100 mL in any 20-minute period.
    
    
  
  
  • For oral dosage form (solution for freezer pop):
    
    • Children older than 1 year of age—Freezer pop may be given as often as desired.
    
    
    • Children up to 1 year of age—Use must be determined by your doctor.
    
    
  
  

• For oral rehydration salts


• For rehydration (to replace the water and some important salts [electrolytes]):
  
  • For oral dosage form (solution):
    
    • Adults and teenagers—Dose is based on body weight and must be determined by your doctor. At first, the usual dose is 50 to 100 milliliters (mL) of solution per kilogram (kg) (23 to 45 mL per pound) of body weight taken over four to six hours. Your doctor may change the dose depending on your thirst and your response to the treatment.
    
    
    • Children—Dose is based on body weight and must be determined by your doctor. At first, the usual dose is 50 to 100 mL per kg (23 to 45 mL per pound) of body weight taken over the first four hours. Your doctor may change the dose depending on your thirst and your response to the treatment.
    
    
  
  

Storage

Keep out of the reach of children.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Do not keep outdated medicine or medicine no longer needed.

Make a fresh solution each day. Discard unused solution at the end of each day. Be sure that any discarded medicine is out of the reach of children.

Precautions While Using Hydra-1

Eat soft foods, if possible, such as rice cereal, bananas, cooked peas or beans, and potatoes to keep up nutrition until the diarrhea stops and regular food and milk can be taken again. Breast-fed infants should be given breast milk between doses of the solution.

If your diarrhea does not improve in 1 or 2 days, or if it becomes worse, check with your doctor.

Also, check with your doctor immediately if your baby or child appears to have severe thirst, doughy skin, sunken eyes, dizziness or lightheadedness, tiredness or weakness, irritability, difficult urination, loss of weight, or convulsions (seizures). These signs may mean that too much water has been lost from the body.

For patients (except nursing babies) using the powder form of this medicine:

• Drink plain water whenever thirsty between doses of solution.

For patients taking the premixed liquid form of this medicine:

• Do not drink fruit juices or eat foods containing added salt until the diarrhea has stopped.

Hydra-1 Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

Symptoms of too much sodium (salt) in the body

• Convulsions (seizures)


• dizziness


• fast heartbeat


• high blood pressure


• irritability


• muscle twitching


• restlessness


• swelling of feet or lower legs


• weakness

Symptoms of too much fluid in the body

• Puffy eyelids

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Vomiting (mild)

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

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More Hydra-1 resources

• Hydra-1 Support Group
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