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Wednesday, 5 October 2016

Ramipril

Class: Angiotensin-Converting Enzyme Inhibitors
VA Class: CV800
Chemical Name: [2S - [1[R*(R*)],2α,3aβ,6aβ]] - 1 - [2 - [[1 - (Ethoxycarbonyl) - 3 - phenylpropyl]amino] - 1 - oxopropy l]octahydrocylopenta[b]pyrrole-2-carboxylic acid
Molecular Formula: C₂₁H₂₈N₂O₅
CAS Number: 87333-19-5
Brands: Altace

May cause fetal and neonatal morbidity and mortality if used during pregnancy.¹ ³⁸ ³⁹ ⁴⁰ ⁴¹ ⁴² ⁴³ ⁴⁴ ⁴⁵ ⁴⁶ ⁸⁸ ⁸⁹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

If pregnancy is detected, discontinue ramipril as soon as possible.¹ ⁸⁹

Introduction

Nonsulfhydryl ACE inhibitor.¹ ² ³

Uses for Ramipril

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).¹ ² ⁴ ¹¹ ³⁸

One of several preferred initial therapies in hypertensive patients with heart failure, postmyocardial infarction, high coronary disease risk, diabetes mellitus, chronic renal failure, and/or cerebrovascular disease.⁶⁹

Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.⁶⁹

CHF after AMI

Reduction of the risk of mortality in hemodynamically stable patients who have demonstrated clinical signs of CHF within a few days following AMI.¹ ² ¹² ¹⁸ ²¹ ²⁴ ²⁷ ²⁸ ⁶² Also may reduce rate of heart failure-associated hospitalization and progression to severe and/or resistant heart failure.¹ ² ¹² ¹⁸ ²¹ ²⁴ ²⁷ ²⁸ ⁶²

Prevention of Cardiovascular Events

Reduction of the risk of cardiovascular death, MI, and stroke in patients ≥55 years of age who are at high risk for cardiovascular events (e.g., those with a history of CAD, stroke, peripheral vascular disease, or diabetes mellitus in addition to ≥1 other cardiovascular risk factor [e.g., hypertension, elevated total cholesterol and/or decreased HDL-cholesterol concentrations, smoking, documented microalbuminuria]) but who are not known to have low ventricular ejection fraction or heart failure.¹ ⁴⁷ ⁴⁸

Reduction in the incidence of diabetic complications and in new diagnosis of diabetes also reported.⁴⁷ ⁴⁸

CHF

Management of symptomatic CHF†, usually in conjunction with cardiac glycosides, diuretics, and β-blockers.⁶² ⁷⁰ ⁷¹ ⁷² ⁷³ ⁷⁴

Diabetic Nephropathy

A first-line agent in the treatment of diabetic nephropathy† in hypertensive patients with type 2 diabetes mellitus.⁷⁸ ⁷⁹

Ramipril Dosage and Administration

Administration

Oral Administration

Administer orally once or twice daily.¹

Swallow capsules whole.¹ Alternatively, open capsules and sprinkle contents on small amount (about 4 oz) of applesauce or mix in 120 mL of water or apple juice.¹ Consume entire mixture to ensure that no drug is lost.¹ (See Storage under Stability.)

Dosage

Adults

Hypertension

Oral

Initially, 1.25–2.5 mg once daily in patients not receiving diuretic therapy.¹ ² ³ ¹¹ ³⁸ Adjust dosage at approximately monthly intervals (more aggressively in high-risk patients) to achieve BP control.¹

In patients currently receiving diuretic therapy, discontinue diuretic, if possible, 2–3 days before initiating ramipril.¹ May cautiously resume diuretic therapy if BP not controlled adequately with ramipril alone.¹ If diuretic cannot be discontinued, increase sodium intake or initiate ramipril at 1.25 mg daily under close medical supervision.¹

Usual dosage: 2.5–20 mg daily,⁶⁹ given in 1 dose or 2 divided doses.¹ ¹¹ ³⁸

If effectiveness diminishes toward end of dosing interval in patients treated once daily, consider increasing dosage or administering drug in 2 divided doses.¹ ³⁸

CHF after MI

Oral

Initially, 2.5 mg twice daily, beginning as early as 2 days after MI.¹ ¹² If hypotension occurs, reduce dosage to 1.25 mg twice daily.¹ After 1 week at initial dosage, adjust dosage as tolerated at 3-week intervals to target dosage of 5 mg twice daily.¹ ¹

Following initial dose, monitor closely for ≥2 hours and until BP has stabilized for at least an additional hour.¹ To minimize risk of hypotension, reduce diuretic dosage, if possible.¹

Prevention of Cardiovascular Events

Oral

Initially, 2.5 mg once daily for 1 week, followed by 5 mg once daily for 3 weeks; subsequently increase dosage as tolerated to maintenance dosage of 10 mg once daily.¹ In patients with hypertension or those with recent MI, may administer total daily dosage in divided doses.¹

Special Populations

Renal Impairment

Initial dosage of 1.25 mg once daily recommended in patients with renal artery stenosis.¹

In patients with Cl_cr <40 mL/minute per 1.73 m², 25% of the usual doses are expected to induce full therapeutic concentrations of ramiprilat.¹

Hypertension

Oral

Initially, 1.25 mg once daily in patients with Cl_cr <40 mL/minute per 1.73 m².¹ Titrate until BP is controlled or to maximum dosage of 5 mg daily.¹

CHF after MI

Oral

Initially, 1.25 mg once daily in patients with Cl_cr <40 mL/minute per 1.73 m².¹ May increase dosage to 1.25 mg twice daily; subsequently titrate according to clinical response and tolerance up to maximum dosage of 2.5 mg twice daily.¹

Volume-and/or Salt-Depleted Patients

Correct volume and/or salt depletion prior to initiation of therapy or initiate therapy at dosage of 1.25 mg once daily.¹

Cautions for Ramipril

Contraindications

Known hypersensitivity (e.g., history of angioedema) to ramipril or another ACE inhibitor.¹

Warnings/Precautions

Warnings

Hepatic Effects

Clinical syndrome that usually is manifested initially by cholestatic jaundice and may progress to fulminant hepatic necrosis (occasionally fatal) reported rarely with ACE inhibitors.¹

If jaundice or marked elevation of liver enzymes occurs, discontinue drug and monitor patient.¹

Hypotension

Possible symptomatic hypotension, particularly in volume- and/or salt depleted patients (e.g., those receiving prolonged diuretic therapy or undergoing dialysis, those with dietary salt restriction, patients with diarrhea or vomiting).¹ Risk of excessive hypotension, sometimes associated with oliguria, azotemia, and, rarely, acute renal failure and death in patients with CHF with or without associated renal insufficiency.¹

Hypotension may occur in patients undergoing surgery or during anesthesia with agents that produce hypotension; recommended treatment is fluid volume expansion.¹

To minimize potential for hypotension, consider recent antihypertensive therapy, extent of BP elevation, sodium intake, fluid status, and other clinical circumstances.¹ Correct volume and/or salt depletion (e.g., by withholding diuretic therapy, increasing sodium intake) prior to initiation of ramipril or reduce initial dosage.¹ (See Dosage and also Special Populations, under Dosage and Administration.)

In patients at risk of excessive hypotension, initiate therapy under close medical supervision; monitor closely for first 2 weeks following initiation of ramipril or any increase in ramipril or diuretic dosage.¹

If hypotension occurs, place patient in supine position, and if necessary, administer IV infusion of physiological saline.¹ Ramipril therapy usually can be continued following restoration of volume and BP.¹

Hematologic Effects

Neutropenia and agranulocytosis reported with captopril; risk appears to depend principally on presence of renal impairment and/or presence of collagen vascular disease (e.g., systemic lupus erythematosus, scleroderma);¹ also reported in patients receiving immunosuppressive therapy.⁵ ⁶ Hematologic effects (e.g., agranulocytosis; pancytopenia; bone marrow depression; reductions in hemoglobin content or leukocyte, erythrocyte, or platelet counts) reported rarely with ramipril.¹

Consider monitoring leukocytes in patients with collagen vascular disease, especially if renal impairment exists.¹

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when used during pregnancy.¹ ⁸⁸ ⁸⁹ (See Boxed Warning.) Such potential risks occur throughout pregnancy, especially during the second and third trimesters.⁸⁹

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.⁸⁸ ⁸⁹

Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.⁸⁹ Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.⁴⁴ ⁴⁶

Sensitivity Reactions

Anaphylactoid reactions and/or head and neck angioedema possible; if associated with laryngeal edema, may be fatal.¹ Immediate medical intervention (e.g., epinephrine) for involvement of tongue, glottis, or larynx.¹

Intestinal angioedema possible; consider in differential diagnosis of patients who developabdominal pain.¹

Anaphylactoid reactions reported in patients receiving ACE inhibitors while undergoing LDL apheresis with dextran sulfate absorption or following initiation of hemodialysis that utilized high-flux membrane.¹

Life-threatening anaphylactoid reactions reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom.¹

Contraindicated in patients with a history of angioedema associated with ACE inhibitors.¹ ⁴⁷ Patients with history of angioedema unrelated to ACE inhibitors may be at increased risk of angioedema associated with ACE inhibitor therapy.¹

General Precautions

Renal Effects

Transient increases in BUN and S_cr possible, especially in patients with preexisting renal impairment or those receiving concomitant diuretic therapy.¹ Possible increases in BUN and S_cr in patients with unilateral or bilateral renal artery stenosis; generally reversible following discontinuance of ramipril and/or diuretic therapy.¹

Possible oliguria, progressive azotemia, and, rarely, acute renal failure and/or death in patients with severe CHF.¹

Closely monitor renal function for the first few weeks of therapy in hypertensive patients with unilateral or bilateral renal-artery stenosis.¹ Some patients may require dosage reduction or discontinuance of ACE inhibitor or diuretic therapy.¹

Hyperkalemia

Possible hyperkalemia, especially in patients with renal impairment or diabetes mellitus and those receiving drugs that can increase serum potassium concentration (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes).¹ (See Interactions.)

Cough

Persistent and nonproductive cough; resolves after drug discontinuance.¹

Specific Populations

Pregnancy

Category C (1st trimester); Category D (2nd and 3rd trimesters).¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions and see Boxed Warning.)

Lactation

Undetectable in human milk following single oral dose; not known whether distributed into milk following multiple doses.¹ Use not recommended.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹

Geriatric Use

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

Hepatic Impairment

Use with caution in patients with cirrhosis and/or ascites, due to possible increased activity of renin-angiotensin-aldosterone system.¹

Possible marked increase in plasma ramipril concentrations; peak plasma ramiprilat concentrations not appreciably altered. (See Absorption: Special Populations, under Pharmacokinetics.)¹

Renal Impairment

Systemic exposure to ramiprilat may be increased.¹ (See Pharmacokinetics.) Initial dosage adjustment may be necessary depending on degree of renal impairment.¹ (See Renal Impairment under Dosage and Administration.)

Deterioration of renal function may occur.¹ (See Renal Effects under Cautions.)

Blacks

BP reduction may be smaller in black patients compared with nonblack patients;¹ ¹⁴ ¹⁵ ⁶⁷ ⁶⁸ however, no apparent population difference during combined therapy with ACE inhibitor and thiazide diuretic.¹¹ ¹⁴ ¹⁶ ¹⁷ ³⁸ Use in combination with a diuretic.¹¹ ¹⁴ ¹⁶ ¹⁷ ³⁸

Higher incidence of angioedema reported with ACE inhibitors in blacks compared with other races.¹ ⁶⁸ ⁶⁹

Common Adverse Effects

Patients with hypertension: Headache, dizziness, fatigue.¹

Patients with CHF: Dizziness, cough, nausea, vomiting, angina pectoris, syncope, postural hypotension, vertigo, hypotension.¹

Interactions for Ramipril

Specific Drugs

Drug	Interaction	Comments
Antacid	Pharmacokinetic interaction unlikely¹
Antidiabetic agents (insulin, oral agents)	Possible hypoglycemia in diabetic patients¹	Monitor closely for symptoms of hypoglycemia following initiation or dosage adjustment of ramipril; adjust dosage of antidiabetic agent as necessary¹
Cimetidine	Pharmacokinetic interaction unlikely¹
Digoxin	Pharmacokinetic interaction unlikely¹
Diuretics	Increased hypotensive effect¹	If possible, discontinue diuretic before initiating ramipril¹ (see Dosage and also Special Populations, under Dosage and Administration)
Diuretics, potassium-sparing (amiloride, spironolactone, triamterene)	Enhanced hyperkalemic effect¹	Use with caution; monitor serum potassium concentrations frequently¹
Lithium	Increased serum lithium concentrations; possible toxicity¹	Use with caution; monitor serum lithium concentrations frequently¹
NSAIAs	Potential for reduction of renal function and increase in serum potassium¹ No interaction observed with indomethacin¹
Potassium supplements or potassium-containing salt substitutes	Enhanced hyperkalemic effect¹	Use with caution; monitor serum potassium concentrations frequently¹
Simvastatin	Pharmacokinetic interaction unlikely¹
Warfarin	Pharmacologic interaction unlikely¹

Ramipril Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations of ramipril usually attained within 1 hour.¹ Peak plasma concentrations of ramiprilat attained within 2–4 hours after oral dose.¹ About ≥50–60% of an oral dose is absorbed.¹

Onset

Following multiple oral doses (≥2 mg), >90% inhibition of plasma ACE activity achieved 4 hours after dosing.¹

Duration

Following multiple oral doses (≥2 mg), inhibition of >80% of plasma ACE activity persists for about 24 hours.¹

Food

Food decreases rate but not extent of absorption.¹ Opening the capsules and sprinkling the contents on applesauce or mixing the contents in apple juice does not alter serum concentrations of ramiprilat.¹ (See Oral Administration under Dosage and Administration.)

Special Populations

In patients with hepatic impairment, plasma concentrations of ramipril are increased; peak plasma ramiprilat concentrations are similar to those in individuals with normal hepatic function.¹

In patients with renal impairment (Cl_cr <40 mL/minute per 1.73m²), plasma concentrations and AUC of ramiprilat are increased, and time to peak plasma ramiprilat concentrations is slightly prolonged.¹

Distribution

Extent

Distributes into a large peripheral compartment.¹ Crosses the placenta.¹ Undetectable in human milk following single oral dose; not known whether distributed into milk following multiple doses.¹

Plasma Protein Binding

Ramipril: About 73%.¹

Ramiprilat: About 56%.¹

Elimination

Metabolism

Metabolized mainly in the liver, principally to an active metabolite, ramiprilat.¹

Elimination Route

Excreted in urine (60%) as unchanged drug and ramiprilat and in feces (approximately 40%).¹

Half-life

Triphasic; apparent elimination half-life of ramiprilat: Approximately 13–17 hours.¹

Special Populations

In patients with Cl_cr <40 mL/minute per 1.73m², urinary excretion of ramipril, ramiprilat, and their metabolites is decreased.¹

Stability

Storage

Oral

Capsules

15–30 ºC.¹

Mixtures of ramipril with applesauce, water, or apple juice (see Oral Administration under Dosage and Administration) are stable for 24 hours at room temperature and 48 hours when refrigerated.¹

ActionsActions

Prodrug; has little pharmacologic activity until metabolized to ramiprilat.¹

Suppresses the renin-angiotensin-aldosterone system.¹

Advice to Patients

Risk of angioedema, anaphylactoid reactions, or other sensitivity reactions.¹ ⁴⁷ Importance of reporting sensitivity reactions (e.g., edema of face, eyes, lips, tongue, larynx, or extremities; hoarseness; swallowing or breathing with difficulty) immediately to clinician and of discontinuing the drug.¹

Importance of reporting signs of infection (e.g., sore throat, fever).¹

Risk of hypotension.¹ Importance of informing clinicians promptly if lightheadedness or fainting occurs.¹

Importance of adequate fluid intake; risk of volume depletion with excessive perspiration, dehydration, vomiting, or diarrhea.¹

Risks of use during pregnancy.¹ ⁸⁸ ⁸⁹ (See Boxed Warning.)

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (including salt substitutes containing potassium).¹

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

Importance of advising patients of other important precautionary information.¹ (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

Ramipril
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	1.25 mg*	Altace	Monarch
			Ramipril Capsules	Cobalt
		2.5 mg*	Altace	Monarch
			Ramipril Capsules	Cobalt
		5 mg*	Altace	Monarch
			Ramipril Capsules	Cobalt
		10 mg*	Altace	Monarch
			Ramipril Capsules	Cobalt

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.

Altace 1.25MG Capsules (MONARCH PHARMACEUTICALS): 30/$67.99 or 90/$185.97

Altace 10MG Capsules (MONARCH PHARMACEUTICALS): 30/$85.99 or 90/$239.95

Altace 2.5MG Capsules (MONARCH PHARMACEUTICALS): 30/$76.99 or 90/$211.97

Altace 5MG Capsules (MONARCH PHARMACEUTICALS): 30/$75.99 or 90/$209.97

Ramipril 10MG Capsules (WATSON LABS): 30/$65.99 or 90/$179.97

Ramipril 2.5MG Capsules (WATSON LABS): 30/$49.99 or 90/$139.97

Ramipril 5MG Capsules (WATSON LABS): 30/$55.99 or 90/$149.99

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 April 2008. 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.

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59. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ. 1998; 317:713-20. [IDIS 412065] [PubMed 9732338]

60. Davis TM. United Kingdom Prospective Diabetes Study: the end of the beginning? Med J Aust. 1998; 169:511-2.

61. American Diabetes Association. Clinical Practice Recommendations 1999. Position Statement. Standard of medical care for patients with diabetes mellitus. Diabetes Care. 1999; (Suppl 1):S32-41.

62. 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.

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

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

65. 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]

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

67. Appel LJ. The verdict from ALLHAT—thiazide diuretics are the preferred initial therapy for hypertension. JAMA. 2002; 288:3039-60. [IDIS 490723] [PubMed 12479770]

68. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288:2981-97. [IDIS 490721] [PubMed 12479763]

69. 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.

70. Merck & Co. Vasotec tablets (enalapril maleate) prescribing information. Whitehouse Station, NJ; 2002 Jan.

71. Bristol-Myers Squibb. Monopril (fosinopril sodium) tablets prescribing information. Princeton, NJ; 2002 Feb.

72. Merck. Prinivil (lisinopril) tablets prescribing information. Whitehouse Station, NJ; 2002 Jan.

73. AstraZeneca. Zestril (lisinopril) tablets prescribing information. Wilmington, DE: 2002 Jan.

74. Parke Davis. Accupril (quinapril hydrochloride) tablets prescribing information. Morris Plains, NJ; 2001 Mar.

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

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

77. Novartis. Diovan (valsartan) tablets prescribing information. East Hanover, NJ; 2002 Aug.

78. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2002; 25:134-47. [IDIS 479088] [PubMed 11772914]

79. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2002; 25(Suppl 1):S33-43.

80. American Diabetes Association. Clinical Practice Recommendations 2002. Position Statement. Diabetic nephropathy. Diabetes Care. 2002; 25(Suppl 1):S85-9.

81. Lewis EJ, Hunsicker LG, Bain RP et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993; 329:1456-62. [IDIS 321612] [PubMed 8413456]

82. Remuzzi G. Slowing the progression of diabetic nephropathy. N Engl J Med. 1993; 329:1496-7. [PubMed 8413463]

83. Kaplan NM. Choice of initial therapy for hypertension. JAMA. 1996; 275:1577-80. [IDIS 365188] [PubMed 8622249]

84. Viberti G, Mogensen CE, Groop LC et al. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes

Retavase

Generic Name: retaplase (RE te plase)

Brand Names: Retavase

What is Retavase (retaplase)?

Retaplase is a thrombolytic (THROM-bo-LIT-ik) drug that is used to dissolve blood clots.

Retaplase is used to improve heart function and prevent congestive heart failure or death in people who have had a heart attack.

Retaplase may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Retavase (retaplase)?

You should not receive this medication if you are allergic to retaplase, or if you have a bleeding disorder, a brain tumor or aneurysm, uncontrolled high blood pressure, a history of stroke or blood clots, or recent brain or spinal injury or surgery.

Before using retaplase, tell your doctor if you have kidney or liver disease, eye complications caused by diabetes, an infection of the lining of your heart, or if you have had any recent surgery, injury, or major bleeding.

Tell your doctor if you take aspirin, a blood thinner such as warfarin (Coumadin), or any medications to prevent blood clots, such as abciximab (ReoPro), dipyridamole (Persantine), and others.

Tell your doctor at once if you have a serious side effect such as sudden numbness or weakness, confusion, problems with speech or vision, chest pain, sudden cough, wheezing, rapid breathing, fast or slow heart rate, darkening or purple discoloration of your fingers or toes, blood in your urine or stools, pale skin, easy bruising, or any bleeding that will not stop.

What should I discuss with my health care provider before I receive Retavase (retaplase)?

You should not receive this medication if you are allergic to retaplase, or if you have certain conditions. Be sure your doctor knows if you have:

any active bleeding;

a bleeding or blood clotting disorder;

a brain tumor, aneurysm, or blood vessel disorder;

untreated or uncontrolled high blood pressure;

a history of stroke or blood clot; or

recent spine or brain injury or surgery.

Before you receive retaplase, tell your doctor if you are allergic to any drugs, or if you have:

kidney disease;

liver disease;

eye complications caused by diabetes;

an infection of the lining of your heart (also called bacterial endocarditis); or

if you have had any recent surgery, injury, or major bleeding.

If you have any of these conditions, you may need a dose adjustment or special tests to safely receive this medicaiton.

FDA pregnancy category C. Retaplase may be harmful to an unborn baby. Before receiving this medication, tell your doctor if you are pregnant. It is not known whether retaplase passes into breast milk or if it could harm a nursing baby. Do not receive this medication without telling your doctor if you are breast-feeding a baby.

How is retaplase given?

Retaplase is given as an injection through a needle placed into a vein. You will receive this injection in a clinic or hospital setting.

Retaplase is usually given in two quick injections through an IV line. These injection are given 30 minutes apart.

This medication can cause you to have unusual results with certain medical tests. Tell any doctor who treats you that you have received retaplase.

What happens if I miss a dose?

Since retaplase is given only when needed by a healthcare professional, it is not likely that you will miss a dose.

What happens if I overdose?

An overdose of retaplase is not likely to occur.

What should I avoid after receiving Retavase (retaplase)?

Follow your doctor's instructions about any restrictions on food, beverages, or activity while you are using retaplase.

Retavase (retaplase) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Tell your doctor at once if you have a serious side effect such as:

sudden numbness or weakness, especially on one side of the body;

sudden headache, confusion, problems with vision, speech, or balance;

chest pain, sudden cough, wheezing, rapid breathing;

fast, slow, or uneven heart rate;

feeling like you might pass out;

weak pulse, fainting, slow breathing (breathing may stop);

darkening or purple discoloration of your fingers or toes;

blood in your urine;

black, bloody, or tarry stools;

coughing up blood or vomit that looks like coffee grounds;

bleeding from needle punctures (such as from needles used in blood tests or in giving injection) injections; or

pale skin, easy bruising, or any bleeding that will not stop.

Less serious side effects may include:

nausea;

vomiting; or

fever.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Retavase (retaplase)?

The following drugs can interact with retaplase. Tell your doctor if you are using any of these:

a blood thinner such as warfarin (Coumadin);

aspirin; or

medication used to prevent blood clots, such as abciximab (ReoPro), dipyridamole (Persantine), and others.

This list is not complete and there may be other drugs that can interact with retaplase. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Retavase resources

Retavase Side Effects (in more detail)
Retavase Use in Pregnancy & Breastfeeding
Retavase Drug Interactions
Retavase Support Group
0 Reviews for Retavase - Add your own review/rating

Retavase Prescribing Information (FDA)

Retavase Monograph (AHFS DI)

Retavase Advanced Consumer (Micromedex) - Includes Dosage Information

Retavase MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Retavase with other medications

Heart Attack

Where can I get more information?

Your doctor or pharmacist can provide more information about retaplase.

See also: Retavase side effects (in more detail)

RE DCP Drops

dextromethorphan hydrobromide, chlorpheniramine maleate, phenylephrine hydrochloride

Dosage Form: oral drops
RE DCP Drops

DESCRIPTION:

RE DCP Drops

Antitussive – Antihistamine – Nasal Decongestant

Rx Only

Each dropperful (1 mL) contains:

Dextromethorphan HBr: 2.75 mg

Chlorpheniramine Maleate: 0.75 mg

Phenylephrine HCl: 1.75 mg

Inactive Ingredients: Cherry Flavor, Citric Acid, Glycerin, Propylene Glycol, Purified Water (Aqua), Red 40 (Cl 16035), Sodium Citrate, Sodium Saccharin, Sorbitol.

CLINICAL PHARMACOLOGY:

Antitussive, Antihistaminic, Nasal decongestant actions.

Dextromethorphan HBr:

Dextromethorphan HBr is a nonopoid antitussive agent. It suppresses the cough reflex by a direct action on the cough center in the medulla of the brain. Dextromethorphan HBr has no significant analgesic or sedative properties. It does not depress the respiration or predispose an individual to addiction with usual doses. In therapeutic dosage, Dextromethorphan HBr does not hihibit ciliary activity. The onset of action is typically within 30 minutes and the duration of actions can be up to 6 hours. Dextromethorphan is rapidly and extensively metabolized by the liver. It is primarily excreted in the kidneys as unchanged Dextromethorphan and demthylated metabolites including dextrophan, an active metabolite.

Phenylephrine Hydrochloride:

Phenylephrine HCl, a nasal decongestant, is a potent postsynaptic alpha-receptor agonist with little effect on the beta receptors of the heart and no effect on the beta-adrenegic receptors of the bronchi or peripheral blood vessels. Therapeutic doses of Phenylephrine HCl may cause vasoconstriction. It increases resistance and, to a lesser extent, decreases capacitance of blood vessels. Total peripheral resistance is increased, resulting in increased systolic and diastolic blood pressure. Pulmonary arterial pressure is usually increased, and renal blood flow is usually decreased. Local vasoconstriction and hemostasis occur following infiltration of Phenylephrine HCl into tissues. The main effect of Phenylephrine HCL on the heart is bradycardia; it produces a positive inotropic effect on the myocardium in doses greater than those usually used therapeutically. Rarely, the drug may increase the irritability of the heart which can cause arrhythmias. Cardiac output is decreased slightly. Phenylephrine HCl has a mild central stimulant effect. Following oral administration of Phenylephrine HCL, contriction of blood vessels in the nasal mucosa relieves nasal congestion associated with allergy or head colds. This may occur within 15 or 20 minutes and may persist for up to 4 hours.

Chlorpheniramine Maleate:

Chlorpheniramine Maleate possesses H1 antihistaminic activity and mild anticholinergic and sedative effects.

INDICATIONS AND USAGE:

For relief of coughs and upper respiratory symptoms, including nasal congestion, associated with allergy or the common cold.

CONTRAINDICATIONS:

RE DCP Drops is contraindicated in patients hypersensitive to any of its ingredients. It is also contraindicated in patients with severe hypertension or severe coronary artery disease, or in those receiving monoamine oxidase (MAO) inhibitors. Antihistamines should not be used to treat lower respiratory tract conditions including asthma.

WARNINGS:

Sympathomimetic amines shoud be used with caution in patients with hypertension, ischemic heart disease, diabetes mellitus, increased intraocular pressure, hyperthyroidism, or prostatic hypertrophy. Sympathomimetics may produce central nervous system stimulation with conclusions or cardiovascular collapse with accompanying hypotension. Do not exceed recommended dosage.

PRECAUTIONS:

General: The underlying cause of cough should be identified before prescribing this medication to suppress or lessen the cough. Avoid alcohol and other CNS depressants while taking this product. Patients sensitive to antihistamines may experience moderate to severe drowsiness.

Information for Patients: Patients should be warned about engaging in activities requiring mental alertness, such as driving or operating dangerous machinery.

Drug Interactions: Antihistamines have additive effects with alcohol and other CHS depressants (hypnotics, sedatives, tranquilizers, antianxiety agents, etc.). MAO inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines. MAO inhibitors may enhance the effect of Phenylephrine HCl. Sympathomimetics may reduce the effects of antihypertensive drugs.

Carcinogenesis, Mutagenesis and Impairment of Fertility: No data are currently available on long term potential for carcinogenesis, mutagenesis, or impairment of fertility in animals or humans.

Pregnancy: Pregnancy Category C: Animal reproduction studies have not been conducted with this product. It is not known whether this product can cause fetal harm when administered to pregnant women or affect reproduction capacity. Give to pregnant women only if clearly needed. Administration of Phenylephrine HCl to patients in late pregnancy or labor may cause fetal anoxia or bradycardia by increasing contractility of the uterus and decreasing uterine blood flow.

Nursing Mothers: Some sympathomimetics are excreted in breast milk. Use of this product by nursing mothers in not recommended.

ADVERSE REACTIONS:

Dextromethorphan HBr:

Adverse effects with Dextromethorpahn HBr are rare, but nausea and/or other gastrointestinal disturbances, headache, slight dizziness and drowsiness can occur.

Phenylephrine HCl:

Hyper-reactive individuals may display ephedrine-like reactions such as tachycardia, palpitations, headache, dizziness, or nausea. Sympathomimetics have been associated with certain adverse reactions including fear, anxiety, nervousness, restlessness, tremor, weakness, pallor, respiratory difficulty, dysuria, insomnia, hallucinations, convulsions, CNS depression, arrhythmias, and cardiovascular collapse with hypotension.

Chlorpheniramine Maleate:

Antihistamines may cause sedation, dizziness, diplopia, vomtting, diarrhea, dry mouth, headache, nervousness, nausea, anorexia, heartburn, weakness, polyuria and, rarely, excitability in children.

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

OVERDOSAGE:

Signs and Symptoms: Overdosage with Dextromethorphan HBr may produce CNS excitement and mental confusion. Overdosage with sympathomimetic amines can cause hypertension, headache, convulsions, cerebral hemorrhage and vomiting may occur. Headache may be a symptom of hypertension. Bradycardia may also be seen early in Phenylephrine HCl overdosage. Excessive CNS stimulation may result in excitement, tremor, restlessness, and insomnia. Other effects may include pallor, mydriasis, hyperglycemia, and urinary retention. Severe overdosage may cause tachypnea or hyperpnea, hallucinations, convulsions, or delirium, but in some individuals, there may be CNS depression. Arrhythmias (including ventricular fibrillation) may lead to hypotension and circulatory collapse. Severe hypokalemia can occur, probably due to a compartmental shift in potassium rather than by its depletion. Should antihistamine effects predominate, central action constitutes the greatest danger. In a small child, symptoms include excitation, hallucination, ataxia, lack of coordination, tremors, flushed face and fever. Convulsions, fixed and dilated pupils, coma and death may occur in severe cases. In the adult, fever and flushing are uncommon, excitement leading to convulsions and postictal depression is often preceded by drowsiness and coma. Respiration is usually not seriously depressed; blood pressure is usually stable.

Treatment: The patient should be induced to vomit, even if emesis has occurred spontaneously. Pharmacologic vomiting by the administration of ipecac syrup a preferred method, however, should not be induced in patients with impaired consciousness. Precautions against aspirations must be taken, especially in infants and children. Folowing emesis, any drug remaining in the stomch may be absorbed by activated charcoal administered as a slurry with water. Treatment of the signs and symptoms of overdosage is symptomatic and supportive.

DOSAGE AND ADMINISTRATION:

FOR ORAL USE ONLY

Children 6 to under 12 years of age:

2 dropperfuls (2.0 mL)

Children 2 to under 6 years of age:

1 dropperful (1.0 mL)

Children under 2:

As directed by a physician

May be repeated every 4-6 hours if required for relief. Not to exceed 4 doses in 24 hours. In mild cases or in particularly sensitive patients, less frequent or reduced doses may be adequate.

HOW SUPPLIED:

RE DCP Drops is a sugar-free, alcohol-free, cherry-flavored liquid and is available in 1 fl oz (30 mL) bottles NDC 68032-317-33, with a calibrated (1 mL) dropper. Store at controlled room temperature 15°-30°C (59°-86°F).

Tamper evident by foil seal under cap. Do not use if foil seal is missing or broken.

WARNING: KEEP THIS AND ALL DRUGS OUT OF REACH OR CHILDREN.

Rx ONLY

Manufactured For:

River’s Edge Pharmaceuticals, LLC

Suwanee, GA 30024

317-11

Iss. 10/08

PACKAGING:

RE DCP Drops
dextromethorphan hydrobromide, chlorpheniramine maleate, phenylephrine hydrochloride liquid

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	NDC Product Code (Source)	68032-317
Route of Administration	ORAL	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
DEXTROMETHORPHAN HYDROBROMIDE (DEXTROMETHORPHAN)	DEXTROMETHORPHAN HYDROBROMIDE	2.75 mg in 1 mL
CHLORPHENIRAMINE MALEATE (CHLORPHENIRAMINE)	CHLORPHENIRAMINE MALEATE	0.75 mg in 1 mL
PHENYLEPHRINE HYDROCHLORIDE (PHENYLEPHRINE)	PHENYLEPHRINE HYDROCHLORIDE	1.75 mg in 1 mL

Inactive Ingredients
Ingredient Name	Strength
CITRIC ACID MONOHYDRATE
GLYCERIN
PROPYLENE GLYCOL
WATER
SODIUM CITRATE
SACCHARIN SODIUM
SORBITOL

Product Characteristics
Color		Score
Shape		Size
Flavor		Imprint Code
Contains

Packaging
#	NDC	Package Description	Multilevel Packaging
1	68032-317-33	30 mL In 1 BOTTLE	None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
unapproved drug other		10/01/2008	02/29/2012

Labeler - River's Edge Pharmaceuticals, LLC (133879135)

Revised: 12/2010River's Edge Pharmaceuticals, LLC

More RE DCP Drops resources

RE DCP Drops Side Effects (in more detail)
RE DCP Drops Dosage
RE DCP Drops Use in Pregnancy & Breastfeeding
RE DCP Drops Drug Interactions
0 Reviews for RE DCP - Add your own review/rating

Compare RE DCP Drops with other medications

Cough and Nasal Congestion

RabAvert (obsolete)

Generic Name: rabies vaccine (ray BEES vack seen)

Brand Names: Imovax Rabies (obsolete), Imovax Rabies I.D. (obsolete), RabAvert (obsolete), Rabies Vaccine (obsolete)

What is RabAvert (obsolete) (rabies vaccine)?

Rabies is a serious disease caused by a virus. Rabies is mainly a disease of animals. Humans get rabies when they are bitten by an infected animal. There may be no symptoms at first, but weeks or even years after a bite from an infected animal, rabies can cause pain, fatigue, headaches, irritability, fever, seizures, hallucinations, and paralysis. Rabies can be fatal.

What is the most important information I should know about RabAvert (obsolete) (rabies vaccine)?

People with minor illnesses, such as a cold, may be vaccinated. Those who are moderately or severely ill should usually wait until they recover before getting rabies vaccine. However, if you have been exposed to the rabies virus, you should get the vaccine regardless of any other illnesses you may have.

What should I discuss with my healthcare provider before receiving RabAvert (obsolete) (rabies vaccine)?

Tell your doctor if you have had a life-threatening allergic reaction to the rabies vaccine or a component of the vaccine.

People at high risk of exposure to rabies include veterinarians, animal handlers, rabies laboratory workers, spelunkers, rabies biologics production workers, or anyone who is likely to come in contact with infected animals or the virus itself. These people should be offered rabies vaccine.

Before receiving rabies vaccine, talk to your doctor if you:

have HIV or AIDS or another disease that affects the immune system;

are taking an antimalarial drug;

are taking a medication that affects the immune system (e.g. steroids, anti-rejection medications);

have cancer; or

are receiving cancer treatment with x-rays, radiation, or medication.

Ask your healthcare provider for more information. Rabies vaccine may not be recommended in some cases.

Talk to your doctor before receiving rabies vaccine if you are pregnant or breast-feeding a baby.

How is rabies vaccine administered?

Your doctor, nurse, or other healthcare provider will administer the rabies vaccine as an injection.

What happens if I miss a dose?

Talk to your doctor if you miss a dose.

What happens if I overdose?

An overdose of rabies vaccine is unlikely to occur.

What should I avoid before or after getting RabAvert (obsolete) (rabies vaccine)?

There are no restrictions on food, beverages, or activity before or after receiving rabies vaccine.

RabAvert (obsolete) (rabies vaccine) side effects

Getting rabies disease is much riskier than getting rabies vaccine. However, a vaccine, like any medicine, is capable of causing serious problems, such as severe allergic reactions. The risk of rabies vaccine causing serious harm, or death, is extremely small.

Seek emergency medical attention or contact your doctor immediately if any of the following rare but serious side effects from rabies vaccine are experienced:

a serious allergic reaction including swelling of the lips, tongue, or face; difficulty breathing; closing of the throat; hives; paleness; weakness; dizziness; or a fast heart beat within a few minutes to a few hours after the shot;

high fever; or

behavior changes.

Some people who get rabies vaccine get a sore spot where the shot was given.

Side effects other than those listed here may also occur. Contact your doctor about any side effect that seems unusual or that is especially bothersome.

What other drugs will affect RabAvert (obsolete) (rabies vaccine)?

Talk to your doctor before receiving rabies vaccine if you are taking any of the following medications that may affect the immune system:

an oral or injectable steroid medication such as betamethasone (Celestone), cortisone (Cortone), dexamethasone (Decadron, Dexone), hydrocortisone (Cortef, Hydrocortone), methylprednisolone (Medrol), prednisolone (Prelone, Pediapred), prednisone (Orasone, Deltasone, others), or triamcinolone (Aristocort);

an inhaled or nasal steroid such as beclomethasone (Qvar, Beclovent, Beconase, Vanceril, Vancenase), budesonide (Pulmicort, Rhinocort), flunisolide (Aerobid, Nasalide, Nasarel), fluticasone (Flovent, Flonase), mometasone (Nasonex), or triamcinolone (Azmacort, Nasacort);

treatment for cancer with chemotherapy (medication), radiation, or x-rays;

azathioprine (Imuran);

basiliximab (Simulect);

cyclosporine (Sandimmune, Neoral, Gengraf);

etanercept (Enbrel);

leflunomide (Arava);

muromonab-CD3 (Orthoclone);

mycophenolate mofetil (CellCept);

sirolimus (Rapamune); or

tacrolimus (Prograf).

Other drugs may affect rabies vaccine, talk to your doctor about any medications you are taking.

Where can I get more information?

Your doctor or pharmacist may have additional information or suggest additional resources regarding rabies vaccine.

resorcinol and sulfur Topical

re-SOR-si-nol, SUL-fur

Commonly used brand name(s)

In Canada

Acne-Aid Gel

Acnomel Skin Tone

Acnomel Vanishing

Night Cast S

Available Dosage Forms:

Cream

Paste

Lotion

Ointment

Liquid

Therapeutic Class: Antiacne

Uses For resorcinol and sulfur

Resorcinol and sulfur combination is used to treat acne and similar skin conditions.

resorcinol and sulfur is available without a prescription.

Before Using resorcinol and sulfur

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For resorcinol and sulfur, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to resorcinol and sulfur 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

Resorcinol may be absorbed through the skin and should not be used on large areas of the bodies of infants and children. In addition, resorcinol should not be used on wounds, since doing so may cause a blood disease called methemoglobinemia.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of resorcinol and sulfur in the elderly with use in other age groups.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

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. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

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.

Proper Use of resorcinol and sulfur

Use resorcinol and sulfur only as directed. Do not use more of it and do not use it more often than recommended on the label, unless otherwise directed by your doctor. To do so may increase the chance of absorption through the skin and the chance of resorcinol poisoning.

Before using resorcinol and sulfur, wash the affected areas thoroughly and gently pat dry. Then apply a small amount to the affected areas and spread on gently, but do not rub in.

Immediately after using resorcinol and sulfur, wash your hands to remove any medicine that may be on them.

Keep resorcinol and sulfur away from the eyes. If you should accidentally get some in your eyes, flush them thoroughly with water.

Dosing

The dose of resorcinol and sulfur 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 resorcinol and sulfur. 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 acne and similar skin conditions:
- For cake dosage form:
  - Adults and children—Use two or three times a day.
- For cream dosage form:
  - Adults and children—Use one to three times a day.
- For gel and stick dosage forms:
  - Adults and children—Use as needed.
- For lotion dosage form:
  - Adults and children—Use two times a day.

Missed Dose

If you miss a dose of resorcinol and sulfur, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using resorcinol and sulfur

When using resorcinol and sulfur combination, do not use any of the following preparations on the same affected area as resorcinol and sulfur, unless otherwise directed by your doctor:

Abrasive soaps or cleansers

Alcohol-containing preparations

Any other topical acne preparation or preparation containing a peeling agent (for example, benzoyl peroxide, salicylic acid, or tretinoin [vitamin A acid])

Cosmetics or soaps that dry the skin

Medicated cosmetics

Other topical medicine for the skin

To use any of the above preparations on the same affected area as resorcinol and sulfur may cause severe irritation of the skin.

Do not use any topical mercury-containing preparation, such as ammoniated mercury ointment, on the same affected area as resorcinol and sulfur . To do so may cause a foul odor, may be irritating to the skin, and may stain the skin black. If you have any questions about this, check with your health care professional.

resorcinol and sulfur (depending on the product you are using) may darken light-colored hair. If you have any questions about this, check with your health care professional.

resorcinol and sulfur 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:

Less common or rare

Skin irritation not present before use of resorcinol and sulfur

Symptoms of resorcinol poisoning

Diarrhea, nausea, stomach pain, or vomiting

dizziness

drowsiness

headache (severe or continuing)

nervousness or restlessness

slow heartbeat, shortness of breath, or troubled breathing

sweating

unusual tiredness or weakness

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

Redness and peeling of skin (may occur after a few days)

Less common

Unusual dryness of skin

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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Compare resorcinol and sulfur Topical with other medications

Acne

Refludan

lepirudin

Dosage Form: injection
Refludan®50 mg/vial

lepirudin (rDNA) for injection

Rx Only

Refludan Description

Refludan [lepirudin (rDNA) for injection] is a highly specific direct inhibitor of thrombin. Lepirudin, (chemical designation: [Leu1, Thr2]-63-desulfohirudin) is a recombinant hirudin derived from yeast cells. The polypeptide composed of 65 amino acids has a molecular weight of 6979.5 daltons. Natural hirudin is produced in trace amounts as a family of highly homologous isopolypeptides by the leech Hirudo medicinalis. The biosynthetic molecule (lepirudin) is identical to natural hirudin except for substitution of leucine for isoleucine at the N-terminal end of the molecule and the absence of a sulfate group on the tyrosine at position 63.

The activity of lepirudin is measured in a chromogenic assay. One antithrombin unit (ATU) is the amount of lepirudin that neutralizes one unit of World Health Organization preparation 89/588 of thrombin. The specific activity of lepirudin is approximately 16,000 ATU/mg. Its mode of action is independent of antithrombin III. Platelet factor 4 does not inhibit lepirudin. One molecule of lepirudin binds to one molecule of thrombin and thereby blocks the thrombogenic activity of thrombin. As a result, all thrombin-dependent coagulation assays are affected, eg, activated partial thromboplastin time (aPTT) and prothrombin time (PT /INR) values increase in a dose-dependent fashion (Roethig 1991).

Refludan is supplied as a sterile, white, freeze-dried powder for injection or infusion and is freely soluble in Sterile Water for Injection USP or 0.9% Sodium Chloride Injection USP.

Each vial of Refludan contains 50 mg lepirudin. Other ingredients are 40 mg mannitol and sodium hydroxide for adjustment of pH to approximately 7.

Refludan - Clinical Pharmacology

Pharmacokinetic Properties

The pharmacokinetic properties of lepirudin following intravenous administration are well described by a two-compartment model. Distribution is essentially confined to extracellular fluids and is characterized by an initial half-life of approximately 10 minutes. Elimination follows a first-order process and is characterized by a terminal half-life of about 1.3 hours in young healthy volunteers. As the intravenous dose is increased over the range of 0.1 to 0.4 mg/kg, the maximum plasma concentration and the area-under-the-curve increase proportionally.

Lepirudin is thought to be metabolized by release of amino acids via catabolic hydrolysis of the parent drug. However, conclusive data are not available. About 48% of the administration dose is excreted in the urine which consists of unchanged drug (35%) and other fragments of the parent drug.

The systemic clearance of lepirudin is proportional to the glomerular filtration rate or creatinine clearance. Dose adjustment based on creatinine clearance is recommended (see DOSAGE AND ADMINISTRATION:Monitoring and Adjusting Therapy; Use in Renal Impairment). In patients with marked renal insufficiency (creatinine clearance below 15 mL/min), and on hemodialysis, elimination half-lives are prolonged up to 2 days.

The systemic clearance of lepirudin in women is about 25% lower than in men. In elderly patients, the systemic clearance of lepirudin is 20% lower than in younger patients. This may be explained by the lower creatinine clearance in elderly patients compared to younger patients.

Table 1 summarizes systemic clearance (Cl) and volume of distribution at steady state (Vss) of lepirudin for various study populations.

Table 1: Systemic clearance (Cl) and volume of distribution at steady state (Vss) of lepirudin
HAT: Heparin-associated thrombocytopenia
* CV: Coefficient of variation
	Cl (mL/min) Mean (% CV*)	Vss (L) Mean (% CV*)
Healthy young subjects (n = 18, age 18-60 years)	164 (19.3%)	12.2 (16.4%)
Healthy elderly subjects (n = 10, age 65-80 years)	139 (22.5%)	18.7 (20.6%)
Renally impaired patients (n = 16, creatinine clearance below 80 mL/min)	61 (89.4%)	18.0 (41.1%)
HIT patients (n = 73)	114 (46.8%)	32.1 (98.9%)

Pharmacodynamic Properties

The pharmacodynamic effect of Refludan on the proteolytic activity of thrombin was routinely assessed as an increase in aPTT. This was observed with increasing plasma concentrations of lepirudin, with no saturable effect up to the highest tested dose (0.5 mg/kg body weight intravenous bolus). Thrombin time (TT) frequently exceeded 200 seconds even at low plasma concentrations of lepirudin, which renders this test unsuitable for routine monitoring of Refludan therapy.

The pharmacodynamic response defined by the aPTT ratio (aPTT at a time after Refludan administration over an aPTT reference value, usually median of the laboratory normal range for aPTT) depends on plasma drug levels which in turn depend on the individual patient's renal function (see CLINICAL PHARMACOLOGY:Pharmacokinetic Properties). For patients undergoing additional thrombolysis, elevated aPTT ratios were already observed at low lepirudin plasma concentrations, and further response to increasing plasma concentrations was relatively flat. In other populations, the response was steeper. At plasma concentrations of 1500 ng/mL, aPTT ratios were nearly 3.0 for healthy volunteers, 2.3 for patients with heparin-associated thrombocytopenia, and 2.1 for patients with deep venous thrombosis.

CLINICAL TRIAL DATA

Heparin-induced thrombocytopenia (HIT) is described as an allergy-like adverse reaction to heparin. It can be found in about 1% to 2% of patients treated with heparin for more than 4 days. The clinical picture of HIT is characterized by thrombocytopenia alone or in combination with thromboembolic complications (TECs). These complications comprise the entire spectrum of venous and arterial thromboembolism including deep venous thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, and occlusion of limb arteries, which may ultimately result in necroses requiring amputation. Furthermore, there is evidence to suggest that warfarin-induced venous limb gangrene may be associated with HIT. Without further treatment, the mortality in HIT patients with new TECs is about 20% to 30% (Fondu 1995; Greinacher 1995; Warkentin, Chong, et al., Warkentin, Elavathil, et al. 1997).

The conclusion that Refludan is an effective treatment for HIT is based upon the data of two prospective, historically controlled clinical trials ("HAT-1" study and "HAT-2" study). The trials were comparable with regard to study design, primary and secondary objectives, and dosing regimens, as well as general study outline and organization. They both used the same historical control group for comparison. This historical control was mainly compiled from a recent retrospective registry of HIT patients.

Overall, 198 (HAT-1: 82, HAT-2: 116) patients were treated with Refludan and 182 historical control patients were treated with other therapies. All except 5 (HAT-1: 1, HAT-2: 4) prospective patients and all historical control patients were diagnosed with HIT using the heparin-induced platelet activation assay (HIPAA) or equivalent assays for testing. In total, 113 (HAT-1: 54, HAT-2: 59) prospective patients ("Refludan") and 91 historical control patients ("historical control") presented with TECs at baseline (day of positive test result) and qualified for direct comparison of clinical endpoints.

The gender distribution was found to be similar in Refludan patients and historical control patients. Overall, Refludan patients tended to be younger than historical control patients. Table 2 summarizes the demographic baseline characteristics of patients presenting with TECs at baseline.

Table 2: Demographic baseline characteristics of patients presenting with TECs
	Refludan		Historical Control
	HAT –1 (n = 54)	HAT –2 (n = 59)	(n = 91)
Males	27.8%	44.1%	35.2%
Females	72.2%	55.9%	64.8%
Age <65 years	63.0%	67.8%	44.0%
Age > 65 years	37.0%	32.2%	56.0%
Mean age ± SD (years)	57 ± 17	58 ± 12	64 ± 14

The key criteria of efficacy from a laboratory standpoint (n = 115 evaluable patients) were platelet recovery (increase in platelet count by at least 30% of nadir to values >100,000) and effective anticoagulation (aPTT ratio >1.5 with a maximum total 40% increase in the initial infusion rate). The proportions of Refludan patients presenting with TECs at baseline who showed platelet recovery, effective anticoagulation, or both (laboratory responders) are shown in Table 3. Comparable rates for the historical control group cannot be given, because (1) platelet counts were not monitored as closely as in the Refludan group, and (2) most historical control patients did not receive therapies affecting aPTT.

Table 3: Proportions of laboratory responders among Refludan patients presenting with TECs
	HAT-1	HAT-2
Number of evaluable patients	55	60
Platelet recovery	90.9%	95.0%
Effective anticoagulation	81.8%	75.0%
Both	72.7%	71.7%

Comparisons of clinical efficacy were made between Refludan patients and historical control patients with regard to the combined and individual incidences of death, limb amputation, or new TEC.

The original main analyses included all events that occurred after laboratory confirmation of HIT. This approach revealed to be substantially confounded by the relative contribution of the pretreatment period (time between laboratory confirmation of HIT and start of treatment). Although short in duration (mean length 1.5 days in HAT-1 and 2.0 days in HAT-2), the pretreatment period accounted for 45% and 26% of events observed in the main analyses of HAT-1 Refludan patients and HAT-2 Refludan patients, respectively.

Therefore, initiation of treatment was set as the starting point for the analyses. For the historical control group, the first treatment selected within 2 days of laboratory confirmation of HIT was used for reference.

Seven days after start of treatment, the cumulative risk of death, limb amputation, or new TEC was 3.7% in the HAT-1 Refludan patients and 16.9% in the HAT-2 Refludan patients, as compared to 24.9% in the historical control group. At 35 days, when approximately 10% of patients were still at risk, the cumulative risk was 13.0% in the HAT-1 Refludan patients and 28.9% in the HAT-2 Refludan patients, as compared to 47.8% in the historical control group.

In an additional meta-analysis, the pooled Refludan patients of the HAT-1 and HAT-2 studies who presented with TECs at baseline were compared to the respective historical control patients. Seven and 35 days after start of treatment, the cumulative risks of death were 4.4% and 8.9% in the Refludan group, as compared to 1.4% and 17.6% in the historical control group. The cumulative risks of limb amputation were 2.7% and 6.5% in the Refludan group, as compared to 2.6% and 10.4% in the historical control group. Most importantly, the cumulative risks of new TEC were 6.3 % and 10.1% in the Refludan group, as compared to 22.2% and 27.2% in the historical control group. As shown in Fig 1, differences in the cumulative risk of death, limb amputation, or new TEC between the groups were statistically significant in favor of Refludan in the analysis of time to event (P=0.004 according to log-rank test).

Fig 1: Cumulative risk of death, limb amputation, or new thromboembolic complication after start of treatment

The immediate impact of treatment on the combined risk of death, limb amputation, or new TEC is demonstrated by comparing pretreatment period and treatment period in regard to average combined event rates per patient day. In the pretreatment period, these rates were found to be 0.075 in the HAT-1 Refludan patients, 0.052 in the HAT-2 Refludan patients, and 0.040 in the historical control group. In the treatment period, the rates showed a marked reduction in the Refludan patients, where they dropped to 0.005 (HAT-1) and to 0.018 (HAT-2), while there was only a moderate decrease to 0.030 in the historical control group.

In conclusion, Refludan substantially reduced the risk of serious sequelae of HIT in comparison to a historical control group.

Indications and Usage for Refludan

Refludan is indicated for anticoagulation in patients with heparin-induced thrombocytopenia (HIT) and associated thromboembolic disease in order to prevent further thromboembolic complications.

Contraindications

Refludan is contraindicated in patients with known hypersensitivity to hirudins or to any of the components in Refludan [lepirudin (rDNA) for injection].

Warnings

Hemorrhagic Events

As with other anticoagulants, hemorrhage can occur at any site in patients receiving Refludan. An unexpected fall in hemoglobin, fall in blood pressure or any unexplained symptom should lead to consideration of a hemorrhagic event. While patients are being anticoagulated with Refludan, the anticoagulation status should be monitored closely using an appropriate measure such as the aPTT (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION: Monitoring section.)

Intracranial bleeding following concomitant thrombolytic therapy with rt-PA or streptokinase may be life-threatening. There have been reports of intracranial bleeding with Refludan in the absence of concomitant thrombolytic therapy (see ADVERSE REACTIONS.)

For patients with increased risk of bleeding, a careful assessment weighing the risk of Refludan administration vs its anticipated benefit has to be made by the treating physician:

In particular, this includes the following conditions:

Recent puncture of large vessels or organ biopsy

Anomaly of vessels or organs

Recent cerebrovascular accident, stroke, intracerebral surgery, or other neuraxail procedures

Severe uncontrolled hypertension

Bacterial endocarditis

Advanced renal impairment (see also WARNINGS: Renal Impairment)

Hemorrhagic diathesis

Recent major surgery

Recent major bleeding (eg, intracranial, gastrointestinal, intraocular, or pulmonary bleeding)

Recent active peptic ulcer

Renal Impairment

With renal impairment, relative overdose might occur even with standard dosage regimen. Therefore, the bolus dose and the rate of infusion must be reduced in patients with known or suspected renal insufficiency CAUTION: Preparation of a Refludan bolus injection requires dilution following reconstitution in order to obtain the final concentration of 5 mg/mL. (see CLINICAL PHARMACOLOGY: Pharmacokinetic Properties and DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Use in Renal Impairment).

Precautions

General

Antibodies

Formation of antihirudin antibodies was observed in about 40% of HIT patients treated with Refludan. This may increase the anticoagulant effect of Refludan possibly due to delayed renal elimination of active lepirudin-antihirudin complexes (see also PRECAUTIONS: Animal Pharmacology and Toxicology). Therefore, strict monitoring of aPTT is necessary also during prolonged therapy (see also PRECAUTIONS: Laboratory tests and DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Standard Recommendations). No evidence of neutralization of Refludan or of allergic reactions associated with positive antibody test results was found.

Liver Injury

Serious liver injury (eg, liver cirrhosis) may enhance the anticoagulant effect of Refludan due to coagulation defects secondary to reduced generation of vitamin K-dependent coagulation factors.

Reexposure

During the HAT-1 and HAT-2 studies, a total of 13 patients were reexposed to Refludan. One of these patients experienced a mild allergic skin reaction during the second treatment cycle. In post marketing experience, anaphylaxis after reexposure has been reported. (see PRECAUTIONS—Allergic Reactions below and ADVERSE REACTIONS—Adverse Events from Post Marketing Reports.)

Allergic Reactions

There have been reports of allergic and hypersensitivity reactions including anaphylactic reactions. Serious anaphylactic reactions that have resulted in shock or death have been reported. These reactions have been reported during initial administration or upon second or subsequent reexposure(s).

Laboratory tests

In general, the dosage (infusion rate) should be adjusted according to the aPTT ratio (patient aPTT at a given time over an aPTT reference value, usually median of the laboratory normal range for aPTT); for full information, see DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Standard Recommendations. Other thrombin-dependent coagulation assays are changed by Refludan (see also DESCRIPTION).

Drug interactions

Concomitant treatment with thrombolytics (eg, rt-PA or streptokinase) may

increase the risk of bleeding complications

considerably enhance the effect of Refludan on aPTT prolongation.

(See also WARNINGS: Hemorrhagic Events, ADVERSE REACTIONS: Adverse Events Reported in Other Populations; Intracranial Bleeding and DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Concomitant Use With Thrombolytic Therapy.)

Concomitant treatment with coumarin derivatives (vitamin K antagonists) and drugs that affect platelet function may also increase the risk of bleeding (see also DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Use in Patients Scheduled for a Switch to Oral Anticoagulation).

Animal Pharmacology and Toxicology

General Toxicity

Lepirudin caused bleeding in animal toxicity studies. Antibodies against hirudin which appeared in several monkeys treated with lepirudin resulted in a prolongation of the terminal half-life and an increase of AUC plasma values of lepirudin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the potential for carcinogenesis have not been performed with lepirudin. Lepirudin was not genotoxic in the Ames test, the Chinese hamster cell (V79/HGPRT) forward mutation test, the A549 human cell line unscheduled DNA synthesis (UDS) test, the Chinese hamster V79 cell chromosome aberration test, or the mouse micronucleus test. An effect on fertility and reproductive performance of male and female rats was not seen with lepirudin at intravenous doses up to 30 mg/kg/day (180 mg/m2/day, 1.2 times the recommended maximum human total daily dose based on body surface area of 1.45m2 for a 50 kg subject).

Pregnancy

Teratogenic Effects: Category B

Teratology studies with lepirudin performed in pregnant rats at intravenous doses up to 30 mg/kg/day (180 mg/m2/day, 1.2 times the recommended maximum human total daily dose based on body surface area) and in pregnant rabbits at intravenous doses up to 30 mg/kg/day (360 mg/m2/day, 2.4 times the recommended maximum human total daily dose based on body surface area) have revealed no evidence of harm to the fetus due to lepirudin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Lepirudin (1 mg/kg) by intravenous administration crosses the placental barrier in pregnant rats. It is not known whether the drug crosses the placental barrier in humans.

Following intravenous administration of lepirudin at 30 mg/kg/day (180 mg/m2/day, 1.2 times the recommended maximum human total daily dose based on body surface area) during organogenesis and perinatal-postnatal periods, pregnant rats showed an increased maternal mortality due to undetermined causes.

Nursing Mothers

It is not known whether Refludan is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Refludan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. In the HAT-2 study, two children, an 11-year-old girl and a 12-year-old boy, were treated with Refludan. Both children presented with TECs at baseline. Refludan doses given ranged from 0.15 mg/kg/h to 0.22 mg/kg/h for the girl, and from 0.1 mg/kg/h (in conjunction with urokinase) to 0.7 mg/kg/h for the boy. Treatment with Refludan was completed after 8 and 58 days, respectively, without serious adverse events (Schiffmann 1997).

Adverse Reactions

Adverse Events Reported in Clinical Trials in HIT Patients

The following safety information is based on all 198 patients treated with Refludan in the HAT-1 and HAT-2 studies. The safety profile of 113 Refludan patients from these studies who presented with TECs at baseline is compared to 91 such patients in the historical control.

Hemorrhagic Events

Bleeding was the most frequent adverse event observed in patients treated with Refludan. Table 4 gives an overview of all hemorrhagic events which occurred in at least two patients.

Table 4: Hemorrhagic Events*
* Patients may have suffered more than one event
	HAT-1 HAT-2 (All patients) (n = 198)	Patients with TECs
		Refludan (n = 113)	Historical control (n = 91)
Bleeding from puncture sites and wounds	14.1%	10.6%	4.4%
Anemia or isolated drop in hemoglobin	13.1%	12.4%	1.1%
Other hematoma and unclassified bleeding	11.1%	10.6%	4.4%
Hematuria	6.6%	4.4%	0
Gastrointestinal and rectal bleeding	5.1%	5.3%	6.6%
Epistaxis	3.0%	4.4%	1.1%
Hemothorax	3.0%	0	1.1%
Vaginal bleeding	1.5%	1.8%	0
Intracranial bleeding	0	0	2.2%

Other hemorrhagic events (hemoperitoneum, hemoptysis, liver bleeding, lung bleeding, mouth bleeding, retroperitoneal bleeding) each occurred in one individual among all 198 patients treated with Refludan.

Nonhemorrhagic events

Table 5 gives an overview of the most frequently observed nonhemorrhagic events.

Table 5: Nonhemorrhagic adverse events*
* Patients may have suffered more than one event
	HAT-1 HAT-2 (All patients) (n = 198)	Patients with TECs
		Refludan (n = 113)	Historical control (n = 91)
Fever	6.1%	4.4%	8.8%
Abnormal liver function	6.1%	5.3%	0
Pneumonia	4.0%	4.4%	5.5%
Sepsis	4.0%	3.5%	5.5%
Allergic skin reactions	3.0%	3.5%	1.1%
Heart failure	3.0%	1.8%	2.2%
Abnormal kidney function	2.5%	1.8%	4.4%
Unspecified infections	2.5%	1.8%	1.1%
Multiorgan failure	2.0%	3.5%	0
Pericardial effusion	1.0%	0	1.1%
Ventricular fibrillation	1.0%	0	0

Adverse Events Reported in Clinical Trials in Other Populations

The following safety information is based on a total of 2302 individuals who were treated with Refludan in clinical pharmacology studies (n = 323) or for clinical indications other than HIT (n = 1979).

Intracranial Bleeding

Intracranial bleeding was the most serious adverse reaction found in populations other than HIT patients. It occurred in patients with acute myocardial infarction who were started on both Refludan and thrombolytic therapy with rt-PA or streptokinase. The overall frequency of this potentially life-threatening complication among patients receiving both Refludan and thrombolytic therapy was 0.6% (7 out of 1134 patients). Although no intracranial bleeding was observed in 1168 subjects or patients who did not receive concomitant thrombolysis, there have been post marketing reports of intracranial bleeding with Refludan in the absence of concomitant thrombolytic therapy (seeADVERSE REACTIONS—Adverse Events from Post Marketing Reports and WARNINGS.)

Allergic Reactions

(See PRECAUTIONS.)

Allergic reactions or suspected allergic reactions in populations other than HIT patients include (in descending order of frequency*):

Airway reactions (cough, bronchospasm, stridor, dyspnea):	common
Unspecified allergic reactions:	uncommon
Skin reactions (pruritus, urticaria, rash, flushes, chills):	uncommon
General reactions (anaphylactoid or anaphylactic reactions):	uncommon
Edema (facial edema, tongue edema, larynx edema, angioedema):	rare

* The CIOMS (Council for International Organization of Medical Sciences) III standard categories are used for classification of frequencies:

very common	10% or more
common (frequent)	1 to <10%
uncommon (infrequent)	0.1 to<1%
rare	0.01 to <0.1%
very rare	0.01% or less

About 53% (n = 46) of all allergic reactions or suspected allergic reactions occurred in patients who concomitantly received thrombolytic therapy (eg, streptokinase) for acute myocardial infarction and/or contrast media for coronary angiography.

Adverse Events from Post Marketing Reports

Serious anaphylactic reactions that have resulted in shock or death have been reported. (See PRECAUTIONS.)

Intracranial bleeding has been reported in patients treated with Refludan with or without concomitant thrombolytic therapy. (SeeWARNINGS.) Although no intracranial bleeding was observed in Clinical Trials in those patients who did not receive concomitant thrombolytic therapy (see Adverse Events Reported in Clinical Trials in HIT Patients and Adverse Events Reported in Clinical Trials in Other Populations below), there have been post marketing reports of intracranial bleeding in patients who received Refludan without concomitant thrombolytic therapy.

Overdosage

In case of overdose (eg, suggested by excessively high aPTT values) the risk of bleeding is increased.

No specific antidote for Refludan is available. If life-threatening bleeding occurs and excessive plasma levels of lepirudin are suspected, the following steps should be followed:

Immediately STOP Refludan administration

Determine aPTT and other coagulation levels as appropriate

Determine hemoglobin and prepare for blood transfusion

Follow the current guidelines for treating patients with shock

Individual clinical case reports and in vitro data suggest that either hemofiltration or hemodialysis (using high-flux dialysis membranes with a cutoff point of 50,000 daltons, eg, AN/69) may be useful in this situation.

In studies in pigs, the application of von Willebrand Factor (vWF, 66 IU/kg body weight) markedly reduced the bleeding time. The clinical significance of this data is unknown.

Refludan Dosage and Administration

Initial Dosage

Anticoagulation in adult patients with HIT and associated thromboembolic disease:

0.4 mg/kg body weight (up to 110 kg) slowly intravenously (eg, over 15 to 20 seconds) as a bolus dose. CAUTION: Preparation of a Refludan bolus injection requires dilution following reconstitution in order to obtain the final concentration of 5 mg/mL.

followed by 0.15 mg/kg body weight (up to 110 kg)/hour as a continuous intravenous infusion for 2 to 10 days or longer if clinically needed.

Normally the initial dosage depends on the patient's body weight. This is valid up to a body weight of 110 kg. In patients with a body weight exceeding 110 kg, the initial dosage should not be increased beyond the 110 kg body weight dose (maximal initial bolus dose of 44 mg, maximal initial infusion dose of 16.5 mg/h; see also DOSAGE AND ADMINISTRATION: Administration; Initial Intravenous Bolus, Table 7 and DOSAGE AND ADMINISTRATION: Administration; Intravenous Infusion, Table 8).

In general, therapy with Refludan is monitored using the aPTT ratio (patient aPTT at a given time over an aPTT reference value, usually median of the laboratory normal range for aPTT, see DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Standard Recommendations). A patient baseline aPTT should be determined prior to initiation of therapy with Refludan, since Refludan should not be started in patients presenting with a baseline aPTT ratio of 2.5 or more, in order to avoid initial overdosing.

Monitoring and Adjusting Therapy

Standard Recommendations.

Monitoring

In general, the dosage (infusion rate) should be adjusted according to the aPTT ratio (patient aPTT at a given time over an aPTT reference value, usually median of the laboratory normal range for aPTT).

The target range for the aPTT ratio during treatment (therapeutic window) should be 1.5 to 2.5. Data from clinical trials in HIT patients suggest that with aPTT ratios higher than this target range, the risk of bleeding increases, while there is no incremental increase in clinical efficacy.

As stated in DOSAGE AND ADMINISTRATION: Initial Dosage, Refludan should not be started in patients presenting with a baseline aPTT ratio of 2.5 or more, in order to avoid initial overdosing.

The first aPTT determination for monitoring treatment should be done 4 hours after start of the Refludan infusion.

Follow-up aPTT determinations are recommended at least once daily, as long as treatment with Refludan is ongoing.

More frequent aPTT monitoring is highly recommended in patients with renal impairment or serious liver injury (see DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Use in Renal Impairment) or with an increased risk of bleeding.

Dose Modifications

Any aPTT ratio out of the target range is to be confirmed at once before drawing conclusions with respect to dose modifications, unless there is a clinical need to react immediately.

If the confirmed aPTT ratio is above the target range, the infusion should be stopped for two hours. At restart, the infusion rate should be decreased by 50% (no additional intravenous bolus should be administered). The aPTT ratio should be determined again 4 hours later.

If the confirmed aPTT ratio is below the target range, the infusion rate should be increased in steps of 20%. The aPTT ratio should be determined again 4 hours later.

In general, an infusion rate of 0.21 mg/kg/h should not be exceeded without checking for coagulation abnormalities which might be preventive of an appropriate aPTT response.

Use in Renal Impairment

As Refludan is almost exclusively excreted in the kidneys (see also CLINICAL PHARMACOLOGY: Pharmacokinetic Properties), individual renal function should be considered prior to administration. In case of renal impairment, relative overdose might occur even with the standard dosage regimen. Therefore, the bolus dose and the infusion rate must be reduced in case of known or suspected renal insufficiency (creatinine clearance below 60 mL/min or serum creatinine above 1.5 mg/dL). CAUTION: Preparation of a Refludan bolus injection requires dilution following reconstitution in order to obtain the final concentration of 5 mg/mL. There is only limited information on the therapeutic use of Refludan in HIT patients with significant renal impairment. The following dosage recommendations are mainly based on single-dose studies in a small number of patients with renal impairment.

Therefore, these recommendations are only tentative and aPTT monitoring should be used along with monitoring of renal status.

Dose adjustments should be based on creatinine clearance values, whenever available, as obtained from a reliable method (24 h urine sampling). If creatinine clearance is not available, the dose adjustments should be based on the serum creatinine.

In all patients with renal insufficiency, the bolus dose is to be reduced to 0.2 mg/kg body weight. CAUTION: Preparation of a Refludan bolus injection requires dilution following reconstitution in order to obtain the final concentration of 5 mg/mL.

The standard initial infusion rate given in DOSAGE AND ADMINISTRATION: Initial Dosage and DOSAGE AND ADMINISTRATION: Administration; Intravenous Infusion, Table 8 must be reduced according to the recommendations given in Table 6. Additional aPTT monitoring is highly recommended.