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Thursday, 12 July 2012

Captopril

Class: Angiotensin-Converting Enzyme Inhibitors
VA Class: CV800
CAS Number: 62571-86-2
Brands: Capoten, Capozide

May cause fetal and neonatal morbidity and mortality if used during pregnancy.⁴⁰¹ ⁴⁰² (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

If pregnancy is detected, discontinue captopril as soon as possible.¹¹⁵ ⁴⁰²

Introduction

Sulfhydryl ACE inhibitor.¹ ³ ⁴ ⁵

Uses for Captopril

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).¹⁰⁰ ¹¹⁵ ²¹⁵ ²⁵⁹ ³¹⁶ ³¹⁷

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.³⁸²

Can be used as monotherapy for initial management of uncomplicated hypertension;¹¹⁵ however, thiazide diuretics are preferred by JNC 7.³⁸²

Nephropathy

Stabilization or improvement of effective renal blood flow and glomerular filtration rate and reduction of proteinuria in hypertensive¹¹⁵ ¹⁴¹ ¹⁴² ¹⁴³ ¹⁷⁴ ¹⁸⁷ ¹⁸⁸ ¹⁸⁹ ²⁸¹ ³²³ or normotensive¹¹⁵ ¹⁶² patients with moderately impaired renal function,¹⁴¹ ¹⁴³ ¹⁷⁴ ³²³ moderate to severe renal disease,¹⁴¹ ³²³ or diabetic nephropathy.¹⁴¹ ¹⁴² ¹⁴³ ¹⁸⁷ ¹⁸⁸ ¹⁸⁹ ²⁶⁸ ³³⁴

CHF

Management of symptomatic CHF, usually in conjunction with cardiac glycosides, diuretics, and β-adrenergic blocking agents.¹¹⁵ ²¹⁰ ²⁴⁶ ²⁴⁷ ²⁴⁸ ²⁴⁹ ²⁵⁰ ²⁵² ²⁵³ ²⁵⁴ ²⁵⁶ ²⁵⁷ ²⁹² ³⁰⁴ ³¹⁹ ³²⁰ ³²¹ ³³³ ³⁷⁷

Left Ventricular Dysfunction after AMI

Treatment of clinically stable patients with left ventricular dysfunction (ejection fraction ≤40%) to improve survival following MI and to reduce the incidence of overt heart failure and subsequent hospitalizations for CHF.¹¹⁵ ³¹⁹ ³²¹ ³⁷⁴

Captopril Dosage and Administration

Administration

Oral Administration

Administer orally 1 hour before meals to maximize absorption.¹¹⁵

Dosage

Pediatric Patients

Hypertension

Oral

Dosage has been reduced in proportion to body weight; titrate carefully.¹¹⁵ Some experts recommend an initial dosage of 0.9–1.5 mg/kg daily (given as 0.3–0.5 mg/kg 3 times daily).³⁹⁸ Increase dosage as necessary to a maximum of 6 mg/kg daily.³⁹⁸

Adults

Hypertension

Oral

Initially, 25 mg 2 or 3 times daily.¹¹⁵ ³¹⁶ ³⁸² If BP is not adequately controlled after 1–2 weeks, increase dosage to 50 mg 2 or 3 times daily.¹¹⁵

Lower initial dosages (e.g., 6.25 mg twice daily to 12.5 mg 3 times daily) may be effective in some patients, particularly those already receiving a diuretic.^a (See Hypotension under Cautions.)

Usual dosage: Manufacturers recommend 25–150 mg 2 or 3 times daily (usually not necessary to exceed 450 mg daily).¹¹⁵ ³¹⁶ JNC 7 recommends 25–100 mg daily given in 2 divided doses; JNC 7 recommends adding another drug, if needed, rather than continuing to increase dosage.³⁸²

If combination therapy is initiated with captopril/hydrochlorothiazide fixed-combination preparation, captopril 25 mg and hydrochlorothiazide 15 mg daily initially;¹⁰² ²⁵⁹ adjust dosage (generally at 6-week intervals) by administering each drug separately or by advancing the fixed-combination preparation.¹⁰² ²⁵⁹

Hypertensive Crises

Oral

25 mg 2 or 3 times daily, initiated promptly under close supervision with frequent monitoring of BP.¹¹⁵ May continue previous diuretic therapy, but discontinue other hypotensive agents.¹¹⁵ May increase dosage at intervals of ≤24 hours under continuous supervision until optimum BP response is attained or 450 mg daily is given.¹¹⁵ Adjunctive therapy with other hypotensive agents may be necessary.^a

Acute therapy (e.g., 12.5–25 mg, repeated once or twice if necessary at intervals of 30–60 minutes or longer) has been effective²³¹ ²³² ²³⁶ ²⁵⁹ in adults with hypertensive urgencies†²³¹ ²³² ²⁵⁹ and emergencies†.²³³ ²³⁴ ²³⁵ ²³⁶ ²³⁷ ²³⁸ ²⁵⁹ ³¹⁰

Nephropathy

Diabetic Nephropathy

Oral

25 mg 3 times daily.¹¹⁵ ²⁶²

CHF

Oral

Manufacturers recommend initial dosage of 25 mg 3 times daily;¹¹⁵ in patients with normal or low BP who may be volume- and/or salt-depleted, initial dosage of 6.25 or 12.5 mg 3 times daily.¹¹⁵ Increase dosage gradually to 50 mg 3 times daily; delay further dosage increases for ≥2 weeks to assess response.¹¹⁵

Some clinicians recommend initial dosage of 6.25 or 12.5 mg 3 times daily, with gradual titration over several weeks to 50 mg 3 times daily, regardless of BP, salt/volume status, or concomitant diuretic therapy.³²¹ ³³³ ³⁷⁷ Generally titrate dosage to prespecified target (i.e., ≥150 mg daily) or highest tolerated dosage rather than according to response.³³³ ³⁷⁷

Left Ventricular Dysfunction after AMI

Oral

Manufacturers recommend initiation of therapy ≥3 days post-MI with single dose of 6.25 mg, followed by 12.5 mg 3 times daily.¹¹⁵ Increase dosage over next several days to 25 mg 3 times daily and then over next several weeks (as tolerated) to 50 mg 3 times daily.¹¹⁵

Some clinicians recommend initiation of therapy <24 hours post-MI with initial dose of 6.25 mg, followed by 12.5 mg 2 hours later, 25 mg 10–12 hours later, and then 50 mg twice daily as tolerated.³¹⁹ Recommended maintenance dosage: 50 mg 3 times daily.¹¹⁵

Prescribing Limits

Pediatric Patients

Hypertension

Oral

Maximum 6 mg/kg daily.³⁹⁸

Adults

Hypertension

Oral

Maximum 450 mg daily.¹¹⁵

Dosage of captopril/hydrochlorothiazide fixed-combination generally should not exceed captopril 150 mg and hydrochlorothiazide 50 mg daily.¹⁰²

CHF

Oral

Maximum dosage recommended by manufacturer and some experts is 450 mg daily.¹¹⁵ ³³³ Other experts suggest maximum dosage of 50 mg 3 times daily.³⁷⁷

Special Populations

Renal Impairment

Manufacturers recommend initial dosage of <75 mg daily; increase dosage in small increments at 1- to 2-week intervals.¹¹⁵ After desired therapeutic effect has been attained, slowly reduce dosage to minimum effective level.¹¹⁵

Patients with Cl_cr 10–50 mL/minute: 75% of usual captopril dosage or administration of usual dose every 12–18 hours suggested by some clinicians.²¹¹

Cl_cr <10 mL/minute: 50% of usual dosage or administration of usual dose every 24 hours suggested by some clinicians.²¹¹

Patients undergoing hemodialysis may require supplemental dose after dialysis.²¹¹

Fixed-combination captopril/hydrochlorothiazide tablets usually are not recommended for patients with severe renal impairment.¹⁰²

Geriatric Patients

Hypertension

Usual adult dosages generally have been used; dosages of 6.25–12.5 mg 1–4 times daily used occasionally.¹⁷⁵

Volume-and/or Salt-Depleted Patients

Correct volume and/or salt depletion prior to initiation of therapy or initiate therapy under close medical supervision using lower initial dosage.¹¹⁵ ¹¹⁶ ¹⁴⁸ ¹⁵³ (See Dosage: CHF, under Dosage and Administration.)

Cautions for Captopril

Contraindications

Known hypersensitivity (e.g. history of angioedema) to captopril or another ACE inhibitor.¹¹⁵ ¹⁴⁷ ³²⁵ ³²⁶ ³³³

Warnings/Precautions

Warnings

Hematologic Effects

Possible neutropenia or agranulocytosis; risk of neutropenia appears to depend principally on degree of renal impairment and presence of collagen vascular disease (e.g., systemic lupus erythematosus, scleroderma).¹¹⁵

Use with caution and only after careful risk/benefit assessment in patients with collagen vascular disease or those taking drugs known to affect leukocytes or immune response.¹¹⁵

If used in patients with renal impairment, determine complete and differential leukocyte counts prior to initiation of therapy, at about 2-week intervals for the first 3 months of therapy, and periodically thereafter.¹¹⁵ Discontinue therapy if confirmed neutrophil count is <1000/mm³.¹¹⁵

Proteinuria

Proteinuria possible, particularly in patients with prior renal disease and/or those receiving relatively high dosages (>150 mg daily).¹¹⁵ Usually occurs by the 8th month of treatment¹ ³ ⁴⁶ and subsides or clears within 6 months whether or not therapy is continued;¹¹⁵ however, may persist in some patients.^a

Hypotension

Possible excessive hypotension, particularly in volume- and/or salt-depleted patients (e.g., those treated with diuretics or undergoing dialysis, patients with severe CHF).¹ ⁵ ¹⁷ ²³ ²⁵ ³¹ ⁶⁶ ⁸⁵ ¹¹⁵ ¹¹⁶ ¹⁴⁸ ¹⁵⁴ ¹⁵⁶

Hypotension may occur in patients undergoing surgery or during anesthesia with agents that produce hypotension; recommended treatment is fluid volume expansion.¹¹⁵

Transient hypotension is not a contraindication to additional doses; may reinstate therapy cautiously after BP is stabilized (e.g., with volume expansion).¹¹⁵

To minimize potential for hypotension, consider recent antihypertensive therapy, extent of BP elevation, sodium intake, fluid status, and other clinical conditions.^a (See Special Populations under Dosage and Administration.) Discontinue other antihypertensive therapy, if possible, 1 week before initiating captopril, except in patients with severe hypertension.¹¹⁵ ^a Withholding diuretic therapy and/or increasing sodium intake approximately 3–7 days prior to initiation of captopril may minimize potential for severe hypotension.¹¹⁵ ¹¹⁶ ¹⁴⁸ ¹⁵³

Initiate therapy in patients with CHF under close medical supervision; monitor closely for first 2 weeks following initiation of captopril or any increase in captopril or diuretic dosage.¹¹⁵

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when used during pregnancy.¹⁰² ¹¹⁵ ²³⁹ ²⁴⁰ ²⁴¹ ⁴⁰² (See Boxed Warning.) Such potential risks occur throughout pregnancy, especially during the second and third trimesters.⁴⁰²

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.⁴⁰¹ ⁴⁰²

Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.⁴⁰² Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.²³⁹

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.¹⁰² ¹¹⁵ ³⁷⁰

If jaundice or marked elevation of liver enzymes occurs, discontinue drug and monitor patient.¹¹⁵

Sensitivity Reactions

Anaphylactoid reactions and/or angioedema possible; if associated with laryngeal edema, may be fatal.¹¹⁵ ³³³ Immediate medical intervention (e.g., epinephrine) for involvement of tongue, glottis, or larynx.¹¹⁵ Intestinal angioedema possible; consider in differential diagnosis of patients who develop abdominal pain.¹¹⁵

Anaphylactoid reactions reported in patients receiving ACE inhibitors while undergoing LDL apheresis with dextran sulfate absorption¹¹⁵ ²⁷⁵ ²⁷⁶ ²⁷⁷ or following initiation of hemodialysis that utilized high-flux membrane.¹⁰² ¹¹⁵ ²⁴² ²⁴³ ²⁴⁴

Life-threatening anaphylactoid reactions reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom.¹⁰² ¹⁵⁵ ²⁷⁸

Not recommended in patients with a history of angioedema associated with or unrelated to ACE inhibitors.^a

General Precautions

Renal Effects

Transient increases in BUN and S_cr possible, especially in patients with preexisting renal impairment, sodium depletion, or hypovolemia; patients with renovascular hypertension, particularly those with bilateral renal-artery stenosis or those with renal-artery stenosis in a solitary kidney;⁵ ⁸⁶ ¹¹⁵ ¹¹⁷ ¹²² ¹²³ ¹²⁴ ²⁰⁷ ²⁰⁸ ²⁰⁹ ³³³ ³⁷² or patients with chronic or severe hypertension in whom the glomerular filtration rate may decrease transiently.¹ ¹¹⁵

Possible increases in BUN and S_cr in patients with CHF;¹¹⁵ ²⁰⁶ ³³³ rapidity of onset and magnitude may depend in part on degree of sodium depletion.¹⁴⁸ ¹⁵⁶ ²⁰⁶ ³⁷²

Closely monitor renal function following initiation of therapy in such patients.⁸⁶ ⁸⁷ ¹¹⁵ ¹¹⁷ ¹²² ¹²³ ¹²⁴ ³³³ ³⁷² Some patients may require dosage reduction or discontinuance of ACE inhibitor or diuretic and/or adequate sodium repletion.¹¹⁵ ¹⁵⁶ ²⁰⁶ ²⁰⁷ ²⁰⁹

Hyperkalemia

Possible hyperkalemia,⁵ ⁷ ³⁸ ⁶⁹ ⁷⁰ ⁸⁵ ¹¹⁵ ¹²² ¹²⁵ ¹²⁶ ¹⁶² ¹⁶³ ¹⁶⁴ ¹⁷⁷ especially in patients with impaired renal function, CHF, or diabetes mellitus and those receiving drugs that can increase serum potassium concentration (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes).³⁸ ⁸⁵ ¹¹⁵ ¹²⁵ ¹²⁶ ¹⁴⁸ ¹⁶² ¹⁶³ ¹⁶⁴ ³³³ ³⁷² (See Interactions.)

Monitor serum potassium concentration carefully in these patients.¹²⁶ ¹⁶² ¹⁶³

Cough

Persistent and nonproductive cough; resolves after drug discontinuance.¹⁰² ¹¹⁵ ³³³

Valvular Stenosis

Possible risk of decreased coronary perfusion in patients with aortic stenosis when treated with captopril.^a ¹¹⁵

Use of Fixed Combinations

When used in fixed combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with hydrochlorothiazide.¹⁰²

Specific Populations

Pregnancy

Category C (1st trimester); Category D (2nd and 3rd trimesters).¹¹⁵ (See Fetal/Neonatal Morbidity and Mortality under Cautions and see Boxed Warning.)

Lactation

Distributed into milk.¹¹⁵ Discontinue nursing or the drug.¹¹⁵

Pediatric Use

Safety and efficacy not established; however, captopril has been used in children.¹¹⁵ Manufacturer states that captopril should be used only when other measures for controlling BP have not been effective.¹¹⁵

Possible excessive, prolonged, and unpredictable decreases in BP and associated complications (e.g., oliguria, seizures) in infants.¹¹⁵

Renal Impairment

Systemic exposure to captopril may be increased.¹¹⁵ (See Special Populations under Pharmacokinetics.) Initial dosage adjustment recommended in patients with severe renal impairment.¹¹⁵ (See Renal Impairment under Dosage and Administration.)

Deterioration of renal function may occur.¹¹⁵ ²¹¹ Possible increased risk of neutropenia/agranulocytosis,¹¹⁵ proteinuria,¹¹⁵ and hyperkalemia.¹¹⁵ (See Warnings and General Precautions under Cautions.)

Use of captopril/hydrochlorothiazide fixed combination usually is not recommended in patients with severe renal impairment.¹⁰²

Blacks

BP reduction may be smaller in black patients compared with nonblack patients;¹¹⁵ ¹³⁹ ¹⁷⁷ ¹⁷⁸ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ³⁵¹ however, no apparent population difference during combined therapy with ACE inhibitor and thiazide diuretic.¹⁷⁹ ¹⁹³ ¹⁹⁴ ²¹⁷ ²¹⁸ ²¹⁹ ³¹⁶ Use in combination with a diuretic.¹⁷⁹ ¹⁹³ ¹⁹⁴ ²¹⁷ ²¹⁸ ²¹⁹ ³¹⁶

Higher incidence of angioedema reported with ACE inhibitors in blacks compared with other races.¹⁰² ¹¹⁵ ³²⁵ ³²⁶ ³²⁷ ³⁵¹ ³⁷⁹ ³⁸⁰

Common Adverse Effects

Rash, pruritus, cough, dysgeusia, proteinuria, tachycardia, chest pain, palpitations.¹¹⁵

Interactions for Captopril

Specific Drugs and Laboratory Tests

Drug	Interaction	Comments
Adrenergic neuron blocking agents (guanethidine)	Possible increased hypotensive effect¹¹⁵	Use with caution¹¹⁵
Antacids	Decreased rate and extent of captopril absorption¹⁹⁷ ²⁰¹	Clinical importance is uncertain¹⁹⁷ ²⁰¹
Antidiabetic agents, oral	Possible hypoglycemia in diabetic patients¹⁰¹	Consider risk of hypoglycemia if used concomitantly¹⁰¹
Allopurinol	Pharmacokinetic interaction unlikely¹¹⁵
β-adrenergic blocking agents	Increased (but less than additive) hypotensive effect¹¹⁵
Cimetidine	Neuropathy reported^a	Further documentation of interaction necessary^a
Digoxin	Possible increased serum digoxin concentrations in patients with CHF¹⁹⁸ ¹⁹⁹ ²⁰⁰	Monitor serum digoxin concentration;¹⁹⁸ ²⁰⁰ reduction of digoxin dosage not required upon initiation of captopril¹⁹⁸
Diuretics	Possible additive hypotensive effects^a Pharmacokinetic interaction with furosemide unlikely¹¹⁵	Adjust dosage carefully^a (see Dosage under Dosage and Administration)
Diuretics, potassium-sparing (amiloride, spironolactone, triamterene)	Possible hyperkalemia, especially in patients with renal impairment¹⁶² ³²⁹ ³³¹ ³³⁵	Use cautiously and only if hypokalemia is documented; monitor serum potassium carefully;⁸⁵ ¹¹⁵ ¹²⁵ ¹²⁶ ¹⁴⁸ ¹⁶² ¹⁶³ ¹⁶⁴ discontinue or reduce dosage of potassium-sparing diuretic as necessary⁸⁵ ¹²⁶ ¹⁴⁸ ¹⁶² ¹⁶³
Insulin	Possible hypoglycemia in diabetic patients¹⁰¹	Consider risk of hypoglycemia¹⁰¹
Lithium	Possible increased serum lithium concentrations, particularly in patients receiving concomitant diuretic therapy¹¹⁵	Use with caution; monitor serum lithium concentrations frequently¹¹⁵
NSAIAs	Possible decreased antihypertensive response to captopril;²⁸³ ²⁸⁴ ²⁸⁵ ²⁸⁶ ²⁸⁷ ²⁸⁸ ²⁸⁹ ²⁹⁰ ³³³ ³⁶⁴ potential for acute reduction of renal function;²⁸⁵ ²⁹¹ possible attenuation of hemodynamic actions of ACE inhibitors in patients with CHF³³³ ³⁶⁴	Monitor BP carefully and be alert for evidence of impaired renal function;²⁸⁵ if interaction is suspected, discontinue NSAIA or modify captopril dosage or use another hypotensive agent²⁸⁵ ²⁸⁶
Potassium supplements or potassium-containing salt substitutes	Possible hyperkalemia, especially in patients with renal impairment¹⁶²	Use cautiously and only if hypokalemia is documented; monitor serum potassium carefully;⁸⁵ ¹¹⁵ ¹²⁵ ¹²⁶ ¹⁴⁸ ¹⁶² ¹⁶³ ¹⁶⁴ discontinue or reduce dosage of potassium supplement as necessary⁸⁵ ¹²⁶ ¹⁴⁸ ¹⁶² ¹⁶³
Probenecid	Possible increased blood concentrations of captopril and its metabolites²⁰³ ²⁰⁴ ²⁰⁵ ²¹³
Test for urine acetone	Possible false-positive results with sodium nitroprusside reagent⁵⁴ ¹¹⁵
Vasodilating agents (e.g., hydralazine, nitrates, prazosin)	Possible increased hypotensive effect¹¹⁵	If possible, discontinue vasodilating agent before starting captopril; if vasodilating agent is resumed during captopril therapy, administer with caution and possibly at a lower dosage¹¹⁵

Captopril Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration in fasting individuals,¹⁹ ²⁰ ⁸⁴ ¹¹⁵ with peak blood concentration attained in 1 hour.¹⁹ Approximately 60–75% of an oral dose is absorbed.¹⁹ ²⁰ ⁸⁴ ¹¹⁵

Onset

Hypotensive effect may be apparent within 15 minutes⁵ ⁶ ¹⁶ ²³ and usually is maximal in 1–2 hours after a single oral dose.¹ ³ ¹⁰ ¹⁵ ¹⁶ ¹⁷ ²¹ ²⁴ ²⁹ Several weeks of therapy may be required before full effect on BP is achieved.¹ ³ ⁵ ¹⁶ ²¹ ²⁸

Duration

Duration of action generally is 2–6 hours but appears to increase with increasing doses.^a

Food

Food may decrease absorption of captopril by up to 25–40%;¹ ³ ¹¹⁵ ¹⁹¹ ¹⁹⁵ ¹⁹⁶ ¹⁹⁷ ²⁰² effect may not be clinically important.¹⁹¹ ¹⁹² ¹⁹⁵

Distribution

Extent

Appears to be rapidly distributed into most body tissues, except CNS.¹ ⁵

Crosses the placenta and is distributed into milk.¹¹⁵

Plasma Protein Binding

25–30%¹ ³ ²² (mainly albumin).³

Elimination

Metabolism

About half the absorbed dose is rapidly metabolized.³ ⁵ ¹⁹ Captopril and its metabolites may undergo reversible interconversions.³

Elimination Route

Excreted in urine (95%) as unchanged drug (40–50%) and metabolites.³ ¹⁹ ²⁰ ²² ¹¹⁵

Half-life

<2 hours.¹¹⁵

Special Populations

Elimination half-life is about 20–40 hours in patients with Cl_cr <20 mL/minute ³ and up to 6.5 days in anuric patients.⁵ ²²

Stability

Storage

Oral

Tablets

Tight containers at ≤30°C.¹¹⁵

Tablets (Captopril and Hydrochlorothiazide)

Tight containers at ≤30°C.¹⁰²

ActionsActions

Suppresses the renin-angiotensin-aldosterone system.¹

Advice to Patients

Risk of angioedema, anaphylactoid reactions, or other sensitivity reactions.¹¹⁵ Importance of reporting sensitivity reactions (e.g., edema of face, eyes, lips, tongue, or extremities; hoarseness; swallowing or breathing with difficulty) immediately to clinician and of discontinuing the drug.¹¹⁵

Importance of reporting signs of infection (e.g., sore throat, fever).¹¹⁵

Risk of hypotension.¹¹⁵ Importance of informing clinicians promptly if lightheadedness or fainting occurs.¹¹⁵

Importance of adequate fluid intake; risk of volume depletion with excessive perspiration, dehydration, vomiting, or diarrhea.¹¹⁵

Importance of not discontinuing or interrupting therapy unless instructed by a clinician.¹¹⁵

Risks of use during pregnancy.¹¹⁵ ⁴⁰¹ ⁴⁰² (See Boxed Warning.)

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (including salt substitutes containing potassium) as well as any concomitant illnesses.¹¹⁵

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹¹⁵

Importance of taking 1 hour before meals.¹¹⁵

Importance of advising patients of other important precautionary information.¹¹⁵ (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

Captopril
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	12.5 mg*	Capoten (scored)	Par
		25 mg*	Capoten (scored)	Par
		50 mg*	Capoten (scored)	Par
		100 mg*	Capoten (scored)	Par

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

Captopril and Hydrochlorothiazide
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	25 mg Captopril and Hydrochlorothiazide 15 mg*	Capozide (scored)	Par
			Captopril and Hydrochlorothiazide Tablets	Endo, Mylan, Sandoz, Teva
		25 mg Captopril and Hydrochlorothiazide 25 mg*	Capozide (scored)	Par
			Captopril and Hydrochlorothiazide Tablets	Endo, Mylan, Sandoz, Teva
		50 mg Captopril and Hydrochlorothiazide 15 mg*	Capozide (scored)	Par
			Captopril and Hydrochlorothiazide Tablets	Endo, Mylan, Sandoz, Teva
		50 mg Captopril and Hydrochlorothiazide 25 mg*	Capozide (scored)	Par
			Captopril and Hydrochlorothiazide Tablets	Endo, Mylan, Sandoz, Teva

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.

Capozide 50-25MG Tablets (PAR): 30/$95.99 or 90/$269.98

Captopril 100MG Tablets (WEST-WARD): 90/$19.99 or 180/$29.97

Captopril 12.5MG Tablets (WEST-WARD): 100/$12.99 or 200/$18.98

Captopril 25MG Tablets (TEVA PHARMACEUTICALS USA): 90/$13.99 or 180/$26.99

Captopril 50MG Tablets (WEST-WARD): 100/$16.99 or 200/$22.97

Captopril-Hydrochlorothiazide 25-15MG Tablets (MYLAN): 90/$47.99 or 270/$114.97

Captopril-Hydrochlorothiazide 25-25MG Tablets (MYLAN): 90/$44.99 or 270/$125.99

Captopril-Hydrochlorothiazide 50-15MG Tablets (TEVA PHARMACEUTICALS USA): 60/$53.99 or 180/$154.98

Captopril-Hydrochlorothiazide 50-25MG Tablets (MYLAN): 60/$53.99 or 180/$154.99

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.

References

1. ER Squibb & Sons, Inc. Capoten prescribing information. Princeton, NJ; 1981 Mar.

3. ER Squibb & Sons, Inc. Capoten (captopril) monograph. Princeton, NJ; 1981 Apr.

4. Atkinson AB, Robertson JIS. Captopril in the treatment of clinical hypertension and cardiac failure. Lancet. 1979; 2:836-9. [IDIS 102581] [PubMed 90928]

5. Heel RC, Brogden RN, Speight TM et al. Captopril: a preliminary review of its pharmacological properties and therapeutic efficacy. Drugs. 1980; 20:409-52. [IDIS 134943] [PubMed 7009133]

6. Ferguson RK, Turini GA, Brunner HR et al. A specific orally active inhibitor of angiotensin-converting enzyme in man. Lancet. 1977; 1:775-8. [IDIS 78256] [PubMed 66571]

7. Gavras H, Brunner HR, Turini GA et al. Antihypertensive effect of the oral angiotensin converting-enzyme inhibitor SQ 14225 in man. N Engl J Med. 1978; 298:991-5. [IDIS 80115] [PubMed 205788]

8. Larochelle P, Genest J, Kuchel O et al. Effect of captopril (SQ 14225) on blood pressure, plasma renin activity and angiotensin I converting enzyme activity. Can Med Assoc J. 1979; 121:309-16. [IDIS 100999] [PubMed 223756]

9. Swartz S, Williams GH, Hollenberg NK et al. Increase in prostaglandins during converting enzyme inhibition. Clin Sci. 1980; 59(Suppl):133-5S.

10. Brunner HR, Gavras H, Waeber B et al. Oral angiotensin-converting enzyme inhibitor in long-term treatment of hypertensive patients. Ann Intern Med. 1979; 90:19-23. [IDIS 96700] [PubMed 217289]

11. Johnston CI, Millar JA, McGrath BP et al. Long-term effects of captopril (SQ 14225) on blood-pressure and hormone levels in essential hypertension. Lancet. 1979; 2:493-6. [IDIS 103099] [PubMed 90216]

12. McCaa CS, Langford HG, Cushman WC et al. Response of arterial blood pressure, plasma renin activity and aldosterone concentration to long-term administration of captopril to patients with severe, treatment-resistant malignant hypertension. Clin Sci. 1979; 57(Suppl):371-3S.

13. Fagard R, Amery A, Reybrouck T et al. Acute and chronic systemic and pulmonary hemodynamic effects of angiotensin converting enzyme inhibition with captopril in hypertensive patients. Am J Cardiol. 1980; 46:295-300. [IDIS 122485] [PubMed 6250392]

14. Maruyama A, Ogihara T, Naka T et al. Long-term effects of captopril in hypertension. Clin Pharmacol Ther. 1980; 28:316-23. [IDIS 123828] [PubMed 6996895]

15. Mimran A, Brunner HR, Turini GA et al. Effect of captopril on renal vascular tone in patients with essential hypertension. Clin Sci. 1979; 57(Suppl):421-3S. [IDIS 109948] [PubMed 519950]

16. Case DB, Atlas SA, Laragh JH et al. Clinical experience with blockade of the renin-angiotensin-aldosterone system by an oral converting-enzyme inhibitor (SQ 14,225, captopril) in hypertensive patients. Prog Cardiovasc Dis. 1978; 21:195-206. [PubMed 214819]

17. Morganti A, Pickering TG, Lopez-Ovejero JA et al. Endocrine and cardiovascular influences of converting enzyme inhibition with SQ 14225 in hypertensive patients in the supine position and during head-up tilt before and after sodium depletion. J Clin Endocrinol Metab. 1980; 50:748-54. [IDIS 124889] [PubMed 6245101]

19. Kripalani KJ, McKinstry DN, Singhvi SM et al. Disposition of captopril in normal subjects. Clin Pharmacol Ther. 1980; 27:636-41. [IDIS 113124] [PubMed 6989546]

20. McKinstry DN, Kripalani KJ, Migdalof BH et al. The effe

Friday, 6 July 2012

Inexium 2care4

Inexium 2care4 may be available in the countries listed below.

Ingredient matches for Inexium 2care4

Esomeprazole

Esomeprazole magnesium, trihydrate (a derivative of Esomeprazole) is reported as an ingredient of Inexium 2care4 in the following countries:

Denmark

International Drug Name Search

Mirtazapine 15mg Tablets (Actavis UK Ltd)

1. Name Of The Medicinal Product

Mirtazapine 15mg Tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 15mg of mirtazapine

Excipient: Lactose monohydrate.

Each tablet contains 101.8mg

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Yellow, scored on both sides, 10 x 5.2 mm oval, biconvex, film-coated tablets. Marked with I on one side.

The tablet can be divided into equal halves

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of episodes of major depression.

4.2 Posology And Method Of Administration

Adults

The effective daily dose is usually between 15 and 45mg; the starting dose is 15 or 30mg.

Mirtazapine begins to exert its effect in general after 1-2 weeks of treatment. Treatment with an adequate dose should result in a positive response within 2-4 weeks. With an insufficient response, the dose can be increased up to the maximum dose. If there is no response within a further 2-4 weeks, then treatment should be stopped.

Elderly

The recommended dose is the same as that for adults. In elderly patients an increase in dosing should be done under close supervision to elicit a satisfactory and safe response.

Children and adolescents under the age of 18 years

Mirtazapine should not be used in children and adolescents under the age of 18 years (see section 4.4).

Renal impairment

The clearance of mirtazapine may be decreased in patients with moderate to severe renal impairment (creatinine clearance <40ml/min). This should be taken into account when prescribing Mirtazapine to this category of patients (see section 4.4).

Hepatic impairment

The clearance of mirtazapine may be decreased in patients with hepatic impairment. This should be taken into account when prescribing Mirtazapine to this category of patients, particularly with severe hepatic impairment, as patients with severe hepatic impairment have not been investigated (see section 4.4).

Mirtazapine has an elimination half-life of 20-40 hours and therefore Mirtazapine is suitable for once daily administration. It should be taken preferably as a single night-time dose before going to bed. Mirtazapine may also be given in two divided doses (once in the morning and once at night-time, the higher dose should be taken at night).

The tablets should be taken orally, with fluid, and swallowed without chewing.

Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.

It is recommended to discontinue treatment with mirtazapine gradually to avoid withdrawal symptoms (see section 4.4).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Concomitant use of mirtazapine with monoamine oxidase (MAO) inhibitors (see section 4.5).

4.4 Special Warnings And Precautions For Use

Use in children and adolescents under 18 years of age

Mirtazapine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than years old.

Close supervision of patients and in particular those at high risk should accompany therapy with antidepressants especially in early treatment and following dose changes. Patients (and care givers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

With regard to the chance of suicide, in particular at the beginning of treatment, only a limited number of Mirtazapine film-coated tablets should be given to the patient.

Bone marrow depression

Bone marrow depression, usually presenting as granulocytopenia or agranulocytosis, has been reported during treatment with mirtazapine. Reversible agranulocytosis has been reported as a rare occurrence in clinical studies with mirtazapine. In the postmarketing period with mirtazapine very rare cases of agranulocytosis have been reported, mostly reversible, but in some cases fatal. Fatal cases mostly concerned patients with an age above 65. The physician should be alert for symptoms like fever, sore throat, stomatitis or other signs of infection; when such symptoms occur, treatment should be stopped and blood counts taken.

Jaundice

Treatment should be discontinued if jaundice occurs.

Conditions which need supervision

Careful dosing as well as regular and close monitoring is necessary in patients with:

– epilepsy and organic brain syndrome: Although clinical experience indicates that epileptic seizures are rare during mirtazapine treatment, as with other antidepressants, Mirtazapine should be introduced cautiously in patients who have a history of seizures. Treatment should be discontinued in any patient who develops seizures, or where there is an increase in seizure frequency.

– hepatic impairment: Following a single 15mg oral dose of mirtazapine, the clearance of mirtazapine was approximately 35% decreased in mild to moderate hepatically impaired patients, compared to subjects with normal hepatic function. The average plasma concentration of mirtazapine was about 55% increased.

– renal impairment: Following a single 15mg oral dose of mirtazapine, in patients with moderate (creatinine clearance <40ml/min) and severe (creatinine clearance <10ml/min) renal impairment the clearance of mirtazapine was about 30% and 50% decreased respectively, compared to normal subjects. The average plasma concentration of mirtazapine was about 55% and 115% increased respectively. No significant differences were found in patients with mild renal impairment (creatinine clearance <80ml/min) as compared to the control group.

– cardiac diseases like conduction disturbances, angina pectoris and recent myocardial infarction, where normal precautions should be taken and concomitant medicines carefully administered– low blood pressure – diabetes mellitus: In patients with diabetes, antidepressants may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted and close monitoring is recommended.

Like with other antidepressants, the following should be taken into account:

– Worsening of psychotic symptoms can occur when antidepressants are administered to patients with schizophrenia or other psychotic disturbances; paranoid thoughts can be intensified

– When the depressive phase of bipolar disorder is being treated, it can transform into the manic phase. Patients with a history of mania/hypomania should be closely monitored. Mirtazapine should be discontinued in any patient entering a manic phase.

– Although mirtazapine is not addictive, post-marketing experience shows that abrupt termination of treatment after long term administration may sometimes result in withdrawal symptoms. The majority of withdrawal reactions are mild and self-limiting. Among the various reported withdrawal symptoms, dizziness, agitation, anxiety, headache and nausea are the most frequently reported. Even though they have been reported as withdrawal symptoms, it should be realized that these symptoms may be related to the underlying disease. As advised in section 4.2, it is recommended to discontinue treatment with mirtazapine gradually.

– Care should be taken in patients with micturition disturbances like prostate hypertrophy and in patients with acute narrow-angle glaucoma and increased intra-ocular pressure (although there is little chance of problems with Mirtazapine because of its very weak anticholinergic activity).

– Akathisia/psychomotor restlessness: The use of antidepressants have been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Hyponatraemia

Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been reported very rarely with the use of mirtazapine. Caution should be exercised in patients at risk, such as elderly patients or patients concomitantly treated with medications known to cause hyponatraemia.

Serotonin syndrome

Interaction with serotonergic active substances: serotonin syndrome may occur when selective serotonin reuptake inhibitors (SSRIs) are used concomitantly with other serotonergic active substances (see section 4.5). Symptoms of serotonin syndrome may be hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma. From post marketing experience it appears that serotonin syndrome occurs very rarely in patients treated with mirtazapine alone (see section 4.8).

Elderly patients

Elderly patients are often more sensitive, especially with regard to the undesirable effects of antidepressants. During clinical research with mirtazapine, undesirable effects have not been reported more often in elderly patients than in other age groups.

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Pharmacodynamic interactions

- Mirtazapine should not be administered concomitantly with MAO inhibitors or within two weeks after discontinuation of MAO inhibitor therapy. In the opposite way about two weeks should pass before patients treated with mirtazapine should be treated with MAO inhibitors (see section 4.3).

In addition, as with SSRIs, co-administration with other serotonergic active substances (L-tryptophan, triptans, tramadol, linezolid, SSRIs, venlafaxine, lithium and St. John's Wort – Hypericum perforatum – preparations) may lead to an incidence of serotonin associated effects (serotonin syndrome: see section 4.4). Caution should be advised and a closer clinical monitoring is required when these active substances are combined with mirtazapine.

- Mirtazapine may increase the sedating properties of benzodiazepines and other sedatives (notably most antipsychotics, antihistamine H1 antagonists, opioids). Caution should be exercised when these medicinal products are prescribed together with mirtazapine.

- Mirtazapine may increase the CNS depressant effect of alcohol. Patients should therefore be advised to avoid alcoholic beverages while taking mirtazapine.

- Mirtazapine dosed at 30mg once daily caused a small but statistically significant increase in the international normalized ratio (INR) in subjects treated with warfarin. As at a higher dose of mirtazapine a more pronounced effect can not be excluded, it is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine.

Pharmacokinetic interactions

- Carbamazepine and phenytoin, CYP3A4 inducers, increased mirtazapine clearance about twofold, resulting in a decrease in average plasma mirtazapine concentration of 60% and 45%, respectively. When carbamazepine or any other inducer of hepatic metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with such medicinal product is discontinued, it may be necessary to reduce the mirtazapine dose.

- Co-administration of the potent CYP3A4 inhibitor ketoconazole increased the peak plasma levels and the AUC of mirtazapine by approximately 40% and 50% respectively.

- When cimetidine (weak inhibitor of CYP1A2, CYP2D6 and CYP3A4) is administered with mirtazapine, the mean plasma concentration of mirtazapine may increase more than 50%. Caution should be exercised and the dose may have to be decreased when co-administering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, cimetidine or nefazodone.

- Interaction studies did not indicate any relevant pharmacokinetic effects on concurrent treatment of mirtazapine with paroxetine, amitriptyline, risperidone or lithium.

4.6 Pregnancy And Lactation

Limited data of the use of mirtazapine in pregnant women do not indicate an increased risk for congenital malformations. Studies in animals have not shown any teratogenic effects of clinical relevance, however developmental toxicity has been observed (see section 5.3). Caution should be exercised when prescribing to pregnant women. If Mirtazapine is used until, or shortly before birth, postnatal monitoring of the newborn is recommended to account for possible discontinuation effects.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN to mirtazapine treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations).

Animal studies and limited human data have shown excretion of mirtazapine in breast milk only in very small amounts. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Mirtazapine should be made taking into account the benefit of breastfeeding to the child and the benefit of Mirtazapine therapy to the woman.

4.7 Effects On Ability To Drive And Use Machines

Mirtazapine has minor or moderate influence on the ability to drive and use machines. Mirtazapine may impair concentration and alertness (particularly in the initial phase of treatment). Patients should avoid the performance of potentially dangerous tasks, which require alertness and good concentration, such as driving a motor vehicle or operating machinery, at any time when affected.

4.8 Undesirable Effects

Depressed patients display a number of symptoms that are associated with the illness itself. It is therefore sometimes difficult to ascertain which symptoms are a result of the illness itself and which are a result of treatment with mirtazapine.

The most commonly reported adverse reactions, occurring in more than 5% of patients treated with mirtazapine in randomized placebo-controlled trials (see below) are somnolence, sedation, dry mouth, weight increased, increase in appetite, dizziness and fatigue.

All randomized placebo-controlled trials in patients (including indications other than major depressive disorder), have been evaluated for adverse reactions of mirtazapine. The meta-analysis considered 20 trials, with a planned duration of treatment up to 12 weeks, with 1501 patients (134 person years) receiving doses of mirtazapine up to 60 mg and 850 patients (79 person years) receiving placebo. Extension phases of these trials have been excluded to maintain comparability to placebo treatment.

Table 1 shows the categorized incidence of the adverse reactions, which occurred in the clinical trials statistically significantly more frequently during treatment with mirtazapine than with placebo, added with adverse reactions from spontaneous reporting. The frequencies of the adverse reactions from spontaneous reporting are based on the reporting rate of these events in the clinical trials. The frequency of adverse reactions from spontaneous reporting for which no cases in the randomized placebo-controlled patient trials were observed with mirtazapine has been classified as 'not known'.

Table 1. Adverse reactions of mirtazapine

System organ class	Very common (	Common (	Uncommon (	Rare (	Frequency not known
Investigations	Weight increased¹
Blood and the lymphatic system disorders					Bone marrow depression (granulocytopenia, agranulocytosis, aplastic anemia thrombocytopenia) Eosinophilia
Nervous system disorders	Somnolence^{1, 4} Sedation^{1, 4} Headache²	Lethargy¹ Dizziness Tremor	Paraesthesia² Restless legs Syncope	Myoclonus	Convulsions (insults) Serotonin syndrome Oral paraesthesia
Gastrointestinal disorders	Dry mouth	Nausea³ Diarrhea² Vomiting²	Oral hypoaesthesia		Mouth oedema
Skin and subcutaneous tissue disorders		Exanthema²
Musculoskeletal and connective tissue disorders		Arthralgia Myalgia Back pain¹
Metabolism and nutrition disorders	Increase in appetite¹				Hyponatraemia
Vascular disorders		Orthostatic hypotension	Hypotension²
General disorders and administration site conditions		Oedema peripheral¹ Fatigue
Hepatobiliary disorders				Elevations in serum transaminase activities
Psychiatric disorders		Abnormal dreams Confusion Anxiety^{2, 5} Insomnia^{3, 5}	Nightmares² Mania Agitation² Hallucinations Psychomotor restlessness (incl. akathisia, hyperkinesia)		Suicidal ideation⁶ Suicidal behaviour⁶
Endocrine disorders					Inappropriate antidiuretic hormone secretion

¹ In clinical trials these events occurred statistically significantly more frequently during treatment with mirtazapine than with placebo.

² In clinical trials these events occurred more frequently during treatment with placebo than with mirtazapine, however not statistically significantly more frequently.

³ In clinical trials these events occurred statistically significantly more frequently during treatment with placebo than with mirtazapine.

⁴N.B. dose reduction generally does not lead to less somnolence/sedation but can jeopardize antidepressant efficacy.

⁵ Upon treatment with antidepressants in general, anxiety and insomnia (which may be symptoms of depression) can develop or become aggravated. Under mirtazapine treatment, development or aggravation of anxiety and insomnia has been reported.

⁶ Cases of suicidal ideation and suicidal behaviours have been reported during mirtazapine therapy or early after treatment discontinuation (see section 4.4).

In laboratory evaluations in clinical trials transient increases in transaminases and gammaglutamyltransferase have been observed (however associated adverse events have not been reported statistically significantly more frequently with mirtazapine than with placebo).

4.9 Overdose

Present experience concerning overdose with mirtazapine alone indicates that symptoms are usually mild. Depression of the central nervous system with disorientation and prolonged sedation have been reported, together with tachycardia and mild hyper- or hypotension. However, there is a possibility of more serious outcomes (including fatalities) at dosages much higher than the therapeutic dose, especially with mixed overdoses.

Cases of overdose should receive appropriate symptomatic and supportive therapy for vital functions.

Activated charcoal or gastric lavage should also be considered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: other antidepressants, ATC code: N06AX11

Mirtazapine is a centrally active presynaptic α2-antagonist, which increases central noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission is specifically mediated via 5-HT1 receptors, because 5-HT2 and 5-HT3 receptors are blocked by mirtazapine. Both enantiomers of mirtazapine are presumed to contribute to the antidepressant activity, the S(+) enantiomer by blocking α2 and 5-HT2 receptors and the R(-) enantiomer by blocking 5-HT3 receptors.

The histamine H1-antagonistic activity of mirtazapine is associated with its sedative properties. It has practically no anticholinergic activity and, at therapeutic doses, has practically no effect on the cardiovascular system.

5.2 Pharmacokinetic Properties

After oral administration of mirtazapine, the active substance mirtazapine is rapidly and well absorbed (bioavailability ≈ 50%), reaching peak plasma levels after approx. two hours. Binding of mirtazapine to plasma proteins is approx. 85%. The mean half-life of elimination is 20-40 hours; longer half-lives, up to 65 hours, have occasionally been recorded and shorter half-lives have been seen in young men. The half-life of elimination is sufficient to justify once-a-day dosing. Steady state is reached after 3-4 days, after which there is no further accumulation. Mirtazapine displays linear pharmacokinetics within the recommended dose range. Food intake has no influence on the pharmacokinetics of mirtazapine.

Mirtazapine is extensively metabolized and eliminated via the urine and faeces within a few days. Major pathways of biotransformation are demethylation and oxidation, followed by conjugation. In vitro data from human liver microsomes indicate that cytochrome P450 enzymes CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas CYP3A4 is considered to be responsible for the formation of the N-demethyl and N-oxide metabolites. The demethyl metabolite is pharmacologically active and appears to have the same pharmacokinetic profile as the parent compound.

The clearance of mirtazapine may be decreased as a result of renal or hepatic impairment.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, carcinogenicity or genotoxicity.

In reproductive toxicity studies in rats and rabbits no teratogenic effects were observed. At two-fold systemic exposure compared to maximum human therapeutic exposure, there was an increase in postimplantation loss, decrease in the pup birth weights, and reduction in pup survival during the first three days of lactation in rats.

Mirtazapine was not genotoxic in a series of tests for gene mutation and chromosomal and DNA damage. Thyroid gland tumours found in a rat carcinogenicity study and hepatocellular neoplasms found in a mouse carcinogenicity study are considered to be species-specific, non-genotoxic responses associated with long-term treatment with high doses of hepatic enzyme inducers.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core:

Lactose monohydrate

Pregelatinised maize starch

Anhydrous colloidal silica

Croscarmellose sodium

Magnesium stearate.

Coating:

Hypromellose

Macrogol 8000

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions

6.5 Nature And Contents Of Container

Pack sizes

10, 14, 20, 28, 30, 50, 56 and 100 tablets in clear PVC/Al blister.

30, 100 and 500 tablets in white polypropylene tablet containers with LDPE/HDPE caps.

The pack size of 500 tablets is intended for hospital use. Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Actavis Group PTC ehf.

Reykjavíkurvegi 76-78

IS-220 Hafnarfjordur

Iceland

8. Marketing Authorisation Number(S)

PL 30306/0170

9. Date Of First Authorisation/Renewal Of The Authorisation

20/03/2008

10. Date Of Revision Of The Text

20.07.2010

Wednesday, 4 July 2012

Sentry AQ Mardel Tablet

Dosage Form: FOR ANIMAL USE ONLY
Medication for Saltwater and Freshwater Fish

Indications and Usage for Sentry AQ Mardel Tablet

For the treatment and control of visible parasites that cause symptoms of gasping for air, rapid breathing, flicking, listless behavior and excess mucus production.

Treats Parasites including: Leaches, Lice (Argulus), Flukes, Hexamita, Ick, Anchor Worms (Lernia), Protozoan/Parasites.

DIRECTIONS FOR USE

It is recommended to treat infected fish in a separate isolation tank. Remove carbon from the filter but do not discontinue filtration. Take a disposable cup and half fill with aquarium water. Dissolve one tablet for every 10 gallons (38 liters) of aquarium water. Dispense the medication throughout the treatment aquarium. One treatment should be adequate. If parasites or symptoms are still present 24 hours after initial treatment, change 25% of the water and treat again. Replace filter carbon 24 hours after final treatment. If fish show signs of stress during treatment, change 50-75% of the water immediately.

Warnings

This product contains a chemical known to the State of California to cause cancer. For aquarium use only. Not for use on fish intended for human consumption Do not use on paranhas, Metyniss species, scaleless fish, bottom feeders, marine sharks, lionfish, live rock, invertebrates and amphibians. Clout may stain silicon sealant and aquarium decorations.

KEEP OUT OF REACH OF CHILDREN

STORAGE

Store at room temperature.

INGREDIENTS

4-[p-(dimethylamino)-)O-phenylbenzylidene]-2, 5-cyclohexadien-1-xylidene dimethylammonium chloride; dimethyl (2,2,2-trichloro-1-hydroxyethel) phosphonate; 1,2-dimethyl-5-nitroimidazole and inert ingredients as non-toxic binders.

QUESTIONS OR COMMENTS

Sentry is committed to providing high quality products. If you have questions or comments about this product, please write:

Sentry Consumer Response

P O Box 540399

Omaha NE 68154-0399

How is Sentry AQ Mardel Tablet Supplied

Sentry AQ Mardel Clout - 10 count

Sentry AQ Mardel Clout - 100 count

PACKAGE LABEL PRINCIPAL DISPLAY PANEL

Sentry AQ Mardel Clout

Distributed by:

Sergeant's Pet Care Products, Inc., Omaha NE 68130

Made in USA

www.sentrypetcare.com

SENTRY AQ MARDEL CLOUT
microcrystalline cellulose tablet

Product Information
Product Type	OTC ANIMAL DRUG	NDC Product Code (Source)	21091-301
Route of Administration	EXTRACORPOREAL	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
CELLULOSE, MICROCRYSTALLINE (CELLULOSE, MICROCRYSTALLINE )	CELLULOSE, MICROCRYSTALLINE	0.29 g
METRONIDAZOLE (METRONIDAZOLE)	METRONIDAZOLE	0.19 g
TRICHLORFON (TRICHLORFON)	TRICHLORFON	0.0095 g
MALACHITE GREEN (MALACHITE GREEN)	MALACHITE GREEN	0.0038 g

Inactive Ingredients
Ingredient Name	Strength
No Inactive Ingredients Found

Product Characteristics
Color	blue (blue-green with dark blue specks)	Score	no score
Shape	ROUND	Size	11mm
Flavor		Imprint Code	None
Contains

Packaging
#	NDC	Package Description	Multilevel Packaging
1	21091-301-10	1 BLISTER PACK In 1 CARTON	contains a BLISTER PACK
1		10 TABLET In 1 BLISTER PACK	This package is contained within the CARTON (21091-301-10)
2	21091-301-00	100 TABLET In 1 BOTTLE, PLASTIC	None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
unapproved drug other		03/10/2010

Labeler - Sergeant's Pet Care Products, Inc. (876995171)

Establishment
Name	Address	ID/FEI	Operations
Sulzbach Enterprises, Inc.		616846528	manufacture

Revised: 07/2010Sergeant's Pet Care Products, Inc.

Nalex A 12

Generic Name: chlorpheniramine, pyrilamine, and phenylephrine (KLOR fe NEER a meen, pir IL a meen, FEN il EFF rin)

Brand Names: AllerTan, Chlorex-A 12, Conal, MyHist-PD, Nalex A 12, Phena-Plus, Phena-S, Poly Hist PD, R-Tannate, Ru-Hist Forte, Tri-Hist Pediatric, Triotann-S Pediatric, Triple Tannate Pediatric, Triplex AD

What is chlorpheniramine, phenylephrine, and pyrilamine?

Chlorpheniramine and pyrilamine are antihistamines that reduce the effects of natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Phenylephrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of chlorpheniramine, phenylephrine, and pyrilamine is used to treat runny or stuffy nose, sneezing, itching, watery eyes, and sinus congestion caused by allergies, the common cold, or the flu.

Chlorpheniramine, phenylephrine, and pyrilamine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about chlorpheniramine, phenylephrine, and pyrilamine?

Do not use this medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects. Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Ask a doctor or pharmacist before using any other cold, cough, allergy, or pain medicine. Antihistamines and decongestants are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine or decongestant. This medication may cause blurred vision and may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly. Drinking alcohol can increase drowsiness caused by chlorpheniramine, phenylephrine, and pyrilamine. Before using chlorpheniramine, phenylephrine, and pyrilamine, tell your doctor if you regularly use other medicines that make you sleepy (such as sedatives, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by chlorpheniramine and pyrilamine.

What should I discuss with my healthcare provider before taking chlorpheniramine, phenylephrine, and pyrilamine?

severe or uncontrolled high blood pressure;

severe coronary artery disease;

diabetes;

overactive thyroid; or

asthma, pneumonia, or other breathing problems.

Ask a doctor or pharmacist if it is safe for you to take this medicine if you have:

liver disease;

kidney disease;

heart disease or high blood pressure;

glaucoma;

enlarged prostate;

bladder obstruction or other urination problems; or

a blockage in your digestive tract (stomach or intestines).

FDA pregnancy category C. It is not known whether chlorpheniramine, phenylephrine, and pyrilamine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Chlorpheniramine, phenylephrine, and pyrilamine can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using chlorpheniramine, phenylephrine, and pyrilamine.

How should I take chlorpheniramine, phenylephrine, and pyrilamine?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Cough or cold medicine is usually taken only for a short time until your symptoms clear up.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Do not crush, chew, or break an extended-release tablet. Swallow the pill whole. Breaking or crushing the pill may cause too much of the drug to be released at one time.

Measure liquid medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Shake the oral suspension (liquid) well just before you measure a dose. Store at room temperature away from moisture, heat, and light.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include dry mouth, dilated pupils, nausea, vomiting, and warmth, redness, or tingly feeling under your skin.

What should I avoid while taking chlorpheniramine, phenylephrine, and pyrilamine?

Ask a doctor or pharmacist before using any other cold, cough, allergy, or pain medicine. Antihistamines and decongestants are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine or decongestant. This medication may cause blurred vision and may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly. Drinking alcohol can increase certain side effects of this medication.

Avoid taking this medication if you also take diet pills, caffeine pills, or other stimulants (such as ADHD medications). Taking a stimulant together with a decongestant can increase your risk of unpleasant side effects.

Chlorpheniramine, phenylephrine, and pyrilamine 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. Stop using this medication and call your doctor at once if you have a serious side effect such as:

severe dizziness, anxiety, restless feeling, or nervousness;

fast, pounding, or uneven heartbeats;

confusion, hallucinations, unusual thoughts or behavior;

feeling like you might pass out;

urinating less than usual or not at all;

easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms;

increased blood pressure (severe headache, blurred vision, trouble concentrating, chest pain, numbness, seizure); or

nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Less serious side effects may include:

upset stomach, constipation;

dry mouth;

blurred vision;

dizziness, drowsiness;

problems with memory;

sleep problems (insomnia); or

feeling restless or excited (especially in children).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect chlorpheniramine, phenylephrine, and pyrilamine?

Cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety can add to sleepiness caused by chlorpheniramine or pyrilamine. Tell your doctor if you regularly use any of these medicines, or any other cough and cold medications.

Tell your doctor about all other medications you use, especially:

digoxin (Lanoxin);

blood pressure medication;

an antidepressant;

a barbiturate such as phenobarbital (Solfoton) and others;

a diuretic (water pill);

medication to treat irritable bowel syndrome;

bladder or urinary medications such as oxybutynin (Ditropan, Oxytrol) or tolterodine (Detrol);

aspirin or salicylates (such as Disalcid, Doan's Pills, Dolobid, Salflex, Tricosal, and others); or

a beta-blocker such as atenolol (Tenormin), carteolol (Cartrol), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), timolol (Blocadren), and others.

This list is not complete and there may be other drugs that can interact with chlorpheniramine, phenylephrine, and pyrilamine. 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.

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Where can I get more information?

Your pharmacist can provide more information about chlorpheniramine, phenylephrine, and pyrilamine.

See also: Nalex A2 side effects (in more detail)