LESCOL XL® (fluvastatin sodium)
Description
Lescol XL® (fluvastatin sodium; Novartis Pharmaceuticals Corporation) is a newly released dosage and formulation of Lescol®. Lescol® was the first synthetic HMG‐CoA reductase inhibitor used in the treatment of hypercholesterolemia.
Indications
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Lescol XL® is to be used in conjunction with diet to reduce total cholesterol, low‐density lipoprotein (LDL) cholesterol, triglycerides, and Apo‐B, as well as to increase high‐density lipoprotein cholesterol.
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It is also indicated to slow the progression of coronary atherosclerosis.
Mechanism of Action
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Lescol® blocks the production of cholesterol in the liver via competitive inhibition of HMG‐CoA reductase.
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This stimulates the LDL receptors, thereby increasing uptake of the LDL particle.
Pharmacokinetics and Metabolism
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The drug is rapidly absorbed following oral ingestion.
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Peak concentrations of Lescol XL® are achieved in about 3 hours under fasting conditions, and are metabolized primarily through the 2c9 pathway.
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Administration of the drug following a high‐fat meal delays its absorption.
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The drug is 98% bound to plasma proteins.
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It is metabolized in the liver via hydroxylation.
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Elimination is primarily via the feces as metabolites, with very little (<5%) excreted in the urine.
Precautions and Adverse Reactions
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Potential for drug accumulation exists in patients with hepatic insufficiency.
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Women tend to have slightly higher plasma concentrations than men.
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Liver function studies must be performed before therapy and at 12‐week intervals after drug initiation or an increase in the dose.
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The drug must be discontinued if there is a three‐fold increase above the upper limited normal in the liver function tests.
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The drug must be discontinued if myalgias develop or there is an increase in creatine phosphokinase enzymes.
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The most common adverse reactions, although rare, are diarrhea, dyspepsia, fatigue, nausea, and flatulence.
Contraindications
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Lescol XL® is contraindicated in patients with liver disease.
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It is contraindicated in patients who are pregnant or are trying to become pregnant.
Dosage and Administration
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Prior to initiation of therapy, patients should be placed on a low‐fat, low‐cholesterol diet.
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In patients whose LDL cholesterol goal reduction is >25%, the recommended starting dose is 40 or 80 mg/day.
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The dosing range is 20–80 mg/day.
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The drug can be taken in the evening, without regard to meals.
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Periodic liver function checks should be performed, as noted above.
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Dosage changes can be made no more frequently than every 4 weeks.
Summary
Lescol XL® (co‐marketed with Reliant Pharmaceuticals) is a new dosage and preparation of the previously released synthetic HMG‐CoA reductase inhibitor Lescol®. The higher dosage is encouraging in the management of elevated lipid levels and the progression of the coronary atherosclerotic process.
JCH. 2001;3:60.
INNOHEP® (TINZAPARIN SODIUM INJECTION)
Description
Innohep® (tinzaparin sodium injection; Du Pont Pharmaceuticals Company) is a low‐molecular weight heparin indicated for the treatment of acute, symptomatic deep vein thrombosis with or without pulmonary embolism, administered with warfarin sodium.
Indications
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Tinzaparin sodium is indicated for the treatment of acute, symptomatic deep vein thrombosis with or without pulmonary embolism, administered with warfarin sodium.
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Other potential, unlabeled uses are for the prevention of deep vein thrombosis in patients undergoing orthopedic surgery of the lower extremities or abdominal surgery; treatment of unstable angina and non‐Q wave myocardial infarction; and treatment of transient ischemic attacks.
Mechanism of Action and Metabolism
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Tinazaparin sodium is a low‐molecular weight heparin with antithrombotic actions.
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It inhibits factor Xa, which catalyzes the conversion of prothrombin (Factor IIa).
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It also exerts inhibitory action on thrombin, which converts fibrinogen to fibrin.
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The drug is metabolized by desulfation and polymerization.
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The elimination half‐life is 3–4 hours, on the basis of anti‐Xa activity.
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The primary route of elimination is renal.
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Age and gender do not influence metabolism.
Adverse Reactions and Precautions
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Bleeding is the most common adverse event.
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The incidence of significant bleeding is 0.8%.
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Thrombocytopenia was seen in 1 % of patients, and severe thrombocytopenia (platelet count <50,000/mm3) in 0.13%.
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Asymptomatic elevations in aminotransferases—aspartate aminotransferase and alanine aminotransferase—were reported in 8.8% and 13%, respectively. These elevations are reversible and rarely associated with an increase in bilirubin.
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Hypersensitivity rash occurred in 1.2%.
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The drug is contraindicated in patients with active bleeding.
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It should not be used in patients with a history of heparin‐induced thrombocytopenia.
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The drug should not be used in patients with a known sensitivity to heparin, sulfites, benzyl alcohol, or pork products.
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Because of the increased risk of bleeding, the drug should be used with caution in patients already taking oral anticoagulants, platelet inhibitors, or thrombolytic agents.
Contraindications
Tinzaparin sodium is injected subcutaneously, once daily. The recommended dose is calculated as follows:
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Patient's weight (kg)×0.00875 mL/kg=volume administered (mL) or patient's weight (lb) × 0.00397 mL/lb=volume administered (mL)
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Warfarin therapy is usually initiated within 1–3 days of initiation of tinzaparin sodium.
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The drug is administered for at least 6 days and until the patient is adequately anticoagulated with warfarin to an international normalized ratio of 2–3 for at least 2 consecutive days.
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Patients with severe renal impairment showed a 24% reduction in tinzaparin sodium clearance; therefore, the drug should be administered with caution to patients with renal impairment.
Summary
Innohep® (tinzaparin sodium) is a newly released, low‐molecular weight heparin product used in combination with warfarin sodium for the treatment of acute deep venous thrombosis with or without pulmonary embolus. It offers the convenience of once‐a‐day dosing, with no dose adjustment required for elderly or obese patients.
JCH. 2001;3:127.
TOPROL‐XL® (metoprolol succinate)
Description
Toprol‐XL® (metoprolol succinate, AstraZeneca) is a selective β1 adrenergic receptor blocking agent formulated in extended release for once‐a‐day administration. It has a new indication for stable, symptomatic heart failure secondary to ischemia, hypertension, or cardiomyopathy.
Clinical Pharmacology
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At lower plasma concentrations, metoprolol succinate is cardioselective, while at higher concentrations it exhibits β2‐adrenergic receptor blocking activity in vascular and bronchial musculature.
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At higher plasma concentrations, the β1 selectivity diminishes and the β2 receptor blocking activity increases.
Pharmacodynamics
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Heart rate and cardiac output are reduced during exercise and at rest.
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Systolic blood pressure is also reduced during exercise and reflex orthostatic tachycardia.
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In asthmatic patients, metoprolol does not reduce the forced expiratory volume in 1 second or the forced vital capacity to the same extent as noncardioselective β blockers.
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At maximal effect, heart rate is reduced by 28%.
Pharmacokinetics
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Metoprolol is rapidly and completely absorbed from the gastrointestinal tract.
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This agent crosses the blood‐brain barrier.
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About 12% is bound to serum albumin.
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The drug is eliminated by biotransformation in the liver.
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The plasma half‐life ranges from 3–7 hours, with less than 5% of the initial dose recovered unchanged in the urine.
Clinical Indications
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The initial indication for the drug was in treating hypertension and angina pectoris.
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The new indication is for the treatment of stable, symptomatic heart failure (New York Heart Association [NYHA] class II or III) of ischemic, hypertensive, or cardiomyopathic origin.
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Metoprolol can be used either alone or in combination with other medications typically used to treat hypertension, angina pectoris, and congestive heart failure.
Warnings and Precautions
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The drug should be given with caution to patients with known bronchospastic disease.
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Abrupt cessation of treatment can cause reflex tachycardia, which exacerbates angina pectoris or hypertension.
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Diabetic patients should be watched because of the ability of β blockers to mask the effects of hypoglycemia.
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β Blockers can also mask the clinical effects of thyrotoxicosis.
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The drug should be used with caution in patients with impaired hepatic function.
Adverse Reactions
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Fatigue and dizziness have been reported in 10% of patients receiving the drug.
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Depression has been reported in 5% of patients.
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Dyspnea and symptomatic bradycardia have been reported in 1% and 3%, respectively.
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Rash and gastrointestinal complaints have been reported in approximately 5% of patients.
Dosage and Administration
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The 25‐mg tablets are scored.
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The recommended starting dose for treatment of heart failure is 25 mg/day for patients with NYHA class II heart failure and 12.5 mg/day for patients with more severe heart failure.
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The dose can then be doubled every 2 weeks, as tolerated, to a maximal dose of 200 mg/day.
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The usual initial dosage for patients with angina pectoris is 100 mg/day, and it can be increased to achieve the desired effect, to a maximum of 400 mg/day.
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The initial dosage for the treatment of hypertension is 50–100 mg/day, either alone or in combination with a diuretic. The dose can be increased at weekly intervals, up to 400 mg/day.
Summary
Toprol‐XL® (metoprolol succinate) is a familiar β blocker used in the treatment of hypertension and angina for many years. It is now approved and indicated for the treatment of stable, symptomatic heart failure. The new scored, 25‐mg tablets will make dosing easy and convenient.
JCH. 2001;3:196.
MICARDIS®/HCT(telmisartan/hydrochlorothiazide)
Description
Micardis®/HCT (telmisartan/HCT, Boehringer Ingelheim Pharmaceuticals) is a new FDA‐approved combination angiotensin II receptor (type AT1 ) antagonist and thiazide diuretic. It is approved for the treatment of hypertension, either alone or in combination with other agents.
Pharmacokinetics
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Following oral administration, peak plasma concentration is achieved in 0.5–1 hour.
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Food slightly reduces the bioavailability of the drug.
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Absolute bioavailability is dose‐dependent.
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The terminal elimination half‐life of telmisartan is 24 hours.
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Most of the drug is eliminated in the feces via biliary excretion.
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Cytochrome P‐450 isoenzymes are not involved in the metabolism of the drug.
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The drug is highly protein‐bound.
Pharmacodynamics
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The plasma concentration of angiotensin II and plasma renin activity increase in a dose‐dependent fashion.
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Thiazide diuretics influence renal tubular mechanisms, affecting tubular electrolyte reabsorption and thus reducing plasma volume.
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Following once‐daily dosing of up to 80 mg, there was no influence on the aldosterone concentration.
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On initiation of treatment with telmisartan/HCT, blood pressure is reduced after the first dose.
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Blood pressure reduction is maximal by 4 weeks.
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The antihypertensive effect of the drug is not affected by age, gender, or body mass.
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The blood pressure response in low‐renin populations (black individuals) is noticeably lower.
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The onset of activity is 3 hours after a single dose and the antihypertensive effect is maintained for 24 hours.
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The antihypertensive response is dose‐dependent.
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Combining an angiotensin receptor blocker with a thiazide diuretic tends to reduce the amount of potassium loss associated with diuretic monotherapy.
Contraindications and Precautions
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The drug should not be used in pregnancy.
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When pregnancy is detected the drug must be discontinued.
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Use in volume‐ and/or salt‐depleted patients may cause symptomatic hypotension.
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Care must be taken when the drug is given to patients already on a diuretic, for the above‐mentioned reason.
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Hypovolemia and hypokalemia must be corrected and monitored.
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Since most of the drug is eliminated via biliary excretion, patients with hepatic insufficiency may have reduced clearance.
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Use of angiotensin‐converting enzyme inhibitors in patients with unilateral or bilateral renal artery stenosis increases serum creatinine and/or blood urea nitrogen.
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Use of the drug with digoxin increases the digoxin concentration.
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Coadministration of the drug with warfarin slightly decreases the warfarin concentration.
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The drug should not be used if creatinine clearance is <30 mL/min.
Adverse Events
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Adverse events occurred at a rate of only 1%.
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The main reported adverse events were upper respiratory tract infection (7%), back pain (3%), sinusitis (3%), diarrhea (3%), and pharyngitis (1 %).
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Dizziness, gastrointestinal upset, fatigue, orthostasis, hyperglycemia, hyperuricemia, and adverse lipid values have also been reported.
Dosage and Administration
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The drug is not used as initial treatment of hypertension.
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If blood pressure is not controlled with Micardis® alone or hydrochlorothiazide alone, Micardis®/HCT 40 mg/12.5 mg can be started.
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The dose can be increased to 80 mg/12.5 mg per day as needed, on the basis of the blood pressure response.
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The drug can be increased to 160 mg/25 mg per day.
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Care must be taken in administering the drug to patients who may be salt‐ or volume‐depleted.
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Most antihypertensive effects are seen within 2 weeks.
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No dosing adjustments are necessary in the elderly or in patients with mild renal impairment.
Summary
Micardis®/HCT (telmisartin/HCT) is a newly approved combination angiotensin II receptor blocker and thiazide diuretic used in the treatment of hypertension. The addition of a diuretic to the already available Micardis® provides additional blood pressure control in patients not controlled on one drug alone.
JCH. 2001;3:261.
DYRENIUM® (triamterene)
Description
Dyrenium® (triamterene, GlaxoSmithKline) is a potassium‐sparing diuretic used in the treatment of edema associated with congestive heart failure, liver cirrhosis, nephrotic syndrome, and use of steroids or secondary hyperaldosteronism. The drug is also used in combination with other diuretics in the treatment of hypokalemia and hypertension.
Clinical Pharmacology
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Triamterene inhibits the reabsorption of sodium in exchange for potassium and hydrogen in the distal tubule.
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The action of the drug is under the control of mineralocorticoid (aldosterone) activity.
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The more sodium reaching the distal tubule, the stronger the diuretic effect and potassium conservation.
Pharmacokinetics and Pharmacodynamics
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After oral administration, the drug is rapidly absorbed.
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The onset of action is in 2–4 hours, and peak effect occurs after several days of therapy.
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The duration of action is 7–9 hours.
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80% of the drug is metabolized in the liver and 50% is excreted in the urine.
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The plasma half‐life is 1.5–2.5 hours.
Contraindications and Precautions
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The drug is contraindicated in patients with anuria or severe, progressive renal disease and diabetic nephropathy.
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It should not be given to patients with severe hepatic dysfunction.
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It should not be used in patients with elevated potassium levels or patients already taking another potassium‐sparing diuretic.
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During triamterene administration, blood pressure, urine output, weight, and serum electrolytes should be monitored.
Adverse Effects and Drug Interactions
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Arrhythmias, orthostatic hypotension, and angina are the most common adverse cardiac reactions.
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Dehydration, fatigue, muscle cramps, nausea, and diarrhea are other reported adverse effects.
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The drug should not be used with other potassium‐sparing diuretics, such as spironolactone and amiloride.
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Care must be taken when the drug is administered with other potassium‐sparing agents, such as angiotensin‐converting enzyme inhibitors and angiotensin II receptor‐blocking agents.
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Drug interactions have been reported with lithium, nonsteroidal anti‐inflammatory agents, and cardiac glycosides.
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Triamterene can raise blood glucose levels in patients with adult‐onset diabetes mellitus.
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Concomitant use of the drug with chlorpropamide can increase the risk of hyponatremia.
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The drug can be used in pregnancy if clearly indicated; it is not recommended during breast feeding.
Dosage and Administration
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The usual starting dose is 100 mg/b.i.d. after meals.
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The daily dosage should not exceed 300 mg.
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Once symptoms of edema are controlled, the dosage can be reduced to administration every other day or to 50 mg/day.
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When triamterene is used in combination with other kaluretic diuretics, the initial dosage is 25 mg/day, with increases as needed to a maximum dose of 100 mg/day.
Summary
Dyrenium® is a familiar potassium‐sparing diuretic used in the treatment of symptomatic edema of various etiologies. The drug can also be used in combination with other diuretics in the treatment of hypertension. Monitoring of electrolytes is important to ensure its safe use.
JCH. 2001;3:332.