Pharmacy & Therapeutics - February 2008 - (Page 115)

Pharmaceutical Approval Update adjusted within the range of 5 to 20 mg/kg per day according to the response to therapy. Doses of Kuvan tablets above 20 mg/kg per day have not been evaluated in clinical trials. Contraindications: No contraindications have been reported. Commentar y: PKU is a rare genetic, congenital metabolic disorder caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH). If PKU remains untreated, the interrupted metabolism of dietary phenylalanine results in accumulation of the amino acid in body fluids with resultant, progressive, and irreversible mental retardation. PKU, which causes a reduced brain size, delayed speech, and other neurological problems, occurs in one of every 12,000 to 15,000 live births in the U.S. Kuvan is the first drug approved to slow the effects of PKU. Patients with PKU cannot break down phenylalanine, an amino acid found in foods that contain proteins, such as meat, dairy foods, and egg products. As a result, PKU patients can develop high blood levels of phenylalanine, which are toxic to the brain. Kuvan tablets work by increasing PAH enzyme activity in PKU patients who have some residual PAH enzyme function. This activity then leads to an increased breakdown of phenylalanine, resulting in lower levels of phenylalanine in the blood. Source: www.kuvan.com As with other beta blockers, when discontinuation of nebivolol is planned, patients should be carefully observed and should be advised to minimize physical activity. Nebivolol should be tapered over one to two weeks when possible. If angina worsens or if acute coronary insufficiency develops, nebivolol should be promptly reinstituted, at least tem porarily. Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure (CHF), and beta blockade may result in further depression of myocardial contractility and precipitate more severe failure. In patients with compensated CHF, nebivolol should be administered cautiously. If CHF worsens, discontinuation of nebivolol should be considered. Angina and Acute Myocardial Infarction: Nebivolol was not studied in patients with angina pectoris or in those who had a recent MI. Bronchospastic Diseases: In general, patients with bronchospastic diseases should not receive beta blockers. Anesthesia and Major Surgery: If nebivolol is to be continued perioperatively, patients should be closely monitored when anesthetic agents that depress myocardial function (e.g., ether, cyclopropane, trichloroethylene) are used. If beta-blocking therapy is withdrawn before major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The beta-blocking effects of nebivolol can be reversed by beta agonists (e.g., dobutamine, isoproterenol). However, patients might be subject to protracted severe hypotension. In addition, difficulty in restarting and maintaining the heartbeat has been reported with the use of beta blockers. Diabetes and Hypoglycemia: Beta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective beta blockers may potentiate insulininduced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Patients subject to spontaneous hypoglycemia or diabetic patients receiving insulin or oral hypoglycemic agents should be advised about these possibilities, and nebivolol should be used with caution. Thyrotoxicosis: Beta blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta blockers may be followed by an exacerbation of the symptoms of hyperthyroidism, or it may precipitate a thyroid storm. Peripheral Vascular Disease: Beta blockers can precipitate or exacerbate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in these patients. Non-dihydropyridine Calcium-Channel Blockers: Because of significant negative inotropic and chronotropic effects in patients treated with beta blockers and calciumchannel blockers such as verapamil (Calan, Pfizer) and diltiazem (Cardizem, Biovail/Abbott), caution should be used in patients who are being treated concomitantly with these agents; electrocardiograms and blood pressure should be monitored. Precautions: Use with Cytochrome P450 (CYP 2D6) Inhibitors. Nebivolol exposure increases with inhibition of CYP 2D6. The Nebivolol (Bystolic) Tablets Manufacturer: Forest Laboratories, New York, and Mylan, Pittsburgh, Pa. Indication: Nebivolol is used to treat hypertension. It may be taken alone or in combination with other antihypertensive agents. Dr ug Class: Nebivolol is a racemate composed of D-nebivolol and L-nebivolol with the stereochemical designations of [SRRRI]-nebivolol and [RSSSI]-nebivolol, respectively. Uniqueness of Drug: Nebivolol is a beta-adrenergic receptor blocking agent. In extensive metabolizers (i.e., in most people) and at doses less than or equal to 10 mg, nebivolol is preferentially beta1-selective. In poor metabolizers and at higher doses, nebivolol inhibits both beta1-adrenergic and beta2-adrenergic receptors. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. Nebivolol’s mechanism of action differs from that in many older beta blockers. It is preferentially beta1-selective at doses less than or equal to 10 mg by selectively blocking the effects of adrenaline at the heart. Nebivolol also expands the blood vessels. Warnings: Abrupt Cessation of Therapy: Patients with coronary artery disease who are taking nebivolol should be advised against suddenly stopping therapy. Severe exacerbation of angina as well as myocardial infarction (MI) and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with beta blockers. MI and ventricular arrhythmias may occur with or without a preceding exacerbation of the angina pectoris. Even patients without overt coronary artery disease should be cautioned against interrupting or abruptly discontinuing therapy. Vol. 33 No. 2 • February 2008 • P&T® 115 http://www.kuvan.com

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Pharmacy & Therapeutics - February 2008 Contents Editorial Medication Errors Prescription: Washington The Language of (Forgive Us) Change, As P&T Enters the Digital Age New Drugs/Drug News/New Medical Devices Drug Forecast Use and Outcomes of Antifibrinolytic Therapy in Patients Undergoing Cardiothoracic Surgery at 20 Academic Medical Centers in the United States Evaluation of the Management of Acute Venous Thromboembolism and Its Outcomes: One Institution's Experience American Society of Hematology, 49th Annual Meeting Pharmaceutical Approval Update

Pharmacy & Therapeutics - February 2008

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