Fixed dose appropriate

The combination of nitrates and hydralazine improves the composite endpoint of mortality, hospitalizations for HF, and quality of life in African Americans who receive standard therapy. A fixed-dose combination product is available that contains ISDN 20 mg and hydralazine 37.5 mg (BiDil). Practice guidelines recommend adding ISDN and hydralazine as part of standard therapy in African Americans with moderately severe to severe HF. The combination may also be reasonable for patients of other ethnicities with persistent symptoms despite optimized therapy with an ACE inhibitor (or ARB) and /Tblocker. The combination is also appropriate as first-line therapy in patients unable to tolerate ACE inhibitors or ARBs because of renal insufficiency, hyperkalemia, or possibly hypotension. 

The guidance document offers a comparison of TG 420 (Fixed Dose Method), TG 423 (Acute Toxic Class Method), and TG 425 (Up-and-Down Procedure). The purpose of this Guidance Document is to provide information to assist with the choice of the most appropriate Guideline to enable particular data requirements to be met while reducing the number of animals used and animal suffering. The Guidance Document also contains additional information on the conduct and interpretation of test guidelines 420, 423, and 425. 

The Committee noted the information presented by the HIV/AIDS department, The importance of the quality of APIs was stressed, including the necessity for appropriate analytical methodology. It was noted that the development of monographs for APIs and final dosage forms, including fixed-dose combinations (FDCs), together with the introduction of alterna-... 

Two COMT inhibitors are available for this use, tolcapone (tasmar) and entacapone (comtan). Tolcapone has a relatively long duration of action, allowing for administration two to three times a day, and appears to act by both central and peripheral inhibition of COMT. The duration of action of entacapone is short, around 2 hours, so it usually is administered simultaneously with each dose of levodopa/carbidopa. The action of entacapone is attributable principally to peripheral inhibition of COMT. The common adverse effects of these agents are similar to those observed in patients treated with levodopa/carbidopa alone and include nausea, orthostatic hypotension, vivid dreams, confusion, and hallucinations. An adverse effect associated with tolcapone is hepatotoxicity tolcapone should be used only in patients who have not responded to other therapies and with appropriate monitoring of hepatic transaminases. Entacapone has not been associated with hepatotoxicity and requires no special monitoring. Entacapone also is available in fixed-dose combinations with levodopa/carbidopa (stalevo). 

When angina occurs more frequently than once a day, chronic prophylactic therapy should be instituted. 8-Blockers may be preferable because of less frequent dosing and other desirable properties (e.g., potential cardioprotective effects, antiarrhythmic effects, lack of tolerance, antihypertensive efficacy). The appropriate dose should be determined by the goals outlined for HR and DP. An agent should be selected that is well tolerated by individual patients at a reasonable cost. Patients most likely to respond well to 8-blockade are those with a high resting HR and those with a relatively fixed anginal threshold (i.e., their symptoms appear at the same level of exercise or workload on a consistent basis). 

There are many circumstances in which a fixed drug dose is likely to be ineffective or toxic in a significant number of individuals, e.g. cytotoxic chemotherapy, aminoglycoside antibiotics. It is usual then to calculate the dose according to body weight. Adjustment according to body surface area is also used and may be more appropriate, for this... 

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