Fixed dosing

Estrogens and progestins (combination oral contraceptives) are used as oral contraceptives. There are three types of estrogen and progestin combination oral contraceptives monophasic, biphasic, and triphasic. The monophasic oral contraceptives provide a fixed dose of estrogen and progestin throughout the cycle The biphasic and triphasic oral contraceptives deliver hormones similar to the levels naturally produced by the body (Table 52-1). 

Beasley C, Sanger T, Satterlee W, et al (1996a). Olanzapine vs placebo results of a double blind fixed dose olanzapine trial. Psychopharmacology 24, 159—67. 

Chouinard G, Jones B, Remington G, et al (1993). A Canadian multicentre placebo controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic inpatients./Clin Psychopharmacol25—40. 

Because of their limited effects on allergic symptoms, decongestants often are used in combination with antihistamines.8 Many antihistamines are available in fixed-dose combinations with pseudoephedrine, which enhances the reduction in nasal congestion and allows for the patient convenience of one tablet. Optimally, therapy should be initiated with an antihistamine alone, adding the adrenergic agent only if nasal congestion does not resolve with antihistamine monotherapy. Use of separate antihistamine and pseudoephedrine also permits independent dose titration.4,11,12... 

Rectal Administration. The administration of drugs by a solid rectal dosage form (i.e., suppositories) results in a wide variability in the rate and extent of absorption in children [79]. This fact, coupled with the inflexibility of a fixed dose, makes this a route that should not be promoted for pediatric patients. At least one death involving a 7-month-old infant can be directly attributed to the use of solid rectal dosage form of a therapeutic dose of morphine [80]. 

The equivalence of high and low doses of antidepressants is well known, yet doctors often increase the dose of the antidepressant when their patients do not improve. Why do they do this The official Summary of Product Characteristics for Prozac provides a clue. It notes that in the fixed dose studies of patients with major depression there is a flat dose response curve, providing no suggestion of advantage in terms of efficacy for using higher than the recommended doses . Nevertheless, despite the absence of evidence that higher doses produce better effects, the very same document advises physicians as follows ... 

Fixed dose procedure for acute oral toxicity testing Fixed dose procedure for acute oral toxicity testing EU... 

Sugarman SB, Mobarhan S, Bowen PE, Stacewicz-Sapuntzakis M and Langenberg P. 1991. Serum time curve characteristics of a fixed dose of (3-carotene in young and old men. J Am Coll Nutr 10 297— 307. 

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. 

Obstacles to successful therapy with this drug combination include the need for frequent dosing (i.e., three times daily with the fixed-dose combination product), a high frequency of adverse effects (e.g., headache, dizziness, GI distress), and increased cost for the fixed-dose combination product. 

Fixed Dose Procedure. The fixed dose design (Figure 5.7) was proposed by the British Toxicology Society (1984). It is designed to supply the data needed for classification or labeling purposes. It is essentially a three-step limit test. 

FIGURE 5.7. British Toxicology Society fixed dose procedure. 

The fixed dose procedure is relatively new and apparently results in a large decrease in animal usage. It is also noteworthy in that it utilizes not only lethality but also evident toxicity, which, in all likelihood, refers to obvious signs of CNS effect, such as seizures or prostration. Whether or not this protocol design becomes widely accepted by various regulatory agencies remains to be established. 

TABLE 5.2. Comparison of Toxicity Classification Based on LD50 versus Fixed Dose Procedure... 

Toxicity Classification Based on LD5o Fixed-dose Number of Laboratories Classifying Chemical ... 

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