Fixed dose combination products

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 combination products will require explicit justification for each component. 

Class 3 Compound and fixed dose combination products... 

Class 3 Compound and fixed dose combination products Class 4 NCEs previously registered for import into China Class 5 Registered products for which a new indication is sought... 

Peigolizzi IV Jr, Taylor R Jr, Raffa RB (2015) The potential role of an extended-release, abuse-deterrent oxycodone/acetaminophen fixed-dose combination product for the treatment of acute pain. Adv Ther 32 485-495... 

Because this product is a fixed-dose combination doseform, avoid use in patients requiring dosage reduction. 

Fixed-dose combination This combination contains fixed doses of 2 nucleoside analogs, abacavir and lamivudine, and should not be administered concomitantly with other abacavir-containing and/or lamivudine-containing products. Hypersensitivity reactions Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir/lamivudine and other abacavir-containing products. 

The Committee expressed its appreciation of the immense contribution of various persons and groups, including the NICPBP (People s Republic of China), to the work on the development of monographs for artemisinin combination drugs, including that of artesunate. The Committee was informed of the emerging need for monographs for fixed-dose combinations (FDC) for antimalarial products. 

The Committee noted that dissolution test methods were being developed and agreed that rifampicin should serve as the marker for dissolution testing in the relevant fixed-dose combinations, as it was the least soluble substance. For other products, standard dissolution test methods could be applied. 

A test that determines the equivalence between the multisource product and the comparator product using in vivo and/or in vitro approaches. fixed-dose combination (FDC)... 

If the pharmacokinetic bioequivalence of fixed-dose combination (FDC) products is assessed by in vivo studies the study design should follow the same general principles as described in previous sections. The multisource FDC product should be compared with the pharmaceutically equivalent comparator FDC product. In certain cases (e.g. when no comparator FDC product is available on the market) separate products administered in free combination can be used as a comparator (5). Sampling times should be chosen to enable the pharmacokinetic parameters of all APIs to be adequately assessed. The bioanalytical method should be validated on respect... 

Guidelines for registration of fixed-dose combination medicinal products. In WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth report. Geneva, World Health Organization, 2005 (WHO Technical Report Series, No. 929), Annex 5 94-142. 

The treatment of tuberculosis still largely relies on the use of rifampin, isoniazid, pyrazinamide, and ethambutol HCl. Although the chromatographic analysis of these drugs is well established, the recently notified USP gradient HPLC method for quantitative determination of rifampicin, isoniazid, and pyrazinamide in fixed-dose combination (FDC) formulations has enhanced our analytical capability to ensure the quality of these products. 

Singh, S. Mohan, B. A pilot stability study on four-drug fixed-dose combination anti-tuberculosis products. Int. J. Tuberc. Lung Dis. 2003, 7 (3), 298-303. 

Product presentation Single fixed dose combination tablet for the entire regimen, not weight-banded Pediatric formulation (chewable, sprinkles, or liquid) available... 

CASE STUDY 3 HPLC PURITY METHOD DEVELOPMENT CHALLENGES FOR A FIXED COMBINATION PRODUCT CONTAINING A LOW-DOSE ACTIVE INGREDIENT AND A HIGH-DOSE ACTIVE INGREDIENT... 

A combination product of timolol 0.5% and dorzolamide 2% is available (Cosopt). This fixed-combination dosed twice daily is equivalent to dorzolamide 2% three times daily and timolol 0.5% twice daily dosed separately. Moreover, the combination product is more convenient, requiring one bottle and fewer drops per day than separate bottles. The combination product used twice daily has been compared with monotherapy with either dorzolamide 2% three times daily or timolol 0.5% twice daily. The mean reduction in lOP was 27.4% (-7.7 mm Hg), 15.5% (-4.6 mm Hg), and 22.2% (-6.4 mm Hg) for the combination product, dorzolamide, and timolol, respectively (Figure 10-16). The dorzolamide-timolol combination was compared with either individual component in patients not controlled on timolol twice daily alone. The combination product was more effective than either timolol 0.5% twice daily or dorzolamide 2% three times daily fitr up to 3 months. The most frequently reported ocular side effect was ocular burning or stinging, with the overall adverse effects being similar for the combination product and dorzolamide, but less for timolol. 

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