Guidelines on Fixed Dosage Combinations (FDCs): A Review

Introduction

Single-dose dosage forms that contain two or more active pharmacological components are known as combination products sometimes referred to as fixed dose drug combinations (FDCs). In the United States, the Food and Drug Administration defines a “product” as “any combination of a drug and a tool or a biological product.” Common wisdom holds that single compounds should be used to manufacture the majority of drugs. Regulatory Bodies plays vital role in improving patient’s health by enforcing stringent rules and regulation on new drug molecules but also on previously marketed drugs and fixed dosage combinations developed from previously marketed APIs or new drug molecules. In

India CDSCO have laid down various rules and regulations on FDCs and classifying them into four different types on the basis of their origin status, whether the molecules used in FDCs formulation is previously marketed or not and their concentration in dosage forms (Figure 1), rules and regulations are amended processing of applications for Clinical Trials, review, approval, and follow-up until study completion, as well as evaluation of applications for final formulations approval, additional dosage form, modified dosage form, additional indication, additional strength, and additional method of administration for manufacture and marketing/import and marketing of FDCs. Such FDC developments are significant from the point of the general population’s health. Making “fixed dosage combination” medications has a pair of primary objectives: either to accordance with policy as well as to gain from the additional benefits of the two medications when taken together. When treating infectious disorders like HIV, malaria, and TB, when the administration of numerous antimicrobial drugs is customary, FDCs have shown to be very helpful. FDCs are helpful in treating chronic illnesses, particularly when many problems coexist. Mainly Schedule Y under rule 122 have covered forms and data requirement in appendix I item 9 while new clinical trials rule 2019 laid down fees (Table 1) and forms and other data requirement for manufacture/ sale/ import of FDCs in Figure 2 so far at least 1319 FDCs have been approved from 1961 to 2019 [1, 2, 3, 4].

Click to enlarge

Click to enlarge

Click to enlarge

Status of Fixed Dose Combinations in National List of Essential Medicines (NLEM) India and World Health Organisation (WHO) Essential Lists of Drugs

The National List of Essential Medicines of India (NLEM) 2015 contained 24 FDCs out of 376 entities, following thorough debate in national meetings, these FDCs were incorporated with scientific reasons [5]. The bulk of the FDCs on both lists are antimalarial, ant tubercular, and antiretroviral drugs, underlining the importance of FDC use in treatment adherence and the effectiveness of antiretroviral treatments Essentials list of drugs given by World Health Organisation (WHO) Essential drugs are those that address the population’s highest priority healthcare requirements and are created to be accessible in the shortest amount of time, in ample supply, and at a fair price. The list was created following a thorough analysis of medication effectiveness, safety, and comparative cost-effectiveness for each condition. Of the 414 drugs in the 19th WHO List of Essential Medicines, 27 are FDCs [6].

Discussion and Conclusion

Fixed Dose Combinations are products that include more than two active pharmacological ingredients and are delivered as single dose forms. Several International Bodies- United States Food and Drug Administrations and European Medicines Agency along with National bodies like CDSCO (India) have laid down guidelines for Quality and Safe to Public health production of dosage combinations involving studies like pharmacodynamic and pharmacokinetics properties along with other toxicological studies evidenced by clinical data. Analgesics combinations with Antispasmodics play vital role in treatment of pains. Apart from its benefits such as synergistic impact with a single prescription, amnesia of so many medications, and prevention of drug resistance (chronic illnesses), it also has numerous problems such as pharmacodynamic and pharmacokinetic compatibility, drug- drug interactions, side effects, and inability to identify active moiety if adverse/side effects occur. In India DCGI a part of CDSCO have approved 1319 multiple dosage combination from 1961 to June 2019.