|LETTER TO THE EDITOR
|Year : 2021 | Volume
| Issue : 2 | Page : 170-172
Fixed-dose combinations: An essential for rational preparation
Pugazhenthan Thangaraju1, Shoban Babu Varthya2, Sajitha Venkatesan3
1 Department of Pharmacology, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
2 Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
3 Department of Microbiology, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
|Date of Submission||13-May-2019|
|Date of Decision||29-Apr-2021|
|Date of Acceptance||05-May-2021|
|Date of Web Publication||26-May-2021|
Dr. Pugazhenthan Thangaraju
Department of Pharmacology, All India Institute of Medical Sciences, Raipur, Chhattisgarh
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Thangaraju P, Varthya SB, Venkatesan S. Fixed-dose combinations: An essential for rational preparation. Indian J Pharmacol 2021;53:170-2
| » Background|| |
A fixed-dose combination (FDC) is defined as the combination of more than one drug at a fixed ratio in a single dosage form for a particular indication. FDCs are considered a double-edged sword because a rational FDC can give increase patient compliance and decrease in bill burden and cost-effectiveness; however, at the same time, an irrational combination results in ineffective or increased adverse effects.
Therapeutic classes of fixed-dose combinations
- Cardiovascular system: FDCs such as aspirin with clopidogrel are rational, but aspirin with antacids is irrational
- Anti-psychotics: Olanzapine + fluoxetine are rational, but the combination of escitalopram + clonazepam is irrational because two drugs of the same class combined without due safety and efficacy
- Chemotherapy agents: Treatment for anti-HIV, anti-tuberculosis, and anti-malarial drugs are rational, but some of the preparations related to antibacterials are irrational example, levofloxacin and azithromycin, both these drugs associated with cardiac arrhythmias.
Similarly, in other therapeutic classes such as pain/musculoskeletal system, gastrointestinal, dermatology, ophthalmology, respiratory system, central nervous system, and endocrinology, there are rational and irrational combinations of drugs.
| » Global Prospective of Fixed-Dose Combination|| |
Worldwide, FDCs and its role in the management of disease are well established. The World Health Organization (WHO) has anticipated that the FDC of drugs will be an important component inpatient care. Under WHOs model list of essential medicines, included FDCs but their number is less and restricted for only some important therapeutic classes such as antibacterial, antiviral including antiretroviral and antimalarial. Recent trends of approvals to FDCs by the Food and Drug Administration (FDA) show that nearly 63 products. It means that FDA policy is flexible in approving FDCs and it is justified as they are essential.
FDCs become the new era of new drug development because it can pass easily through the regulatory process. Kwon and Lee observed that FDCs become the new area of Research and Development. Pharmaceutical companies are entrusted with the development and marketing of FDCs because of their positive impact on patient care and business growth.
Recently, European Medicines Agency (EMA) updated their guideline for clinical development of FDC of pharmaceutical products. The important aspect of this guideline is that FDCs shall focus on their clinical benefit for indicated disease condition than the market authorization. Major drug regulating agencies are giving free hand to the developer on the one side, strictly regulating its approval for irrational FDCs.
| » Indian Prospective|| |
In the updated National List of Essential Medicines, 2015, a total of 851 medicines, including stunts, are present in the list. However, the FDCs are merely 24 under the list. This gives us an insight that the majority of FDCs are not very essential for public healthcare.
In India, the Drugs and Cosmetics Rules, 1945 under the Drugs and Cosmetics Act, 1940 regulate the manufacture, sale, and distribution of FDC. Drugs and Cosmetics Rules authorize Central Drugs Standard Control Organization (CDSCO) to oversee the FDCs. CDSCO classifies FDCs into four different groups:
- Under Group 1: FDCs included are the ones that are having one or more of the active ingredient/s are new drugs. In this group, drug development process must be similar to the new drug
- Under Group 2: FDCs that are individually marketed and the combination have potential to prove significant pharmacodynamic or pharmacokinetic (PK/PD) benefit, then if
- It is marketed in any country, then data of FDC re adequate
- In case the individual drugs are marketed and used concomitantly, then the chemical and pharmacy data will be essential along with the stability of the proposed dosage form
- In other conditions, the dosage form is considered as a new drug and clinical trials is to be conducted.
- Under Group 3: FDCs that are marketed, but the ratio of active ingredients are changed or indented for other therapeutic use. In this scenario, rationality based on pharmacological data is taken for permission
- Under Group 4: FDC, individual active ingredients are used since many years, and for convenience, this FDC is prepared. Under such conditions, marketing permission can be given based on studies which demonstrate the stability of dosage form and no significant PK/PD interaction.
There are >6300 FDCs available till today. Such a rapid expansion of FDCs is due to India's regulatory structure. In India, drug development is regulated by both central agency and state agency. Though the permission for drug development is routed through central agency, due to lax administration, it is seen that there is a rapid expansion of FDC manufacturing because state authority permitted for marketing such FDCs. Ministry of Health and Family Welfare in India constituted a committee headed by Prof. C. K. Kokate to examine the safety and efficacy of FDCs, which were approved by the State Licensing Authority without prior approval from the Drug Controller General of India. This committee report was observed by the CDSCO and taken for rationalizing the FDCs four categories:
- Category “a”: Irrational FDCs, around 1083 such FDCs identified and issued show-cause notice
- Category “b”: There is a need for further deliberations with subject experts, around 1265 such FDCs identified
- Category “c”: Rational FDCs and concerned manufacturers received approval letters
- Category “d”: Under this category, further data are required. In such scenario, SLC will issue letters for submitting Phase IV trial protocol to the concerned manufacturers.
Because of the above initiatives, the CDSCO is able to put an end to irrational FDCs. Such a move was upheld by the honorable Supreme Court of India based on the rationality and safety of FDCs. A total of 405 FDCs were banned between November 2018 and January 2019. These FDCs were banned because they are irrational, for example:
- Ambroxol along with ammonium chloride, chlorpheniramine maleate, guaiphenesin, menthol, and phenylephrine
- Chlorpheniramine maleate along with ammonium chloride, sodium citrate, and menthol
- Amoxicillin and potassium clavulanic acid along with cefixime
- Aceclofenac and paracetamol along with rabeprazole.
Such a combination of drugs is not merely irrational but also ineffective and increases side effects.
This is a very good initiative of the Government of India and should revise its policy towards the FDCs and must consider the approval regulations of the US FDA and EMA for future development
To conclude that FDCs are essential as it increases the compliance, is cost-effective, and reduces the pill burden, especially when treating the chronic disease conditions or conditions which requires long-term therapy. Therefore, there should be a periodic review of all previously approved FDCs which are >10 years old. This also helps in accommodating advances in the medical sciences.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Kwon KC, Lee C. Analysis of fixed-dose combination products approved by the US food and drug administration, 2010-2015: Implications for designing a regulatory shortcut to new drug application. Ther Innov Regul Sci 2017;51:111-7.
Gupta YK, Ramachandran SS. Fixed dose drug combinations: Issues and challenges in India. Indian J Pharmacol 2016;48:347-9.
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