Fixed Dose Combination Drugs

Why in the News?

The Ministry of Health and Family Welfare in India has recently prohibited the manufacture, sale, or distribution of 156 fixed-dose combination (FDC) medicines. This action is aligned with the powers granted under the Drugs and Cosmetics Act of 1940.

• Previous Actions: Earlier in 2023, the ministry had banned 14 FDCs due to similar concerns.
• Reasons for Ban: The banned FDCs were determined to pose risks to human health, with safer alternatives available. An expert committee, along with the Drugs Technical Advisory Board (DTAB), concluded that there is no therapeutic justification for the ingredients in these FDCs.
• Examples of Banned FDCs: The list includes various medicines, such as antibiotics, painkillers, and multivitamins, with specific examples like Aceclofenac and Paracetamol.

What are Fixed Dose Combinations (FDCs)?

• Definition: FDCs are pharmaceutical products that contain two or more active ingredients (often referred to as "cocktail drugs") intended for a specific medical indication. This definition is in accordance with the Drugs & Cosmetics Rules of 1945.
• Active Ingredients: An active ingredient is the biologically active component of a drug (such as a tablet, capsule, cream, or injectable) responsible for producing the intended therapeutic effects.
• Regulatory Status: According to the Drugs and Cosmetics Act of 1940, FDCs are classified as New Drugs. Approval for these combinations is granted by the Central Drugs Standard Control Organization (CDSCO).
• Common Combinations: FDCs are frequently found in formulations targeting cough, cold, and fever; antimicrobials; as well as vitamins and minerals.

Implications of the Ban

This ban reflects the Indian government's commitment to ensuring the safety and efficacy of pharmaceutical products. By removing potentially harmful FDCs from the market, the ministry aims to protect public health and promote the use of safer alternatives. The move also emphasizes the importance of rigorous evaluation of drug combinations before they are approved for use.

Rationale for the Usage of Fixed Dose Combination Drugs (FDCs)

Fixed Dose Combination (FDC) drugs are increasingly utilized in modern medicine for several compelling reasons.

1. Enhanced Efficacy

• Better Therapeutic Outcomes: FDCs can provide improved therapeutic effects compared to using individual medications. By combining drugs that work synergistically, healthcare providers can target multiple pathways in disease management, often leading to more effective treatment.

2. Cost-Effectiveness

• Affordability: FDCs are generally more cost-effective than purchasing individual medications separately. This can significantly reduce the financial burden on patients, especially for chronic conditions requiring long-term treatment.

3. Reduced Pill Burden

• Convenience and Compliance: FDCs simplify treatment regimens by reducing the number of pills patients need to take. This convenience can lead to improved patient adherence to prescribed therapies, which is crucial for achieving optimal health outcomes.

4. Pharmacokinetic Advantage

• Optimized Absorption and Metabolism: FDCs can offer pharmacokinetic advantages by improving the absorption, distribution, metabolism, and excretion (ADME) of the drugs involved. This can enhance the overall effectiveness of the treatment and minimize potential side effects. For example:
• Synergistic Effects: When two drugs are combined, they may enhance each other's absorption or metabolic pathways, leading to better overall bioavailability.
• Streamlined Metabolism: Combining medications can help in synchronizing their metabolic profiles, allowing for more consistent therapeutic levels in the bloodstream.

Issues Associated with Fixed Dose Combination Drugs (FDCs)

While Fixed Dose Combination (FDC) drugs offer several advantages, they also present significant issues that can impact patient safety and public health.

1. Lack of Individual Dose Flexibility

• Fixed Dosage Limitations: FDCs contain a predetermined dosage of each active ingredient, which may not be suitable for all patients. Individual variations in response to medication, including differences in weight, age, and co-existing medical conditions, can make fixed doses problematic. This lack of flexibility can lead to suboptimal treatment outcomes or increased side effects for certain patients.

2. Unapproved and Banned FDCs

• Hazards of Unlicensed Products: The availability of untested and unlicensed FDCs, particularly in countries like India, raises significant public health concerns. Such FDCs may lack rigorous testing for safety and efficacy, putting patients at risk of adverse effects or ineffective treatment. The ease of access to these medications can lead to their widespread use without proper medical supervision.

3. Increased Risk of Antimicrobial Resistance (AMR)

• Overuse of Antibiotics: The combination of multiple antimicrobial agents in FDCs can lead to potential overuse and misuse, contributing to the rise of antimicrobial resistance. Inappropriate prescribing or self-medication with FDCs containing antibiotics may promote resistance, complicating the treatment of infections and threatening public health.

4. Ethical Concerns

Regulatory Discrepancies: Although the Indian government has imposed bans on certain FDCs due to safety concerns, ethical dilemmas arise when the same drugs are permitted for export to African or SAARC (South Asian Association for Regional Cooperation) countries. This inconsistency raises questions about the responsibility of pharmaceutical companies and regulatory bodies in ensuring the safety of medicines available in both domestic and international markets. The potential exploitation of less stringent regulations in other countries poses a risk to vulnerable populations.

Issues in the Regulation of Fixed Dose Combination Drugs (FDCs) in India

The regulation of Fixed Dose Combination (FDC) drugs in India faces several significant challenges that can compromise patient safety and public health. Here are some key issues:

1. Reformulation of Drugs

• Evasion of Price Control: Some pharmaceutical companies reformulate individual drugs into FDCs to circumvent price control regulations. This practice can lead to the introduction of medications that may not provide additional therapeutic benefits while increasing costs for consumers.

2. Compromised Quality

• Lax Regulatory Oversight: After a four-year period, other manufacturers can produce new FDCs by obtaining licenses from State Licensing Authorities (SLAs) without undergoing rigorous checks related to pharmacological studies. This lack of stringent quality control can result in substandard medications entering the market.

3. Approval Process

• Regulatory Gaps: The Parliamentary Standing Committee on Health and Family Welfare's 59th report highlighted that some SLAs have issued manufacturing licenses for FDCs without prior clearance from the Central Drugs Standard Control Organization (CDSCO). This oversight can lead to the circulation of unsafe or ineffective medications.

4. Other Concerns

• Poor Adverse Drug Reaction Reporting: India has a suboptimal system for reporting adverse drug reactions, which hampers the identification and management of safety concerns associated with FDCs.
• Lack of Comprehensive Data: There is no precise database tracking the currently available FDCs in the market, including their sales turnover and usage patterns. This lack of data makes it difficult to assess the impact of FDCs on public health effectively.

Steps Taken by India for Regulation of FDCs

To address these issues, India has implemented several regulatory measures:

• Drugs & Cosmetics (Amendment) Act, 2008:
• Introduces stringent penalties for manufacturers of spurious and adulterated drugs. Certain offenses related to drug quality have also been made cognizable and non-bailable.
• Strengthening Testing Capacities:
• The Central Drugs Testing Laboratories under the CDSCO are continuously enhancing their testing capabilities to expedite the analysis of drug samples in the country.
• Amendment of Drugs and Cosmetics Rules (2017):
• Requires applicants to submit bioequivalence study results along with applications for manufacturing licenses for oral dosage forms of drugs, enhancing the scrutiny of FDCs.

Suggestions to Improve Regulation of FDCs

To further strengthen the regulation of FDCs in India, the following measures are suggested:

• Periodic Surveys:
• Conduct regular surveys of drug manufacturers and wholesale/retail outlets to gain insights into the existing challenges in the sector and ensure compliance with regulatory standards.
• Establishment of a National Drug Authority (NDA):
• Create a National Drug Authority through an Act of Parliament, as recommended by the Hathi Committee and outlined in the Drug Policy of 1994, to oversee drug quality and safety.
• Strong Punitive Actions:
• Implement robust punitive measures against individuals involved in drug-related corruption, as suggested by the Mashelkar Committee. For instance, consider escalating the penalties for manufacturing or selling spurious drugs from life imprisonment to a death penalty as a deterrent.
• Multistep Approach:
• Adopt a multistep approach involving all stakeholders—consumers, physicians, regulatory authorities, industry representatives, and academia—to address the irrational use of FDCs effectively. Collaborative efforts can enhance awareness, improve practices, and promote safer use of medications.

Conclusion

Regulating FDCs in India requires comprehensive measures to address existing challenges and improve drug safety and efficacy. By implementing the suggested steps, India can enhance its regulatory framework, ensuring that FDCs are both safe and effective for patients.