Fixed Dose Combinations

• Categories of FDC Products

  • Some of the earliest FDC’s have been widely accepted as rational combinations of drugs which are suitable for all of their target groups of patients. On the basis of their pharmacology or patient acceptability. Examples are the combination of estrogen with progesterone in combined oral contraceptives and levodopa with carbidopa to treat Parkinson’s disease. Many topical preparations, such as eye and ear drops and skin formulations, contain combinations which increase potential acceptability by reducing the number of products to be used.
  • Inappropriate drug combinations, where pharmacological claims for synergy are supported by little clinical evidence, e.g. the combination of caffeine with analgesics.
  • Mixtures of drugs which are benefit to only a few patients. Examples are combinations of potassium sparing diuretics with thiazides and multi-component antacid mixtures.
  • Those endorsed for use in resource-limited countries, specifically in the treatment of HIV/AIDS and tuberculosis.
  • Combinations of drugs for chronic conditions in which multiple drug regimens are recommended (eg. HIV/AIDS). Such regimens placed a significant pill burden on patients particularly those with comorbidities, and FDC’s in these patients may improve adherence.
  • Some formulations (e.g. asthma inhalers) contain two drugs but only one prescription charge is payable, which benefits patients which pay for their prescriptions.

• Advantages of FDC Products

  • Simpler dosage schedule improves compliance and therefore improves treatment outcomes.
  • Lower costs of manufacturing compared to the costs of separate products.
  • Reduce complexity of a dosage regimen. It is seen that lesser number of tablets or medications a patient has to take, better will be his patient compliance.
  • More convenient for the patient as he has to buy one drug compared to two.
  • Reduces inadvertent medication errors.
  • Only one expiry date simplifies dosing (single products may have different expiry dates).
  • Procurement, management and handling of drugs are simplified.
  • Potential for drug abuse can be minimized by using one drug of the combination for this purpose (i.e., excessive use of the antidiarrheal narcotic, Diphenoxylate).
  • Prevents and/or slows attainment of antimicrobial resistance by elimination monotherapy.
  • Allows for synergistic combination (e.g. Trimethoprim/Sulfamethoxazole combination allows each drug to selectively interfere with successive steps in bacterial folate metabolisms).
  • Eliminates drug shortages by simplifying drug storage and handling, and thus lowers risk of being “out of stock.”

• Disadvantages of FDC Products.

  • Dosage alteration of one drug is not possible without the alteration of the other drug.
  • Differing pharmacokinetics of constituent drugs pose the problem of frequency of administration of the formulation.
  • By simple logic there are increased chances of adverse drug effects and drug interactions compared with both drugs given individually.
  • The greater are the number of ingredients, the less likely the prescriber or the physician is to know what FDCs are and what their adverse reaction are. A combination makes it more difficult to pinpoint the offending agent responsible for the adverse reaction.
  • Reaction of one of the components (e.g., a rash to sulfamethoxazole in cotrimoxazole) may result in patient avoiding the “innocent” drug trimetophrim in the future.
Success Factors for FDC Product Formulation

• Formulation development challenges

Understanding the chemistry, mechanism of action of each component, as well as drug substance pre-formulation characteristics, are paramount. An experienced formulator can make all the difference in helping you obtain/protect current in-processes (IP), as well as make duplication by competitors extremely difficult. Speed to market is important, as well as holding off competitors. The following are few formulation considerations:

    • Incompatibility
    • Release profile differences
    • Particle size
    • Delivery challenges
    • Regulatory requirements.

• Patent Feasibility

Obtaining patents is not as simple as submitting a concept that appears unique. The product must be innovative and show functionality. Typically, patents are granted under the following criteria:

    • Must be “novel” i.e., not publicly known
    • Must be “inventive”, i.e., not obvious over what was already publicly known. (“prior at”)
    • Must be utilizable, i.e. has functionality
    • It should be noted that the “obviousness” hurdle is getting higher each year. If one’s have an idea or unique concept, chances are, so has somebody else. It is a good idea to research whether someone has gone down that road prior. The more successful combination products typically focus on unmet medical needs. To strengthen any patent, build innovation into formulation. Generic companies are getting better at circumventing formulation patents.

• Pricing and Reimbursement

    • Premium pricing above mono-therapy is becoming more difficult.
    • Increased unit sales should be primary goal.
    • Reimbursement is not typically an issue if combination product is not premium priced.
    • Reimbursement at premium pricing will only hold if there is a clear beneficial outcome.
    • Physician Consideration
    • Many physician prefer to select relative dosing of combination components on an individual patient.
    • Any need to titrate the drug dose can add complications.
    • Identifying source of side effects can be difficult.
    • Patient may potentially be exposed to drugs they do not really need.
    • Conceptually, medication management and compliance should improve with patients. However, little evidence exists regarding compliance improvement.
    • Physician’s increasingly see combination products as industry’s attempt to defend brand revenue against genetic competition.