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Posted 22 December 2015 | By Zachary Brennan 

Proposed Rule Would Revise Regulations on Fixed-Combination Drugs


The US Food and Drug Administration (FDA) is proposing a new rule that would apply its regulations on prescription fixed-combination drugs to a variety of nonprescription fixed-combination and co-packaged drugs, as well as to combinations of over-the-counter active ingredients.

Under its authority to require evidence demonstrating that prescription fixed-combination or co-packaged drugs and OTC ingredients provide enhanced safety or effectiveness and can be labeled as such, this proposed rule (which would not apply to drug-device combinations) describes what applicants must do to show that their fixed-combo or co-packaged drugs are safe and effective.

Under the proposal, FDA says that each active ingredient must make a contribution to the effect(s) of the combination, enhance the safety or effectiveness of an active ingredient, or minimize the potential for abuse of an active ingredient. In addition, the dosage of each active ingredient (amount, frequency of administration, and duration of use) must ensure that the combination is safe and effective and provides rational concurrent therapy.

Fixed-combination drugs can provide convenience, therapeutic benefit, and even economic benefit to patients, according to FDA, though there are potential disadvantages, including a lack of flexibility in adjusting the dosage of each active ingredient to an individual patient’s needs, the related possibility of overexposure or unnecessary exposure to a particular ingredient.


FDA says data on these nonprescription fixed-combination and co-packaged drugs need to demonstrate the contribution of each active ingredient to the effect of the combination and could include:

  • Controlled clinical trials showing a contribution of each active ingredient to the claimed effect;
  • Controlled studies showing an effect of each active ingredient on a pharmacologic parameter or biomarker considered predictive of the therapeutic effect;
  • Clinical pharmacology data;
  • In vitro data; and/or
  • Animal model data.

FDA recommends that some companies use a factorial study for a combination of “n” active ingredients, which would be designed to show that the combination is more effective than all possible n-1 active ingredient combinations.

“Thus, for a combination with two active ingredients, a factorial study would have three arms--the combination (AB) and the individual drugs contained within it (A) and (B)--and would be designed to demonstrate that AB has a larger effect than A alone and B alone (AB versus A and AB versus B). For a combination with four active ingredients, a factorial design would

compare the combination (ABCD) to all possible three-drug combinations of the four active ingredients (ABC, ABD, ACD, and BCD),” FDA explains.

In cases where a factorial design is not possible, FDA says different approaches could be used to demonstrate the contribution of each active ingredient to the effect of the combination by identifying an existing population in which the added effect of one of the active ingredients could be established.

“For example, for a fixed-combination drug containing an older antiplatelet active ingredient and a newer lipid-lowering active ingredient, existing studies of the lipid-lowering active ingredient may have included substantial subsets of subjects who were all receiving the antiplatelet active ingredient and who were randomized to the lipid-lowering active ingredient or placebo,” the agency says.

Examples of Drugs

As for co-packaged drugs, which includes the Monistat 3 Combination Pack for treatment of vaginal yeast infection and co-packaged Sodium Nitrite Injection and Sodium Thiosulfate Injection (Nithiodote) for the treatment of acute cyanide poisoning, FDA says these products can “raise concerns” that are similar to those associated with fixed-combination drugs.

“For example, a drug manufacturer might co-package a lipid-lowering drug with an antihypertensive drug because patients with high cholesterol often also have high blood pressure. In this case, there is an identifiable patient population that needs both drugs. Although there are existing data on the safety and effectiveness of these products individually, before approving their use in combination, FDA would want to be sure that they can be used together safely and that each does not interfere with the effectiveness of the other.”

Other examples of recently approved applications for co-packaged drugs include Pravigard PAC (co-packaged pravastatin sodium tablets and buffered aspirin tablets) for reducing the occurrence of serious cardiovascular and cerebrovascular events; co-packaged peginterferon alfa-2a and ribavirin for the treatment of hepatitis C; and co-packaged bismuth subsalicylate (gastrointestinal agent), metronidazole (antiprotozoal and antibacterial agent), and tetracycline hydrochloride (antibiotic) for the treatment of patients with active duodenal ulcer associated with Helicobacter pylori infection.

Examples of fixed-combination OTC drug products marketed in accordance with OTC drug monographs include a wide variety of "cough/cold" fixed-combination drugs (containing analgesics-antipyretics, cough suppressants, decongestants, and antihistamines), as well as fixed-combination OTC drug products marketed under an NDA, including Imodium Multi-Symptom Relief (loperamide hydrochloride and simethicone tablets), to relieve diarrhea and gas, and Pepcid Complete (famotidine, calcium carbonate, and magnesium hydroxide chewable tablets), to relieve heartburn.

FDA says it’s also aware of a growing interest in the development of two or more new investigational drugs (i.e., drugs that have not been previously developed) for use in combination, either as individual agents labeled for use with one another or as a fixed-combination or co-packaged drug.

“There is particular interest in such development for targeted cancer and anti-infective therapies. In contrast to fixed-combinations or co-packages of previously approved drugs, new investigational products are not well-characterized. Therefore, this type of development is inherently more complex and requires studies to characterize not only the combination, but also the individual agents to the extent necessary and feasible,” the agency says, noting previous guidance from 2013 on Codevelopment of Two or More New Investigational Drugs for Use in Combination.

However, products such as whole blood, individual or pooled transfusible blood components (e.g., pooled platelets), pooled plasma products, and plasma derivatives from human or animal sources (e.g., immune globulins of general or particular specificity) would not be regarded as fixed-combination drugs under the proposed rule, FDA says. In addition, the rule would not apply to individual natural-source drugs, which are drugs derived from natural raw materials, even though those drugs may contain multiple ingredients derived from the same source.


Because there are some products for which it would be unfeasible or medically unreasonable or unethical to meet the requirements of the proposed rule, FDA would be given the authority to grant a waiver of some or all of the proposed requirements at the request of an applicant.

Among the types of products for which FDA would expect to grant a waiver are:

  • Traditional botanical products composed of multiple botanical raw materials in fixed ratios.
  • Traditional medicinal products composed of multiple parts of animals;  
  • Traditional medicinal products composed of substances derived from more than one type of natural source (e.g., a botanical raw material and a single animal raw material); and
  • Cellular and gene therapies.

FDA also expects to waive the requirements of this proposed rule for certain allergenic products, such as allergen patch tests applied to the surface of the skin to determine the specific causes of contact dermatitis.

Drugs will also be generally recognized as safe and effective (GRASE) when the following criteria are met, FDA says: (1) Each active ingredient makes a contribution to the claimed effect(s); (2) combining the active ingredients does not decrease the safety or effectiveness of any of the individual active ingredients; and (3) the fixed-combination, when used in accordance with labeling that provides adequate directions for use and warnings against unsafe use.

Cost Estimates

The agency estimates it will receive about 15 waiver requests (taking about 50 hours to prepare and submit for each) annually, with estimated annual costs of preparing and reviewing proposed waivers ranging between $101,858 and $152,787.

The agency also estimated that the benefits associated with reduction in preparation and review time of information that would not be necessary if the proposed rule were in effect would amount to between $651,891 and $977,836.

Proposed Rule on Fixed-Combination and Co-Packaged Drugs: Applications for Approval; Combinations of Active Ingredients under Consideration for Inclusion in an Over-the-Counter Monograph



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