What Kind of Drugs Are You Dispensing or Selling?
In this edition of the Newsletter, we will discuss the following questions:
- What is an FDA-approved drug?
- Does the FDA approve drug substances (active pharmaceutical ingredients [API])?
- Are all manufactured drugs FDA approved?
- What are Pre-1938 drugs?
- Are compounded drugs FDA approved?
- Are manufactured veterinary drugs FDA approved?
Terminology is oftentimes confusing. What is the difference between an "FDA-approved drug," "unapproved drug," and an "unapprovable drug"? Which ones are legal in the U.S.? Can I dispense/compound FDA-approved, FDA-unapproved, and unapprovable drugs? The FDA often uses the word "drug" to mean "drug product" (i.e., they use them interchangeably).
An FDA-approved drug is one in which the manufacturer or sponsor has received an approval letter; an official communication from the FDA to a New Drug Application (NDA) or an Abbreviated New Drug Application (ANDA) sponsor that allows the commercial marketing of the product.
An unapproved drug is one that has not undergone the FDA review process with subsequent approval, a modified commercial drug product, or a drug that was withdrawn from the market for safety reasons (the negative list).
An unapprovable drug results when a company sponsor of a drug product that has been submitted to the FDA does not gain approval. This may be subsequently changed with an additional application/information, etc.
The FDA does not approve drug substances (active pharmaceutical ingredients); they approve finished drug products.
Background and Introduction
Many health professionals and the public often get the idea or impression that unapproved drug products or compounded preparations are "illegal" and that only "FDA-approved drugs" are legal to use in the U.S. This is not true. FDA approval is required for drug products that are going to be manufactured and marketed by manufacturing facilities around the world that are registered with the FDA. Compounded preparations are prepared pursuant to a prescription issued by a prescriber (legally authorized to prescribe by the state), for a patient, and compounded by a pharmacist (legally authorized by the state to practice pharmacy).
FDA-approved drugs are obviously legal (and can even be compounded under certain conditions, but not if patented); for the most part, they are near ready for administration. It should be noted that an API by itself is not approved by the FDA; the FDA approves a final drug product near-ready for administration. The NDA requires extensive work on the specific formulation for stability, etc. and detailed labeling specific for the commercial product.
A "new drug" is defined by the FDA as "any drug that is not recognized as safe and effective in the conditions recommended for its use among experts who are qualified by scientific training and experience."
A drug product need not involve a new chemical entity to be considered "new." A change in a previously approved drug product's formulation or method of manufacture constitutes "newness under the law," since such changes can alter the therapeutic efficacy and/or safety of a product. Further, a combination of two or more old drugs or a change in the usual proportions of drugs in an established combination product is considered "new" if the change introduces a question of safety or efficacy. Also, a proposed new use for an established drug product, a new dosage schedule or regimen, a new route of administration, or a new dosage form, all result in a drug product's status change to "new" and triggers consideration for safety and efficacy.
It is interesting also that when two FDA-approved drugs are mixed together, as in an intravenous admixture or oral mixture, the resulting preparation is not FDA-approved.
Pre-1938 Drugs are Unapproved but Legal
What do the following drugs have in common?
- Acetaminophen, Codeine Phosphate, and Caffeine Capsules and Tablets
- Amobarbital Sodium Capsules
- Amyl Nitrate Inhalant
- Chloral Hydrate Capsules, Syrup, and Suppositories
- Codeine Phosphate Injection, Oral Solution, and Tablets
- Codeine Sulfate Tablets
- Colchicine Injection and Tablets (Now FDA Approved)
- Digitoxin Tablets
- Digoxin Elixir and Tablets
- Ephedrine Sulfate Capsules and Injection
- Ergonovine Maleate Injection and Tablets
- Ergotamine Tartrate Tablets
- Hydrocodone Bitartrate Tablets
- Hydrocodone Bitartrate, Aspirin, and Caffeine Tablets
- Hydromorphone Hydrochloride Suppositories
- Levothyroxine Sodium for Injection
- Morphine Sulfate Oral Solution and Tablets
- Nitroglycerin SL Tablets
- Opium Tincture
- Oxycodone Tablets
- Oxycodone Hydrochloride Oral Solution
- Phenazopyridine Hydrochloride Tablets
- Phenobarbital Capsules, Elixir, and Tablets
- Phenobarbital Sodium Injection
- Pilocarpine Hydrochloride Ophthalmic Solution
- Potassium Bicarbonate Effervescent Tablets for Oral Solution
- Potassium Chloride Oral Solution
- Potassium Gluconate Elixir and Tablets
- Potassium Iodide Oral Solution
- Quinine Capsules
- Quinine Sulfate Tablets (Now FDA approved)
- Salsalate Capsules
- Sodium Fluoride Oral Solution and Tablets
- Thyroid Tablets
Simple…these are examples of "Pre-1938" drug products that have never been approved by the FDA. They were all "grandfathered in" and allowed to remain on the market without further regulatory approval if they were labeled with the same conditions of use.
What's the point? When someone discusses "FDA-unapproved drugs," inform them that some of the most important drugs on the market today are unapproved by the FDA, including these pre-1938 drugs, compounded preparations, intravenous admixtures, etc. It is interesting that the media and even others in leadership positions, cast disparaging remarks that compounding is involved with FDA-unapproved drugs and do not even realize the number of FDA-unapproved drugs that are on the commercial market manufactured by the pharmaceutical industry. The fact is that patients depend upon FDA-unapproved drugs every day. Any manipulation of an FDA-approved drug outside the FDA-approved labeling can change it to an FDA-unapproved drug.
It is interesting to note that the cost of these pre-1938 drugs to the consumer increase significantly when a company gains FDA-approval; this may be due to the lack of competition once approved. As an example, Quinine Sulfate Capsules and Colchicine Tablets, approved July 30, 2009, were quite inexpensive before approval, but now that they are approved, they are quite expensive.
Most Veterinary Drugs are Unapproved but Legal
There are literally thousands (3,000 to 4,000 estimated) of unapproved veterinary drugs on the market today. They are allowed by the FDA to be manufactured and marketed.
Compounded Drugs are Unapproved but Legal
Do pharmacists compound with "unapproved new drugs"? It sounds like pharmacists are doing something illegal every time the media reports on compounding. After reading this, one can see that technically "yes, pharmacists do compound unapproved new drugs," according to the FDA. However, it must be remembered that the bulk United States Pharmacopeia (USP)- and National Formulary-grade pharmaceuticals (APIs) used in compounding are identical to those used in manufacturing "approved new drugs." The difficulty is in the definition of a "new drug." The active USP ingredients used in compounding are actually components of manufactured "approved new drugs," but, according to the definition by the FDA, the same active ingredients in a different dosage form or in another dosage form that has not specifically gone through the FDA-approval process is a "new drug"; hence, an "unapproved new drug." So, technically, the "drugs" or "drug substances" are the same and of the same quality in both "approved manufactured products" and "unapproved compounded preparations." However, due to the technical definition of the term "new drug," "unapproved new drugs" result from compounding.
Also, using commercial products in compounding results in "unapproved new drugs." For example, if a commercial tablet is pulverized and placed in a liquid vehicle for a pediatric patient (since most commercial drug products do not have a pediatric liquid available), that "approved drug" now becomes an "unapproved new drug" because it has been converted into an oral liquid. Also, intravenous admixtures prepared in hospitals from "approved" drugs become "unapproved new drugs" when the admixture is prepared by the pharmacy for the patient.
All of the above, done appropriately and within the laws and regulations of the state boards of pharmacy, is legal and is done in hospitals, clinics, independent and chain pharmacies, specialty compounding pharmacies, etc. Compounded prescriptions are prepared as the result of a prescription or medication order from a prescriber and are for a specific patient, and not for "manufacturing and marketing" to the public.
A company which has been notified that their NDA drug is unapprovable is an action that is often temporary; as it may be approved later after the company responds to the FDA. This is just the situation where an NDA is rejected by the FDA for marketing by a specific manufacturer; the API may still be suitable for compounding for specific patients. Also, one cannot compound drugs that are on the "Drugs Not to Be Compounded" list.
Not all drugs that are used in health care today are FDA-approved. We all need to be educated so we can appropriately respond to these misrepresentations and untruths that are propagated in the media.
Loyd V. Allen, Jr., PhD, RPh
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy
Lisa D. Ashworth, BS, Pharm, RPh
Children's Medical Center of Dallas