Week 11: Pre-reading Material (week 10 = no class)

The approved drug products in the orange book will be divided into two major categories: A and B. Talk about the A code,

"A" codes apply to drug products considered to be therapeutically equivalent to other pharmaceutically equivalent products. "AA" means drug products in not presenting any bioequivalent problems, "AB" means products meeting bioequivalent requirements after any potentical bioequivalence problems have been resolved.

Hatch-Waxman Act is aka, state the date as well.

Drug Price Competition AND Patent Term Restoration Act in 1984 is aka

Bioequivalent drug products:

Pharmaceutical equivalents or alternatives that have comparable bioavailability when studied under similar experimental conditions

For FDA approval, clinical safety and efficacy studies are generally not performed on generic drug products. (T or F)

T. This is correct, in an effort to push synthesis of more generic drug products.

What's in the Prescription Drug Product and OTC Drug Product Lists

The FDA put a list of reference drugs (i.e., reference standard) to which the in vivo bioequivalence and, in some instances, the in vitro bioequivalence of the applicant's product will be compared.

. "B" codes apply to; what does "BP" mean?

drug products that the FDA does not at this time consider to be therapeutically equivalent to other pharmaceutically equivalent products. active ingredients and dosage forms with potential bioequivalence problems.

Define prescibability (L.O = important)

i) Prescribeability deals with drug naive PATIENTS (not patient). What does that mean? It means that individuals in the population can be administered the generic or the brand-name drug product and will obtain the same pharmacological response, including safety and efficacy.

Switchability (L.O = important)

is related to a patient whose medical condition is successfully controlled on a brand-name or a generic drug product, and then is switched to another generic product, hopefully resulting in the same efficacy and safety profile.

Again: the Durham-Humphrey Amendment to the 1938 Federal Food, Drug, and Cosmetic (FDC)

restricted the sale of prescription drugs to prescription by a licensed practitioner.

OTC Approval process:

1) Sometimes approved require applications just like a new prescription drug 2) More often they are legally marketed without an application by following a regulation called an OTC drug monograph.

Learning objective that was mentioned in the reading: name of the act that distinguished between OTC and prescritpion medication? 2 more things that the amendment allowed.

1) The Durham-Humphrey Amendment explicitly defined two specific categories for medications, legend (prescription) and over-the-counter (OTC). The bill requires any drug that is habit-forming or potentially harmful to be dispensed under the supervision of a health practitioner as a prescription drug and must carry the statement, "Caution: Federal law prohibits dispensing without a prescription."[1] 2) This law also legalized verbal transmission of prescriptions and 3) provided for the legal right of a pharmacist to refill prescriptions as indicated in a provider's initial prescription.

Drug Price Competition AND Patent Term Restoration Act in 1984. By the way both are under 1 Act (they're not 2 separate acts) (Learning objective)

1) The act expedites the availability of less costly generic drugs by permitting the FDA to approve applications to market generic versions of the brand-name drugs. 2) Those that will synthesize the generic version don't need to to repeat the research (i.e., clinical trials) done to prove that the generic is safe and effective (i.e., Abbreviated New Drug Application, ANDA). 3) At the same time (second portion of the act) the brand-name companies can apply for up to five years of additional patent protection for the new medicines they developed [to make up for time lost while their products were going through FDA's approval process]

Drugs that are considered Therapeutically equivalent have to be

1) pharmaceutically equivalent drug products, and 2) have the same clinical effect and safety profile (i.e., same therapeutic effect, identical in duration and intensity) when administered to patients under the conditions specified in the labeling

Generic drug product: (define, selling price) (what are they equivalent to brand-name drugs in)

1. Drug product that "is identical - or bioequivalent - to a brand name drug in dosage form (e.g. both are tablets), route of administration, safety, strength (e.g. potency), quality, performance characteristics and intended use. 2. They are chemically identical (contain the same active ingredient) to their branded counterparts, but are sold at substantial discounts from the branded price".

What do generic drug-product manufacturers need to not worry/ worry about to get approval for their generic drug product. (also mention three types of equivalents in the answer)

1. For FDA approval, they don't need to worry about establishing clinical safety and efficacy of their generic drug product. 2. However, manufacturer must demonstrate that the generic drug product is therapeutically and pharmaceutically equivalent and bioequivalent (will know the difference between the three later) to the comparator brand-name drug product.

Define Brand name (L.O.) (aka, explain, give example)

1. Trade name of the drug. 2. This name is privately owned by the manufacturer or distributor and is used to distinguish the specific drug product from competitor's products. 3. Tylenol® synthetized by McNeil Laboratories).

Give example of Pharmaceutical Substiution:

Ampicillin suspension (like a syrup) is dispensed in place of oral ampicillin capsules. OR tetracycline hydrochloride capsules are dispensed in place of tetracycline phosphate capsules. Again notice that the substitute is not necessarily a generic product.

What is a reference listed drug? (bioequivalence)

An approved drug product to which new generic versions are compared to show that they are bioequivalent. In other words, the drug on the list is identified by the FDA as the drug product that the applicant with a new ANDA seeking approval for his/her generic drug must compare his generic drug to.

It makes sense that by designating a single reference drug as the standard to which all generic versions must be shown to be bioequivalent, FDA hopes to avoid possible significant variations among generic drugs and their brand name counterpart. Such variations could result if generic drugs were compared to different reference listed drugs. However, in some instances there could be a product not designated as a reference listed drug. (let's call it drug بوبي) A pharmaceutical firm wishing to market a generic version of that listed drug (drug بوبي) that is not designated as the reference listed drug may petition the Agency through the

Citizen Petition procedure. When the Citizen Petition is approved, the second listed drug will be designated as an additional reference listed drug and the petitioner may submit an Abbreviated New Drug Application citing the designated reference listed drug.

Therapeutic alternatives vs. Pharmaceutical alternatives

Differ in the same active ingredient vs same active ingredient but in a different moeity, strength or dosage form.

Therapeutic alternatives:

Drug products that contain different active ingredients (wow) but are indicated for the same therapeutic or clinical objectives. This is because active ingredients in therapeutic alternatives are from the same pharmacologic class and are expected to have the same therapeutic effect when administered to patients for such condition of use.

Pharmaceutical alternatives:

Drug products that contain the same therapeutic moiety but differ in the salt or ester of that moiety or in the dosage form or strength. For example: 1. Tetracycline hydrochloride vs tetracycline phosphate (different salt or moeity) 1. Digoxin oral tablet vs. Digoxin solution. (notice same route of admin but different dosage forms) 2. Valium® 2 mg tablets vs. Valium® 10 mg tablets - have different strengths (i.e., different amounts of diazepam). 3. Also applies to products synthetisized by the same manufacturer but differ in strength or dosage form.

The Orange Book contains

EVALUATIONS of the therapeutic equivalence of different drug products made by various manufacturers.

OTC and generic drugs are the same thing (T or F)

F. Doctor may prescribe a generic variation of a brand-name because it is cheaper. Also as you'll see in the next flash card, an OTC variation of prescription drug may become available and then companies can synthesize generics of this OTC medication.

Give example of RLD

For example, Boniva® oral tablet is a RLD for generic versions of ibandronate sodium oral tablets.

Give an example of Generic Substiution (L.O)

For example, a pharmacist can DISPENSE a prescription made by the doctor for a Boniva® brand of ibandronate sodium (150 mg, once a month oral tablets) as a GENERIC ibandronate sodium oral tablet (150 mg once a month) made from Mylan Pharmaceutics, if the generic substitution is permitted and desired by the physician. - In other words if the physician believes that switcheability is not an issue here. lol

Give example for therapetuic and pharmaecutical substituion:

For example, amoxicillin capsules are dispensed for ampicillin capsules. Both amoxicillin and ampicillin are antibiotics. (contain different active ingredients but both ingredients belong to the same class that can fight the same microorganism/s) Example: giving supsension in stead of tablet

Drug Price Competition AND Patent Term Restoration Act in 198 is aka

Hatch-Waxman Act

Abbreviated New Drug Application, ANDA, what does the manufacturer need not to worry about?

In an effort to expedite the availability of generic versions of brand-name drug, those that will synthesize the generic version don't need to to repeat the research (i.e., clinical trials) done to prove that the generic is safe and effective and can just submit an ANDA.

What is the study that makes sure that oral generic drug products are equivalent in terms of performance to the brand drug-product?

In vivo bioequivalence studies are performed in normal healthy adult subjects under fasted and fed conditions.

An OTC drug monograph tells what? OTC that meet requirement vs those that don't meet thre requirement?

It tells the kind of ingredients in the OTC that may be used to treat certain diseases or conditions without a prescription, and the appropriate dose and instructions for use. OTC products that meet a monograph's requirements may be marketed without FDA review. OTC products that do not fit under an existing monograph must be approved under an application like the applications for prescription products".

In the past decades, we have witnessed an increase in the dispensing of generic drug products. Why? And what was the result?

Less expensive than brand-name drug. 1) Hence: physicians were encouraged to write prescriptions specifying a generic product. 2) Second, state anti-substitution laws were modified to permit (even mandate - make it mandatory to write) generic substitution, even if the prescription did not include the generic name of the drug. 3) Third, the FDA published a list of drug products thought to be interchangeable. 4) Finally, Drug Price Competition and Patent Term Restoration Act in 1984 (i.e., Hatch-Waxman Act)

L.O. Pharmaceutical equivalents: define what they're similar on and what they can vary on and still be called pharmaceutical equivalents.

Means drug products that have a) identical amounts of the same active chemical ingredients, same salt or moeity. b) in the same dosage form and meet standards of strength, quality, and purity according to the United States Pharmacopoeia or other nationally recognized compendium (book) c) However, the products may differ in characteristics such as shape, drug release mechanisms, excipients, expiration time, and within-certain-limits labeling.

Chemical name: (who uses this, L.O. = imp)

Name used by the organic chemist to describe the chemical (molecular or atomic) structure of the drug (e.g., N-acetyl-p-aminophenol).

Define OTC (learning objective)

OTC drugs can be purchased and used without a prescription.

In order to Pharmaceutical substitution in the pharmacy you require

Physician's approval even though same acive drug but may vary in strength or potency.

What are the two main issues that concern us regarding generic drug products?

Prescribeability and switchability.

Generic name: (what's key word here, define, L.O. - imp)

The established, NON-PROPRIETARY (can't be owned) or common name of the active ingredient in a drug product (e.g., acetaminophen).

Generic substitution: (define, what's funny about it?

The process of dispensing a different BRAND (even though the term is called GENERIC SUBSTITUTION) or UNBRANDED drug product in place of the prescribed drug product. The substituted drug product contains the same active ingredient or therapeutic moiety but is made by a different manufacturer.

Pharmaceutical substitution:

The process of dispensing a pharmaceutical alternative for the prescribed drug product.

Therapeutic substitution

The process of dispensing a therapeutic alternative in place of the prescribed drug product.

Ibuprofen tablets are given instead of aspirin tablets are examples of Tetracycline hydrochloride vs tetracycline phosphate are examples of

Therapeutic equivalents Pharmaceutical alternative: same active drug but existing in a different salt or moeity.

Define Prescritpion drugs (learning objective)

Those that are deemed unsafe for self-medication and which should therefore be used only under a doctor's supervision.

Difference between prescibability and switchabiliby? (L.O. = important)

We can say Prescribability deals with population bioequivalence while switchability deals with individual bioequivalence

Therapeutic substitution (generally requires; what else requuires that)

physician's approval, pharmaceutical substitution.