Bioequivalence

What is the standard reference to use in terms of bioequivalence?

*Orange book* --> for small molecules

Besides bioequivalence, the Orange Book is also good for finding _________ products

Discontinued

Ceftriaxone sodium is a ________ salt (divalent organic anion); calcium is a divalent ________ cation salt

Disodium Inorganic

What does it mean if there is no symbol in the grid?

Does not mean that they're compatible; means no info has been reported

What are some reasons for being deemed non therapeutically equivalent?

Drug contains active ingredients or is manufactured in dosage forms documented to have bioequivalence problems Quality standards are inadequate or FDA has an insufficient basis to determine equivalence Drug is under regulatory review

There is potential for precipitation of opposite aromatic...

Drug ions

For non-dissociated salts of organic ions, precipitation is likely when...

Oppositely charged organic drug ions with aromatic rings are combined in strong concentrations

Multisource drug products listed under the same heading may have a number added if there is more than one....

Standard (AB1, AB2)

Pharmaceutical alternatives may have different...

Strengths or dosage forms

Medications are considered bioequivalent if...

The *rate and extent* of absorption of the test drug do not show a significant difference from the rate and extent of absorption of the reference drug when administered at the same dose via the same solute

The *Merck Index* is a source for a *visual picture* of the...

Aromatic ring

Sometimes, which two suffix combos denote quaternary ammonium drugs (cations)?

-ium -ate -ium -ide

How to predict the incompatibility of organic drugs?

3 letter suffix of the nondrug ion name in organic drug salts allow identification of a cation or anion A *quaternary ammonium* drug salt with *-ium and -ate* identify a cawtion rather than anion (pretty rare, not many) Observe the drug structure if a cation or anion Expect precipitation when pairs of salts are mixed in high concentrations and when the salts were diluted 20-fold or less from the original concentration

What is a pharmaceutical alternative?

A drug with the *same active ingredient* but differ in salt, ester or complexes --> Ferrous sulfate, ferrous gluconate

*-ate* and *-ide* are _____ cations

Acid

Basis of drug compatibility is classifying organic drugs as either...

Acid cations or base anions

What are the main causes of *visible incompatibility?*

Acid-base reactions Non-dissociated salts of organic ions Salting out Salts of inorganic divalent ions Desolvation of nonionized organic drugs Organic ion-inorganic salts

What does the code *AB* mean?

Actual or potential problems have been resolved with an in vivo or in vitro evidence

What are exceptions to the acid/base rule?

Amphoteric drugs; capable of reacting chemically either as an acid or base

*-ium* and *-ium -ate* (example: sodium succinate) are _____ anions

Base

Drugs are pharmaceutically equivalent if....

Both are approved as safe and effective Equivalent in: -Amount of same active drug ingredient, in same dosage form and route of administration -Meet compendial standards for strength, quality, purity and identity Adequately labeled Manufactured in compliance with Good Manufacturing Processes Bioequivalent (listed in orange book)

What is a good example of organic ion-inorganic salts?

Ceftriaxone precipitation with calcium

What does Trissel's tell you?

Charts/tables of drugs Stability, compatability pH, compatibility in IV admixture as well as mixed in a syringe

Insoluble concentrations of nonionized drug forms can occur in which situations?

Combining organic anions and organic cations Diluting the organic drug salt solution leading to a change in the pH Mixing organic drug ions that have the same charge but difference by more than 1 unit in pKa and solution pH

Pharmaceutical equivalents have _________ bioavailability, and are studied under similar __________ conditions

Comparable Experimental

The *King Guide to Parenteral Admixtures* tells you what?

Compatibility with limited information on stability Focused on IV meds

What does *C* denote in terms of compatibility in Kings?

Compatible; determined by drug concentration, pH, infusion fluid, temperature, type of container, order of mixing, method of admin

What does the 0 with a line denote?

Conflicting data; could be either or

What are pharmaceutical equivalents?

Contain the same active ingredients, same dosage form, route of admin, identical in strength or concentration *May differ* in shape, scoring, packaging, excipients, expiration time

Organic ion-inorganic salts is a rare situation, but can be ________

Critical

Stability is related to the _______ of the medication

Degradation (how long is it good for?)

Dilution in aqueous solutions causes intermolecular hydrogen bonding of the alcohol to water, which does what to the drug?

Deprives the drug of the weaker force with alcohol that solubilizes the drug, such as *diazepam* or *lorazepam* (cannot put these into IV bag)

Why would a second letter be added to a code of A?

Designate if the dosage form presents an actual or potential *bioequivalence problem*

What is in the Orange Book?

Drug products with approval under Section 505 of the FD&C Act Prescription drug products with therapeutic equivalence evaluations OTC drugs that cannot be marketed without an NDA or ANDA because they are not covered under existing OTC monographs Discontinued drug products Orphan product designations and approvals Drug products which must demonstrate in vivo bioavailability only if the product fails to achieve adequate dissolution Drug patent and exclusivity information for: Rx, OTC and d/c drugs

What are the main criteria for inclusion in the Orange Book?

Drugs approved by the FDA based on safety and efficacy Drugs with an active application and the FDA approval has not been withdrawn for safety or efficacy reasons Therapeutic equivalence evaluations for approved multisource prescription drugs

What does the Orange Book NOT include/

Drugs approved only on the basis of safety (DESI, Drug Efficacy Study Implementation) Drugs marketed prior to 1938 (neither nor safety was required; phenobarbital or aspirin)

For therapeutic equivalence evaluation codes, what does *A* mean?

FDA considers drug to be *therapeutically equivalent*

What does the code *B* denote?

FDA considers it to NOT be therapeutically equivalent to other pharmaceutical products

What does *Extended Stability of Parenteral Drugs* include?

Factors affecting extended drug stability Assigning beyond use dates External factors affecting stability Parenteral nutrition is discussed in a separate section Drug monographs are covered

What is another name for *Pharmaceutical Equivalents?*

Generic substitution

Precipitation on dilution in aqueous fluid is common with *nonionized* drugs formulated as an injection with ______% by volume alcohol

Greater than or equal to 40%

What is a major resource to use for injectable drugs?

Handbook of Injectable Drugs (*Trissel's*)

Salting out results when...

Highly hydrated inorganic ions deprive the organic ions and molecules of adequate water to remain dissolved

What does *X* denote?

Incomptibility

What is an OTC monograph?

It lists components that can be contained in said drug

Salts of polyvalent anions and cations are usually ______ soluble than salts with *both ions monovalent* or one is monovalent and the opposite is polyvalent

Less

What's in the Compatibility Guide for Aerosolized Medications?

Limited information on compatibility of aerosolized medications No counterpart to the parenteral IV admixture charts

The Orange Book was originally distributed as a proposal in 1979, and only included what?

Marketed prescription drugs approved by the FDA through submission of an NDA Generic equivalents approved under ANDA

Clinically important potential precipitates are dibasic or...

Monohydrogen calcium phosphate

The most common cause of drug incompatibility is precipitation of ________ drug forms

Nonionized

Drug compatibility is dependent on multiple chemical and ______ factors

Physical

Incompatibility between two drugs is related to which two possibilities?

Precipitation or insolubility

What does the code *AA* mean?

Products contain the same active ingredients and the dosage forms are not regarded as presenting an actual or potential bioequivalence problem

Salts that require 1000mL/g to dissolve or have <0.1% solubility are used to provide...

Prolonged absorption for clinical purposes

What did the 1984 Drug Price Competition and Patent Term Restoration Act do?

Required the FDA make publically available the list of approved drug products; *generics could be made* Monthly supplements were provided

What is an important stability feature of Extended Stability of Parenteral Drugs?

Shows the refrigerated and body temperature stability

What is a reference listed drug?

The drug identified by the FDA as the drug product which is the *standard* against which others submitting an ANDA are compared to *Only one, otherwise drift is possible* Usually the first on the market

What is a good source to ask about the stability of a med?

The manufacturer of the drug

What is another term for *Pharmaceutical Alternatives?*

Therapeutic substitution*

What are key questions to ask about incompatibility and stability?

What route of administration is being used for the patient's meds? What are the doses, concentrations and volumes of the medications? What infusion time or rate of admin is expected or desired? What is the base solution or diluent? Was the product stored in a refrigerator or room temperature and for how long? Was the product exposed to sunlight and for how long? Was the product frozen, and for how long? When was the product compounded or prepared?