PTCE: The Basics of Medications - Drugs Forms, Drug Interactions, Drug Approval Process, Drug Storage Requirements & More

This table lists the usual dosage forms:

- DRUG CLASSIFICATION: Drugs are grouped by their common actions and effects on the body (e.g., anti-infective, anxiolytic, analgesic).
- THERAPEUTIC EQUIVALENCE: This classification is given to drugs that meet certain criteria. The drugs must be proven to be safe and effective, and they must be deemed as pharmaceutically equivalent. This means that identical amounts of active drug are present. The dosage form and route must also be the same. Standards of strength, purity, and quality must be met. Bioequivalence must also be proven.

According to the FDA, this is completed through testing to prove the drugs have similar rates of absorption under similar conditions and dosage parameters. Therapeutic equivalence can be checked by looking at the Approved Drug Products with Therapeutic Equivalence Evaluations, which is commonly referred to as the Orange Book. This publication is the U. S. Food and Drug Administration’s (FDA) official listing for prescription, over-the-counter, biologic, military, discontinued, or otherwise never-marketed drugs.
- SIDE EFFECTS: Secondary effects of the drug other than the primary therapeutic effect it was originally intended for.
- DRUG INTERACTIONS: A desirable or an undesirable effect that can occur when the effect of one drug is altered by the action of another drug or substance. This phenomenon can produce undesirable effects, resulting in a lack of efficacy or even toxicity. Factors that contribute to an increased number of drug interactions include multiple prescribers, poor patient compliance, taking multiple drugs, advanced age, and comorbidity. There are several different types of drug interactions.

Drug-drug interactions occur when a drug interacts with or interferes with another drug. This interaction may be additive, synergistic, potentiated, or antagonistic. An additive interaction results when two drugs given in combination have an effect equal to the sum of the individual effects. A synergistic interaction results when drugs given in combination produce an effect greater than the sum of the individual effects. A potentiated interaction occurs when one drug intensifies the activity of another drug. An antagonistic interaction occurs when drugs given in combination cause a decreased, or diminished, effect in one or more drugs.
Drug-food interactions occur when a drug reacts with a food. An example of this is when drinking grapefruit juice causes an increase in the serum concentration of the antihyperlipidemic drug lovastatin (Mevacor).
Drug-disease interactions may occur when a prescription or an over-the-counter medication interacts or interferes with an existing medical condition. For example, a drug-disease interaction occurs when an individual with hypertension takes pseudoephedrine.
Drug-nutritional supplement interactions occur when a drug affects vitamin absorption or metabolism. For example, anticonvulsants, such as phenytoin, can cause vitamin D deficiency.
Drug-laboratory interactions occur when a drug or a substance alters the concentrations of substances in the body. For example, potassium-sparing diuretics, such as triamterene, increase serum potassium levels. In addition, the H2 blocker cimetidine can elevate serum creatinine levels.
Drug-nutrient interactions occur when a drug affects the use of a nutrient in the body. The drug may affect the nutrient’s absorption, the use of the nutrient by the body, or the excretion of the nutrient. For example, antihyperlipidemic agents, such as cholestyramine, can decrease the absorption of the fat-soluble vitamins (vitamins A, D, E, and K).

The FDA Drug Approval Process
The FDA’s Center for Drug Evaluation and Research (CDER) oversees clinical trial investigations used to explore the safety and effectiveness of medications, safety devices, and medical strategies for humans.

The process of drug approval.




The FDA drug approval process

STEP 1 Preclinical Testing
The FDA requires all drugs to undergo preclinical testing in a laboratory before testing in humans can begin. During this process, the developer or sponsor will compile data on dosing and toxicity levels. Researchers will evaluate the findings to determine if the drug should move to clinical testing.

STEP 2 The Investigational New Drug Process
The drug developer submits an Investigational New Drug (IND) Application to the FDA. This application includes manufacturing information, animal safety data and toxicity, clinical protocols, and information about the investigator. An IND review team will review the data for potential approval. The review team has 30 days to review the application and indicate if the drug is approved, if it is stopped, or if additional information is required before a decision can be made.

STEP 3 Clinical Trials
Three phases of clinical trial testing are required before a drug may be considered for approval on the market. Phase 3 testing is contingent on successful completion of phase 2, which depends on the success of phase 1. (See Figure 4-1). As clinical trials progress, researchers will gather data on safety, appropriate dosage, side effects, interactions, and efficacy. If the drug is approved, the sponsor will conduct postmarketing testing to further evaluate the drug’s safety and long-term side effects.

STEP 4 New Drug Application
The final step is for a New Drug Application (NDA) to be submitted to the FDA to approve the drug for marketing and distribution. The FDA has 60 days to accept the application for review. On average, the CDER will review and act on applications within 10–12 months after receiving the NDA.
On average, a drug takes 12 years to go from laboratory testing to the pharmacy shelf. During its development, the drug sponsor requests a patent to protect the company’s interest in having an exclusive right to the drug. The patent excludes other companies from marketing, developing,
or using the drug while the patent is valid. The term of a patent is 20 years from the initial filing date submitted with the IND application. A patent extension may be granted and is determined on an individual basis.
The FDA has a second regulatory agency that oversees biological products. The Center for Biologics Evaluation and Research (CBER) oversees blood products, gene therapy, blood derivatives, vaccines, allergenics, cellular therapies, and xenotransplantation. Biological products follow a similar drug approval process with the exception of the final stage. These products are approved for interstate commerce using a Biologics License Application (BLA).

Stability and Beyond-Use Dating
Stability refers to the ability of a substance to remain unchanged over time while maintaining its initial characteristics. Chemical compatibility concerns, as well as proper beyond-use date labeling, are both vital to stability.
Chemical compatibility refers to stability, specifically the ability for the substance to remain stable when mixed with other substances. Chemical incompatibilities include visible as well as invisible changes. A change in color or the formation of a precipitate, such as calcium phosphate, are examples of visible changes. The formation of gases or of volatile chemicals, in contrast, are examples of invisible changes.
The beyond-use date is defined by the USP-NF, General Chapter <795>, as “the date after which a compounded preparation shall not be used and is determined from the date when the preparation is compounded.”* Medications may include stability information in their package insert or labeling. In the absence of stability information, packaged, light-resistant, temperature-controlled non-sterile compounded medications may use the beyond-use dates listed in

Table: Maximum Non-Sterile Beyond-Use Dates*

*U.S. Pharmacopeial Convention. “Pharmaceutical compounding–Nonsterile preparations (USP43-NF38)” Auxiliary Labels Auxiliary labels are brightly colored medication labels that are added to prescription bottles in an effort to provide ancillary information to the patient regarding safe administration, use, storage, and disposal of the medication. Common examples of auxiliary labels are “Take with food” and “Medication should be taken with plenty of water.” Prescriptions for controlled substances are required to carry an additional auxiliary label: “Caution: Federal law prohibits the transfer of this drug to any person other than the patient for whom it was prescribed.” Some pharmacies may have auxiliary warnings printed onto the prescription bottle label. This system eliminates the need for personnel to identify appropriate auxiliary labels and eliminates potential errors that may result from improper label selection or exclusions. Conversely, personnel may also select additional warnings to place on the prescription bottle as warranted.
 

Table: Examples of Prescription Auxiliary Labels

Some of the most commonly used prescription auxiliary labels in pharmacy practice. For this exam and your career, learn to be comfortable identifying drugs that carry these labels.

Therapeutic Index
The therapeutic index (TI) is a ratio that compares a therapeutically effective dose to a toxic dose of a drug. It is a relative statement of safety. A dose-response curve is a visual representation of this relationship and is derived by dividing the toxic dose in an average population (TD50) by the effective dose in an average population (ED50).



A higher value therapeutic index is an indication of a more agreeable safety profile. For example, if Drug “X” had a TD50 of 100 and an ED50 of 10, its TI would be 10:



To put this into perspective, a drug with a TI of 10 would be considered safer than another drug with a TI of 5 or a TI of 2.



Figure: Increasing therapeutic index (TI)

Narrow therapeutic index (NTI) drugs are those drugs for which “small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity” as per the U.S. Food and Drug Administration, 2017. These drugs are subject to regular therapeutic drug monitoring to ensure that the patient’s actual blood levels stay within therapeutic range. NTI drugs have less predictable effects that can lead to significant adverse drug effects if a patient is not regularly monitored.
One example of a NTI drug is warfarin (Coumadin), an anticoagulant used to treat or prevent blood clots, such as deep vein thrombosis (DVT). Warfarin is monitored using a standardized calculation in the form of the International Normalized Ratio (or INR). The INR measures how long it takes the blood to clot and provides a result that can be used by patients and prescribers to determine if warfarin dosing is appropriate. If the dose of warfarin is too low, the patient is at risk of developing harmful blood clots. If the dose of warfarin is too high, the patient may be at risk of serious bleeding.



Figure: Dose-response curve comparison: wide TI vs. narrow TI medications

The following is a list of drugs that are frequently monitored due to a NTI:
- carbamazepine (Tegretol)
- cyclosporine (Neoral, Sandimmune)
- digoxin (Lanoxin)
- ethosuximide (Zarontin)
- flecainide (Tambocor)
- gentamicin (Garamycin)
- levothyroxine (Synthroid)
- lithium (Eskalith, Lithobid)
- methotrexate (Rheumatrex, Trexall)
- phenytoin (Dilantin)
- rifampin (Rifadin, Rimactane)
- theophylline (Theo-24, Uniphyl)
- vancomycin (Vancocin)
- warfarin (Coumadin)

Drug Storage Requirements
The majority of prescription medications can be stored at room temperature: 15°C to 30°C or 59°F to 86°F. Some medications require refrigeration: 2°C to 8°C or 36°F to 46°F. A list of these medications can be found in Appendix C of this book. These drugs may also have special storage requirements after being dispensed to the patient. Drugs that must be frozen (−25°C to −10°C or −13°F to −14°F) are less common and are mainly vaccines. See Appendix D of this book for a list of vaccines, including those that must be frozen prior to use.
Medications that are stored outside of a recommended temperature range can incur a number of consequences, including a loss of physical integrity (e.g., suppositories melting), a reduced shelf life, or a partial or complete loss of effectiveness. Medications should be stored in their original packaging and placed in the appropriate storage area. Physical incompatibilities can occur between two or more substances, which can lead to a change in color, odor, taste, viscosity, or morphology. Chemical incompatibilities are the result of a reaction between two or more substances, leading to precipitation, effervescence, color change, decomposition, or an explosion.
Drugs can lose their potency due to exposure to light or moisture. This process can be slow, but some drugs are particularly sensitive to light and/or moisture and can lose their potency much more quickly. It is crucial that these drugs be stored in their original packaging to slow down the loss of potency. Medications should also be stored in their original packaging due to adherence issues or safety concerns.

Table: Medications That Should Be Stored in Their Original Containers

Medications with specific storage requirements may be flagged with shelf tags or stickers in the pharmacy to alert pharmacy staff. A “dispense after” auxiliary label should be placed on any prescription vial that requires special attention. Additional information on storage requirements can also be found in the “storage and handling” section of the medication package insert.