Understanding the Package Insert

What is a package insert (PI)?

A package insert (abbreviated PI) is information provided with a prescription drug that tells you:

• What the drug is
• How it should be used
• How it works
• Safety concerns to be aware of and precautions to take (safety is a consideration with all drugs, even the most well known)
  

PIs are usually written information you receive with your prescription drug. They may literally be thin, folded up sheets of paper placed inside the box your prescription bottle comes in, or they may be computer printouts given to you along with your receipt for the prescription.

Why is the PI important, and who decides what information it contains?

The information in the PI is the official description of the prescription drug product. This information is also known as the prescribing information for a drug because it provides recommendations on how a drug should be prescribed and used based on evidence reviewed by the U.S. Food and Drug Administration (FDA).

The FDA calls the information in the PI the drug product label. The exact wording of the drug product label must be approved by the government before the PI can be printed and distributed. In the United States, the FDA is the government agency that approves the drug product label. The FDA also approves prescription drugs for distribution, regulates the availability and marketing of prescription drugs in the United States, and monitors drug safety.

What are the main sections of a package insert (PI)?

The sections of the PI have recently been redesigned, according to new guidelines from the FDA (as of 2006). These changes are meant to make the PI easier to read. They are also meant to make the information in the PI easier to find.

The first main section of the PI is called Highlights of Prescribing Information. In this section, a brief summary is presented with references to the full prescribing information for more details. Click here (URL to be selected from list of FDA fictitious products immediately below in purple) for an example of a highlights section and other PI sections for a fictional product made up by the FDA as an example. For more information, see Highlights of Prescribing Information: What It Must Include.   

After the Highlights of Prescribing Information section, the next main section of the PI is the Table of Contents for the full prescribing information.

After the Table of Contents, the next main section in the PI is the Full Prescribing Information. Although many of the sections in the full prescribing information have the same titles as in Highlights of Prescribing Information, this time the information is provided in detail, not summarized.

The sections within the Full Prescribing Information main section are numbered (except for the boxed warning, if any), so that they can be referenced more easily. Click here for an example of the Full Prescribing Information for a fictional product made up by the FDA as an example.

Finally, the information approved for the patient package insert may appear as the last main section of the PI.

What are boxed warnings, and what does it mean for a package insert (PI) to have a boxed warning?

A boxed warning is a warning about a drug that the FDA has required a drug manufacturer to present prominently, within a box. The purpose of the box is to call attention to the warning and make sure that physicians and patients are aware of it before the drug is administered. The FDA reserves its requirement for boxed warnings to important warnings about serious safety concerns.

The FDA may require a boxed warning when new information becomes available that points to a serious safety concern about an approved drug. Generally, the FDA uses boxed warnings to draw attention to:

• A possible adverse event that is so serious compared with the expected benefit from the drug (for example, a life-threatening reaction, or one causing permanent disability) that it absolutely must be considered as part of the decision whether or not to use the drug
• A serious adverse event that could be prevented or reduced if the drug is carefully managed in some way (for example, careful patient selection, continual monitoring, avoiding certain drugs or clinical situations in combination with the drug)
• Restrictions that are necessary to ensure safe use of a drug, if the FDA has determined that the drug cannot be prescribed without formal restrictions in its use, due to safety concerns
  

If your doctor recommends that you take a drug with a boxed warning in its prescribing information, read the warning, and be sure to ask your doctor to discuss it with you. Drugs with boxed warnings can still provide important benefits to patients, but the safety concerns associated with the drug should be clearly understood by both doctor and patient.

What is on-label vs. off-label?

The FDA refers to the prescribing information for a drug as the drug product label. Any information in the approved drug product label, including the approved indications for a drug, is called on-label. Any information or use outside the approved drug product label is called off-label.

In the U.S., physicians are allowed to prescribe drugs for off-label uses if good medical practice justifies the use, and if their prescription meets the current standard of medical care. However, drug manufacturers may not bring up off-label uses for a drug with physicians and patients, and may not distribute written materials mentioning off-label uses. The FDA monitors and enforces compliance with these restrictions.

What is a patient package insert?

A patient package insert is similar to the PI, but contains information specifically written for patients. The information is meant to help patients understand how to safely and appropriately use a prescribed drug. This information must also be approved by the FDA, as part of the drug product label.

What do the technical words in a package insert (PI) mean?

The PI contains many technical words because it provides drug information that is learned using medical science. To provide the most accurate and precise information to the physician, the PI must use scientific terms.

One of the sciences that the PI relies on to describe a drug is pharmacology. Pharmacology is the scientific study of drugs and their effects in living organisms.

Pharmacology can be divided into two broad areas: pharmacokinetics and pharmacodynamics.

• Pharmacokinetics is the study of how the body acts on an administered drug, “processing” it from its first entry into the body until its last exit from the body. Pharmacokinetics information tells us how drugs are absorbed, distributed, broken down, and eliminated by the body, and especially how quickly these processes happen.
• Pharmacodynamics is the study of how a drug acts on the body. Pharmacodynamics information tells us how a drug alters body chemistry and the functioning of living tissues, and focuses especially on drug actions that relate to the drug’s effectiveness and safety.
  

Some technical terms commonly used in the PI to convey pharmacologic information are:

• Half-life (t½) - a measure of how quickly an administered drug is “processed” by the body; the amount of time needed for the amount of drug within the body to be reduced by half
• Clearance - another measure of how quickly an administered drug is “processed” by the body; the volume of blood that can be made free, or cleared, of an administered drug by the kidneys over time, as part of drug elimination by the body
• Volume of distribution - an imaginary volume that serves as a measure of drug distribution within the body; it is the volume of fluid that would have to be present if the drug was evenly distributed in the fluid at a certain (measured) blood concentration
• Bioavailability - the extent to which active drug reaches body tissues where it can exert its effects against disease
• Steady state - a condition in which blood levels of an administered drug stay relatively stable over time; steady state is achieved when the amount of drug administered to the patient over time is balanced by the amount of drug eliminated by the patient’s body over time
• Metabolism - the breakdown of administered drugs by the body, as part of normal body functioning
• Oral - by mouth (for example, oral administration of a drug is taking it by mouth)
  
• Intravenous - by vein (for example, to administer a drug intravenously is to introduce it through a tube or by injection into a vein)
  
• Subcutaneous - under the skin (for example, to administer a drug subcutaneously is to inject it under the skin)
  
• First-pass effect - for drugs that have been taken by mouth, the breakdown of drugs by the body in the liver and intestines
  
• Gastrointestinal - having to do with the stomach and intestines
  
• Hepatic - having to do with the liver
  
• Renal - having to do with the kidneys
  
• Excretion - the elimination of drugs by the body
  
• Protein binding - the extent to which drug molecules bind to proteins normally found in the blood
  
• Therapeutic - having to do with treating disease
  
• Mechanism of action - the exact effects (on a molecular basis) that an administered drug has within the body that are useful against disease
  
• Receptors - specialized molecules within the body that interact with a drug and make certain drug effects possible
  
• Enzymes - a molecule, most often a protein, that speeds up a chemical reaction by other molecules
  
• pH - a measure of the acidity of a chemical substance
  

Another scientific area that the PI depends on to describe drug effects is the evidence from clinical trials. Clinical trials are scientific studies conducted in humans, most often patients with the disease that the drug is expected to treat.

Some technical terms commonly used in the PI to convey clinical trial results are:

• Phase I clinical trials - scientific studies of a drug in humans that largely focus on a drug’s safety (nonclinical safety studies are performed and assessed before Phase I trials are allowed to begin)
• Phase II clinical trials - scientific studies of a drug in humans that largely focus on a drug’s effectiveness, actions within the body, and elimination from the body at the drug doses under study
• Phase III clinical trials - scientific studies of a drug in humans that attempt to establish a drug’s effectiveness, safety, usefulness in the clinical setting, and usefulness compared with other drugs or treatments, in as large a patient population as is practical for study
• Controlled clinical trials - scientific studies of a drug in humans that include a group of patients who do not receive the drug, to allow for comparison of effects
• Placebo - an inactive treatment given in some controlled clinical trials, to allow for comparison of effects
• Active comparator - an active drug given in some controlled clinical trials, to allow for comparison of effects
• Randomization - a method used in clinical trials to assign patients randomly to receive active drug, placebo, or active comparator; randomization helps minimize differences between patient groups; that way, any differences in effects are more likely to be due to the drug under study, instead of other factors
• Double-blind - a type of clinical trial in which patients and researchers do not know which patients are receiving the drug under study, and which patients are receiving the placebo or active comparator; this allows for an objective comparison of effects (without the influence of prejudice for or against the drug)
• Open-label - a type of clinical trial in which no attempt is made to conceal which patients are receiving the drug under study vs. placebo or active comparator, and other methods are used to help increase objectivity; this may be a more practical design for certain clinical trials
• Adverse event - side effect; an unwanted drug effect resulting in an unfavorable change in a patient’s health
• Serious adverse event - serious side effect; an unwanted drug effect resulting in an unfavorable change in a patient’s health that puts the patient at serious risk
  

Indexed collections of PIs are regularly updated and printed together in book form for reference. One such reference is the annual Physician’s Desk Reference (PDR), which has been in print for more than 60 years. Today, it is also possible to obtain electronic PIs through the Internet for many prescription drugs. For more information about how to obtain package inserts, see “Where to Find Package Inserts Online.”

What is a package insert called outside the United States?

In Europe, the package insert is called a patient information leaflet (PIL). The European Medicines Agency (EMEA) evaluates and authorizes new drugs and prescribing recommendations for European marketing. The Medicines and Healthcare products Regulatory Agency (MHRA) approves the wording of each PIL for marketing of prescription drugs nationally within the United Kingdom.