NEW ERA in US PRESCRIPTION DRUG LABELING Ch.Teja *, Ch

7572 Ch.Teja et al./ Elixir Pharmacy 44 (2012) 7572-7575

Available online at www.elixirpublishers.com (Elixir International Journal) Pharmacy

Elixir Pharmacy 44 (2012) 7572-7575 NEW ERA IN US PRESCRIPTION DRUG LABELING Ch.Teja *, Ch. Dheeraj Reddy and G. Krishna Chaitanya, Balamuralidhar.V, T.M. Pramod Kumar, Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagar, Mysore- 570 015.

ARTICLE INFO ABSTRACT Article history: The overview of the paper is to give an idea of prescription drug labeling in United States. Received: 15 January 2012; Prescription drug labeling helps in making labels more user friendly and which is an Received in revised form: immediate and important source of medication information for patients. Although patients 15 March 2012; may obtain useful information from prescription drug labeling, its main purpose is to give Accepted: 29 March 2012; healthcare professionals the information they need to prescribe drugs appropriately to the patients. FDA focused its effort on making labeling more informative and easy-to-read and Keywords minimize patient confusion and promote patient awareness on how to use a prescribed Prescription drug label, medicine safely and effectively, thereby reducing risk of medication error. The new drug United States, labeling requirements was initially applied to recently approved prescription drugs and the Labeling Preference, drugs that received approval for new use, and later it was applied in gradually to other drugs. Boxed Warning. As per the new format, the prescription information for newly approved products must meet specific graphical requirements, including the reorganization of critical information so that physicians can find the information quickly. It may conclude in outlining the new format, which is helpful to understand exactly what a prescription drug labeling is in U.S. © 201 2 Elixir all rights reserved.

INTRODUCTION • Made locating and using information difficult. Pharmaceutical labeling/Drug labeling: It refers to all the • Did not facilitate finding answers to specific questions. printed information that accompanies a drug including the label, • Eventually, in many cases, labeling lost its user focus. the wrapping and the packaging insert. It became a document to assure completeness for possible Drug labelling is regulated by the food and drug litigation instead of a source of easy-to-use medical information. administration's division of drug marketing, advertising and Generally a label should contain the following information communications. about the following things 1,4 : These regulations apply to prescription drugs, over the counter • A summary of essential scientific information for the safe and drugs, and dietary supplements. effective use of the drug. The term "labeling" according to the united states code • Must be informative and accurate. 321(m) means all labels and other written, printed, or graphic • Use language that is not promotional in tone, false, or matters(1) upon any article or any of its containers and wrappers misleading. or, (2) accompanying such article. • Not to make claims or suggest uses for drugs when there is no Prescription drug labeling information is also known as 1: sufficient evidence of safety and a substantial evidence of • Prescribing information. effectiveness. • Package inserts. • Must contain information based on whenever possible data • Professional labeling. derived from human experience. • Direction circular. • The labelling must also be updated when new information • Package circular. becomes available. Importance of us prescription drug labeling: And Hence the Patient’s Preference was In the Following According to the Institute of Medicine (IOM) 2006 report 4, Manner 1: more than half a million adverse drug events (ADE’s) occur in • Directions – Avoid vague terminology. the United States each year. Problems with prescription drug • Benefits of the medication (Indication). (Rx) labeling were cited as the cause of a large proportion of • Warnings and possible side effects. patient medication errors and ADE’s, as patients may • Suggested responses to side effects (e.g., when to call doctor unintentionally misuse a prescribed medicine due to improper or stop taking medication). understanding of instructions. The elderly, those with limited • Duration of therapy. literacy skills, and individuals managing multiple medication FDA's goal for the prescription drug labelling 4 was to create regimens were found to be at greater risk for making errors in a more useful risk-safety communication tool and to reduce interpreting container label instructions. errors caused by misunderstanding or incorrectly applied drug Why more emphasis on the labeling??????? information. Over the years, prescription drug labeling was complex: FDA focused its effort on making labelling more informative • Did not identify the approval date. and easy-to-read • Did not indicate whether there were any recent changes to the labeling.

In 1992 FDA conducted focus-group research to learn more Adverse Reactions (listing of most common ARs) about the problems with the old labelling. Drug Interactions Between 1993 and 1994, the agency conducted a national Use in Specific Populations. survey of physicians to gather additional information about how Patient Counseling Information Statement. prescribers used labelling and what problems they had with it. One which are highlighted and in bold are Newly added section Emphasis on the problem associated with the labelling issues. and one which is in italics and underlined contains critical In order to implement a new regulation or change an existing prescribing information. one, FDA must obtain public comments and input on proposals. AN EXAMPLE FOR HIGHLIGHTS OF PRESCRIBING Also must obtain the comments of the prescribers and seek the INFORMATION: suggestions. These highlights do not include all the information needed to In 1995, FDA held a public meeting to discuss the prototype use Imdicon safely and effectively. and received comments to the Federal Register notice See full prescribing information for Imdicon. announcing the meeting. IMDICON (cholinasol) CAPSULES FDA analysed the comments and over the years worked with Initial U.S.Approval: 2000 the pharmaceutical industry and others to revise the prototype and develop what would become the new labelling. WARNING: LIFE THREATENING

On December 22, 2000, the Proposed Rule for the labelling HEAMATOLOGICAL ADVERSE change was published in the Federal Register. REACTIONS

On January 24, 2006, the "Final Rule: Requirements on the See full prescribing information for complete Content and Format of Labelling for Human Prescription Drug boxed warning . Monitor for hematological and Biological Products" was issued. adverse reactions every 2 weeks for first 3 The products affected by the rule include applications for months of treatment (5.2). Discontinue Imdicon prescription drugs and biologics: Immediately if any of the following occur:

Submitted to FDA on or after June 30, 2006 • Neutropenia(5.1) Approved by FDA 5 years prior to June 30, 2006 • Thrombotic thrombocytopenic With major changes in the prescribing information approved five years prior to, on, or after June 30, 2006. purpura(5.1) The above said products shall follow the rules for the labeling • Aplastic anaemia(5.1) requirements abide the labeling requirements. New labeling format: Basing the changes implemented by the FDA a new labeling ------RECENT MAJOR CHANGES------format has been designed 1. Indications and Usage, Coronary Stenting (1.2) 2/200X A. Adds Highlights section Dosage and Administration, Coronary Stenting (2.2) 2/200X B. Adds Contents section ------INDICATIONS AND USAGE------Imdicon is C. Reorders and reorganizes sections an adenosine diphosphate(ADP) antagonist platelet D. Makes additional improvements aggregation inhibitor indicated for: • Reducing the risk of thrombotic stroke in patients who A. HIGHLIGHTS SECTION: have experienced stroke precursors or who have had a

This is perhaps the most significant change in the new completed thrombotic stroke(1.1) labeling rule. • The very above said purpose was solved by incorporating the Reducing the incidence of sub acute coronary stent highlights. thrombosis, when used with aspirin(1.2) The Highlights section was created because prescribers said Important Limitations: they would use labeling more if it included a short, half-page • For stroke, Imdicon should be reserved for patients who synopsis. are intolerant of or allergic to aspirin or who have

It provides the overview of a drug’s benefits and risks that failed aspirin therapy(1.1) healthcare professionals said was most important to them. Highlight’s section consists of information which is not ------DOSAGE AND ADMINISTRATION------repetitive but contains the concise summary of crucial • prescribing information. Stroke: 50 mg once daily with food (2.1) Essentially, the Highlights section is a brief one-half page • Coronary stenting: 50 mg once daily with food, with summary of the more descriptive product labeling. antiplatelet doses of aspirin, for up to 30 days following The highlight section consists mainly of the following parts 4:- stent implantation (2.2) Limitations Statement Product Names and Date of Initial U.S. Approval Discontinue in renally impaired patients if hemorrhagic or Boxed Warning hematopoietic problems are encountered (2.3, 8.6, and 12.3) Recent Major Changes ------DOSAGE FORMS AND STRENGTHS------Capsules: Indications and Usage 50 mg (3) Dosage & Administration ------CONTRAINDICATIONS------ Dosage Forms & Strengths • Hematopoietic disorders or a history of TTP or aplastic

Contraindications anaemia (4) Warnings & Precautions • Haemostatic disorder or active bleeding (4) 7574 Ch.Teja et al./ Elixir Pharmacy 44 (2012) 7572-7575

• Severe hepatic impairment (4,8.7) MODEL EXAMPLE: ------WARNING AND PRECAUTIONS------• Neutropenia (2.4% incidence; may occur suddenly; typically resolves within 1-2 weeks of discontinuation), thrombotic thrombocytopenic purpura (TTP), aplastic anaemia, agranulocytosis, pancytopenia, leukaemia, and thrombocytopenia can occur (5.1) • Monitor for haematological adverse reactions every 2 weeks through the third month of treatment (5.2) ------ADVERSE REACTIONS------Most common adverse reactions (incidence >2%) are diarrhea, nausea, dyspepsia, rash, gastrointestinal pain, neutropenia, and purpura (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact (manufacturer) at (phone # and web address) or FDA at 1- 800-FDA-1088 or www.fda.gov/medwatch .

------DRUG INTERACTIONS------• Anticoagulants: Discontinue prior to switching to Imdicon (5.3, 7.3) B. FULL PRESCRIBING CONTENTS • Phenytoin: Elevated phenytoin in levels has been INFORMATION: reported. Monitor levels. (7.2) Another format feature all prescription drug products will ------USE IN SPECIFIC POPULATIONS------share is the new “Contents” section.

• Hepatic impairment: Dose may need adjustment. The Contents section addresses prescribers' concern “that it was difficult to use the old labeling format” to find specific Contraindicated in severe hepatic disease (4, 8.7, information. 12.3) 1. Navigational Tool • Renal impairment: Dose may need adjustment(2.3, 8.6, • To detailed safety information. 12.3) • To safety sections and subsections in the full prescribing information. The most important change made in the new type of labeling 2. Ease of Reference format includes: • Electronic hyperlinks to sections in the full prescribing Boxed Warning: information. The revised product labelling may contain boxed warning, 5 also referred to as a Black-Box Warning. C. REORDER AND REORGANIZE:

The boxed warning in the Highlights section uses bullets for The next and most important change made to the labeling ease of reading and is limited to 20 lines. includes re-ordering and re-organizing of the sections.

In the United States, a black box warning (also sometimes The "Indications and Usage" and the "Dosage and called a black label warning or boxed warning) is a type of Administration" sections (information that healthcare warning that appears on the package insert for prescription professionals refer to most frequently and consider most drugs that may cause serious adverse effects. important) are located at the beginning of the prescribing

It is so named for the black border that usually surrounds the information. text of the warning. Product identification information such as colour and scoring

The U.S. Food and Drug Administration(FDA) can require is located in both the ''Dosage Forms and Strengths" and the a pharmaceutical company to place a black box warning on the ''How Supplied" sections to preserve the integrity and labeling of a prescription drug or in literature describing it when: understanding of both sections.

The drug has serious adverse reactions. Next, the previous “Warnings and Precautions”sections were

When a serious unwanted reaction can be prevented or can be consolidated into one section that contains the most critical reduced in frequency and severity. safety information.

It is the strongest warning that the FDA requires. Sections previously located in the Precautions section (Drug

The FDA has required that black box warnings be placed on Interactions, Use in Specific Populations, and Patient all antidepressant medications warning they may result in Counselling Information)are now new sections in the labelling. increased risk of suicidal tendencies in children and adolescents. “Clinical Studies”, “Nonclinical Toxicology” “sections now

FDA advisors have recommended Pfizer required to place a required”. black box warning on their non-steroidal anti-inflammatory The ''Adverse Reactions" section follows the Warnings and drug Celebrex (celecoxib) for cardiovascular and gastrointestinal Precautions section and consolidates (provides) risk information risks. in one location

7575 Ch.Teja et al./ Elixir Pharmacy 44 (2012) 7572-7575

D. REVISION AND IMPROVEMENTS: As prescription information is updated in this new format it This section deals with revisions that have been made to the will be added to a new online health information clearing house labeling:- called Daily Med that will provide up-to-date medication 1. Format requires information free to consumers, healthcare professionals and Minimum 8-point font healthcare information providers. Tables and bullets In the future, this new information will also be provided Standardized bolding and white space through a website called [email protected], a comprehensive 2. Encourages Adverse Event Reporting, includes contact Internet resource designed to give one-step access for information information about all FDA-regulated products. Revisions were made to the safety information sections. Labelling Appearance : Specifically, new changes can be seen in the ''Contraindications" Generally covers how it should look, what is the font size and section, the ''Warnings and Precautions" section, and the the appearance of the label are covered in this format. ''Adverse Reactions" section. Font size of minimum 8 point with multiple formats including Contraindications: tables, bullets, bolding and spacing enhances visual and Includes known hazards. i.e. Likelihood of occurrence and cognitive access to the drug information. the size of population being affected. Languages to be used: The statement ALLERGIC to specific component of the drug All labeling information that is required by law or regulation has been removed. must be in English. 3. Warnings and precautions section: Only exception in U.S is Puerto Rico where different language Warnings and precautions have been made into one section If the label or labeling contains any representation in a foreign and has been expanded to include the clinically significant language, all label information required under the FD&C Act adverse reactions. must also appear in that language [21 CFR 701.2(b)] 2. 4. Clinically significant adverse reaction includes: What labeling information is required? Adverse reactions that require discontinuation, dose The following information must appear on the principal adjustment, or addition of another drug. display panel: Adverse reactions that significantly affect patient compliance. An identity statement, indicating the nature and use of the 5. Adverse reactions: product, by means of either the common or usual name, a Covers a separate listing of adverse reactions that occurred descriptive name, a fanciful name understood by the public, or during clinical trials and those that were reported after the drug an illustration [21 CFR 701.11]. was marketed. An accurate statement of the net quantity of contents, in terms Adverse reactions from post-marketing clinical trials should of weight, measure, numerical count or a combination of be included with the clinical trial experience. numerical count and weight or measure [21 CFR701.13] 2. Post-marketing spontaneous adverse reaction reports must be Conclusion: listed separately. This article highlights the U.S revised prescription drug No longer contains the extraneous events or laundry lists of labeling which was region specific and this format made easy adverse reactions. for patients for its effective use and convenient for doctors to It will supplement with additional detail, the nature, severity, prescribe as According to the Institute of Medicine (IOM) 2006 frequency of adverse reactions, and the relationship to dose and report, more than half a million adverse drug events (ADE’s) demographics. occur in the United States each year. Problems with prescription A toll-free number and Internet reporting information for drug (Rx) labeling were cited as the cause of a large proportion suspected adverse events to encourage more widespread of patient medication errors and ADE’s, as patients may reporting of suspected side effects. unintentionally misuse a prescribed medicine due to improper In addition, a new Patient Counseling Information section understanding of instructions places greater emphasis on the importance of communication Bibliography: between professionals and patients. The new section is designed 1. www.fda.gov/downloads/Training/.../UCM090796.pdf - to help doctors advise their patients about important uses and 28/08/2011 limitations of medications. 2. http://law.justia.com/cfr/title21/21cfr201_main_02.html If FDA has approved patient information for a prescription -28/08/2011 drug, it will be printed at the label immediately following the 3. http://en.wikipedia.org/wiki/Black_box_warning- patient counseling information section or will accompany the 4/09/2011. label so it can be easily shared.