The Food and Drug Administration (FDA) recently published Guidance for Industry on Medication Guides, entitled “Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS).” The guidance is intended to address two topics pertaining to Medication Guides for drug and biological products:
- When FDA intends to exercise enforcement discretion regarding when a Medication Guide must be distributed with a drug or biological product dispensed to a healthcare professional for administration to a patient4 instead of being dispensed directly to the patient for self-administration or to the patient’s caregiver for administration to the patient.
- When a Medication Guide will be required as part of a risk evaluation and mitigation strategy (REMS).
In 1998, FDA issued final regulations establishing requirements for the distribution of patient labeling for certain prescription drug and biological products used primarily on an outpatient basis without direct supervision by a health professional (63 FR 66378, December 1, 1998).
These regulations, codified in 21 CFR part 208, apply to certain drug and biological products that FDA determines pose a serious and significant public health concern requiring the distribution of FDA-approved patient medication information that is necessary to patients’ safe and effective use of the drug products (a Medication Guide).
Medication Guides apply primarily to human prescription drug products used on an outpatient basis without direct supervision by a health professional and are applicable to both new and refill prescriptions. FDA is authorized to require a Medication Guide if FDA determines one or more of the following circumstances exist:
· The drug product is one for which patient labeling could help prevent serious adverse effects.
· The drug product is one that has serious risk(s) (relative to benefits) of which patients should be made aware because information concerning the risks could affect patients’ decision to use, or continue to use, the product.
· The drug product is important to health and patient adherence to directions for use is crucial to the drug’s effectiveness.
Part 208 specifies the content and format of Medication Guides and manufacturer requirements to provide Medication Guides for distribution. Manufacturers of drug products for which a Medication Guide is required must:
· Obtain FDA approval of the Medication Guide before the Medication Guide is distributed, and
· Ensure that Medication Guides are provided in sufficient numbers, or provide the means to produce Medication Guides in sufficient numbers, to distributors, packers, and authorized dispensers to permit the authorized dispenser to provide a Medication Guide to each patient receiving a prescription for the drug product.
Part 208 also specifies the requirements for distribution of Medication Guides:
· Distributors and packers who receive the Medication Guides, or the means to produce Medication Guides, must provide the Medication Guides or the means to provide them to authorized dispensers.
· Each authorized dispenser of a prescription drug product for which a Medication Guide is required must provide the Medication Guide directly to each patient or each patient’s agent when the product is dispensed, unless an exemption applies.
FDAAA Requirements for Medication Guides as Part of REMS
The Food and Drug Administration Amendments Act of 2007 (FDAAA) created new section 505-1 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), which authorizes FDA to require a risk evaluation and mitigation strategy (REMS) when necessary to ensure that the benefits of a drug outweigh the risks. Under section 505-1(e), FDA may require that a REMS for a drug include a Medication Guide for distribution to each patient when the drug is dispensed.
Under part 208, Medication Guides may be safety-related, addressing serious risk(s) (relative to benefits) of which patients should be made aware, and/or efficacy-related, when patient adherence to directions for use is crucial to the drug’s effectiveness. Since the enactment of FDAAA, FDA has considered any new Medication Guide (or safety-related changes to an existing Medication Guide) to be part of a REMS. However, the Agency has the authority to determine, based on the risks of a drug and public health concern, whether a Medication Guide should be required as part of a REMS, and may decide the Medication Guide should be required as labeling but not part of a REMS if FDA determines that a REMS is not necessary to ensure the benefits of the drug outweigh its risks.
Consequently, questions have arisen concerning FDA’s policy on whether the Medication Guide must be distributed every time the drug is dispensed because part 208 states that the regulations are intended to apply primarily in the outpatient setting.
FDA can require the development of — or safety-related changes to — a Medication Guide and require these changes to be implemented quickly, whether or not a Medication Guide is part of a REMS. Medication Guides are part of labeling and are subject to the safety labeling change provisions of FDAAA. Under these provisions, FDA can require the development of a Medication Guide (or safety-related changes to an existing Medication Guide) based on new safety information of which FDA becomes aware after approval of the product.
One goal of the guidance is to articulate the circumstances under which FDA intends to exercise enforcement discretion regarding the requirement to dispense Medication Guides in certain settings, such as when it is dispensed to a healthcare professional for administration to a patient in an inpatient setting.
Questions have arisen concerning the requirements for distribution of a Medication Guide when a drug is not dispensed directly to a patient for self-administration or to the patient’s caregiver, but rather is dispensed or distributed to a healthcare professional who then administers the drug to the patient. For example, in an inpatient setting such as a hospital or nursing home, drugs are dispensed by the hospital pharmacy and then administered by hospital staff to patients. Similarly, in an outpatient setting such as a clinic or infusion center, drugs are dispensed or distributed to a healthcare professional who then administers the drug to the patient, sometimes without the involvement of a dispensing pharmacy or pharmacist. In some cases, these drugs are administered to a patient several times a day or several times a week.
Circumstances under which FDA intends to exercise enforcement discretion regarding Medication Guide distribution
A Medication Guide need not be distributed (i.e., FDA intends to exercise enforcement discretion concerning distribution of a Medication Guide to a patient) when a drug is dispensed under the following circumstances:
- When the drug is dispensed to a healthcare professional for administration to a patient in an inpatient setting (with exceptions)
- When the drug is dispensed to a healthcare professional for administration to a patient in an outpatient setting, such as in a clinic or dialysis or infusion center (with exceptions)
In these settings, the drug will be dispensed to a patient by a healthcare professional who should provide the patient instructions on appropriate use of the drug, including what potential side effects may occur or followup that may be required as appropriate, and answer any questions the patient may have.
Circumstances under which FDA will not exercise enforcement discretion and a Medication Guide must be dispensed to a patient in inpatient and outpatient settings
A Medication Guide must be distributed (i.e., FDA does not intend to exercise enforcement discretion) in the following situations:
- When the patient or the patient’s agent requests a Medication Guide.
- When a drug is dispensed in an outpatient setting (e.g., retail pharmacy, hospital ambulatory care pharmacy) and the product will then be used by the patient without direct supervision by a healthcare professional.
- The first time a drug is dispensed to a healthcare professional for administration to a patient in an outpatient setting, such as in a clinic or dialysis or infusion center.
- The first time a drug is dispensed in an outpatient setting of any kind, after a Medication Guide is materially changed. FDA plans to specify in the letter approving a revised Medication Guide when a change is considered to be a material change and applicants will be directed to notify healthcare professionals that a material change was made.
FDA stated that a Medication Guide should be dispensed in outpatient settings, even when the drug is dispensed to a healthcare professional for administration to the patient, the first time the drug is dispensed, and if the Medication Guide is materially changed because it will assist the healthcare professional in communicating important information about the drug to the patient.
Medication Guides as Part of REMS
While all Medication Guides must meet the standard and requirements in part 208, not every newly required Medication Guide will be an element of a REMS. In most cases, FDA expects to include a Medication Guide as part of a REMS only when the REMS includes elements to assure safe use. However, FDA will include a Medication Guide in a REMS that does not include elements to ensure safe use if FDA determines that having the Medication Guide without a REMS will not be sufficient to ensure that the benefits of the drug outweigh the risks.
Applicants with a REMS that includes a Medication Guide, a communication plan, and a timetable for assessment also may submit a prior approval supplement that proposes a REMS modification to remove the Medication Guide from the REMS, if they do not believe that a Medication Guide that is a part of the REMS is necessary to ensure that the benefits of the drug outweigh the risks. FDA will review any such supplements and determine whether the Medication Guide is necessary to ensure that the benefits of the drug outweigh the risks of the drug, as a tool of a REMS under section 505-1. The proposed REMS modification must be accompanied by a REMS assessment (described in the guidance).
Even if the Medication Guide is removed from the REMS or the REMS is eliminated, the Medication Guide will continue to be part of the approved labeling in accordance with part 208, unless the FDA approves a supplement removing the Medication Guide from the approved labeling.