FDA REMS: Blue Print for Prescriber Continuing Education Program for Extended Release-Long Acting Opioids

The Food and Drug Administration (FDA) released a “Blueprint for Prescriber Continuing Education Program” regarding the use of opioids.  The draft Blueprint contains core messages intended for use by continuing education (CE) providers to develop educational materials to train prescribers of long-acting and extended release opioids under the required risk evaluation and mitigation strategy (REMS) for these products (Opioid REMS).

FDA is seeking stakeholder input on the document.  After comments are received, FDA will revise the Blueprint as appropriate, incorporate it into the Opioid REMS when it is approved, and post it on FDA’s Web site for use by CE providers.

Comments on the draft Blueprint are due by December 7, 2011.  Comments can be submitted electronically to http://www.regulations.gov, Docket No. FDA–2011–D–0771. 

Written comments can be sent to the Division of Dockets Management (HFA–305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.  For more information, contact, Michie I. Hunt, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, rm. 6153, Silver Spring, MD 20993–0002, (301) 796–3504. 

Background

Health care professionals who prescribe extended-release (ER) and long-acting (LA) opioids are in a key position to balance the benefits of prescribing ER/LA opioids to treat pain against the risks of serious adverse outcomes including addiction, unintentional overdose, and death.  Opioid misuse and abuse, resulting in injury and death, has emerged as a major public health problem.

Public health experts estimate that more than 35 million Americans age 12 and older have reported non-medical use of opioid analgesics during 2010 – up from 29 million in 200.  In 2009, nearly 342,000 emergency department visits were associated with nonmedical use of opioid analgesics. In 2007, nearly 28,000 Americans died from unintended consequences of drug use, and of these, nearly 12,000 involved prescription drug pain relievers.

REMS for Long-Acting and Extended- Release Opioids 

The Food and Drug Administration Amendments Act of 2007 (FDAAA) gave FDA the authority to require manufacturers to develop and implement a REMS when necessary to ensure the benefits of a drug or biological product outweigh its risks. 

On February 6, 2009, FDA sent letters to manufacturers of certain opioid drug products indicating that these drugs will be required to have a REMS to ensure that the benefits of the drugs continue to outweigh the risks.  The affected opioid drugs include long-acting and extended-release brand name and generic products and are formulated with the active ingredients buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. 

After sending the letters, FDA held a series of meetings with stakeholders and convened an advisory committee to obtain input on the appropriate elements of the Opioid REMS. On April 19, 2011, in conjunction with the Office of National Drug Control Policy (ONDCP) release of the Obama Administration’s Epidemic: Responding to America’s Prescription Drug Abuse Crisis—a comprehensive action plan to address the national prescription drug abuse epidemic, FDA issued letters to application holders directing them to submit a REMS within 120 days and describing the elements that needed to be included in the REMS (REMS notification letters). 

The central component of the Opioid REMS program is an education program for prescribers (e.g., physicians, nurse practitioners, physician assistants) and patients. 

REMS Prescriber Education 

In the REMS notification letters, FDA provided an outline of the required prescriber education. The outline specified that the education must include information on weighing the risks and benefits of opioid therapy, choosing patients appropriately, managing and monitoring patients, and counseling patients on the safe use of these drugs. In addition, the education must include information on how to recognize evidence of, and the potential for, opioid misuse, abuse, and addiction. 

The REMS notification letters stated that although there is no mandatory requirement that prescribers take the course as a precondition to dispensing the medication to patients, application holders will be required to establish goals for the number of prescribers trained, collect the information about the number of prescribers who took the courses, and report the information to FDA as part of periodic required assessments. 

CE Providers Will Conduct Prescriber Education 

The REMS notification letter expressed FDA’s expectation that the training would be conducted by accredited, independent continuing education providers.  FDA later elaborated on its vision for prescriber education stating that we expect the CE training to be provided without cost to the healthcare professionals and that sponsors would offer unrestricted grants to accredited CE providers to develop CE for the appropriate prescriber groups. 

We believe having the training provided by CE organizations will be an incentive and will not create new burdens on prescribers because most healthcare professionals are routinely engaged in CE activity. 

The Blueprint Will Provide the Basic Outline and Core Messages for CE 

In response to the April REMS notification letter, application holders, through an industry working group, submitted an expanded outline of the potential topics to be covered in the CE, noting that education incorporating all of the topics in the outline could require

30 or more hours of education.  FDA’s expectation is that the initial or basic REMS related CE that should be offered to all prescribers of long-acting and extended-release opioids should consist of a ‘‘core’’ content of about 2 to 3 hours. 

FDA reviewed the industry submission and developed a basic outline and the core messages that FDA believes should be conveyed to prescribers in this basic educational module.  After it is completed and approved as part of the REMS, the Blueprint will be posted on FDA’s Web site for use by CE providers in developing CE courses.   

Although FDA recognizes that additional training modules could be helpful, FDA’s goal is to require basic education for all prescribers of long-acting and extended-release opioids, and at this time, FDA does not intend to develop or approve messages as part of the REMS beyond those approved in the basic core module. 

Blueprint for Prescriber Continuing Education Program  

Appropriate prescribing practices and patient education are important steps to help address this public health problem.  Health care professionals who prescribe ER/LA opioids have a responsibility to help ensure the safe and effective use of ER/LA opioids. Prescribers should:

• Understand how to assess patients for treatment with ER/LA opioids.
• Be familiar with how to initiate therapy, modify dose, and discontinue use of ER/LA opioids.
• Be knowledgeable about how to manage ongoing therapy with ER/LA opioids.
• Know how to counsel patients and caregivers about the safe use of ER/LA opioids, including proper storage and disposal.
• Be familiar with general and product specific drug information concerning ER/LA opioids.  

Assessing Patients for Treatment with ER/LA Opioid Therapy

Prescribers should consider risks involved with ER/LA opioids and balance these against potential benefits. Risks include: 

• Risk of overdose due to the high dosage of opioid available as an ER/LA formulation
• Intentional abuse by patient or household contacts
• Addiction
• Interactions with other medications and substances (see table below for specifics)
• Inadvertent exposure to household contacts, especially children  

Prescribers should assess each patient’s risk of abuse, including history of substance abuse and serious mental illness. Prescribers should: 

• Be knowledgeable about risk factors for opioid abuse and risk-assessment methods.
• Complete a comprehensive history and physical examination, including assessment of psychosocial factors and family history of substance abuse, as well as special considerations for the elderly, women, children, and cultural/ethnic groups. Identify appropriate referrals when the condition warrants.
• Understand and appropriately utilize screening tools for addiction or abuse, such as Prescription Drug Monitoring Programs (PDMPs), to help assess potential risks associated with chronic opioid therapy and to help manage patients using opioids products.
• Adequately document all evaluations and treatment plans.

Prescribers should be able to determine if a patient is opioid-tolerant and should know which products are safe for use only in opioid-tolerant patients. 

Initiating Therapy, Modifying Dosing, and Discontinuing Use of ER/LA Opioids

Prescribers should have awareness of federal & state regulations on opioid prescribing.  When initiating therapy with an ER/LA opioid, prescribers should be aware that: 

• Dose selection is critical, particularly when initiating therapy with an ER/LA opioid as the first opioid.
• Titration should be based on efficacy and tolerability.  

When modifying the dose of an ER/LA opioid, prescribers should understand equianalgesic dosing concepts and follow patients closely during all periods of dose adjustments.  Prescribers should also: 

• Be knowledgeable about converting patients from immediate-release to ER/LA products and from one ER/LA opioid product to another ER/LA opioid product.
• Be aware of the concept of incomplete cross-tolerance in order to safely convert patients from one opioid to another.
• Understand that tapering the opioid dose is necessary to safely discontinue treatment with ER/LA opioids when therapy is no longer needed. 

Managing Therapy with ER/LA Opioids  

Prescribers should establish goals for therapy and continuously evaluate pain as well as functioning level and quality of life.  Prescribers should also be aware of the existence of Patient Provider Agreements (PPAs), although FDA is not requiring their use. 

• PPAs are documents signed by both prescriber and patient at the time an opioid is prescribed. PPAs can help ensure patients understand the goals of treatment, the risks, and how to use the medications safely.
• PPAs can include commitments to return for follow-up visits, to comply with appropriate monitoring (such as random drug screens) and to safeguard the medication.  

Prescribers should ensure that patients adhere to a treatment plan and monitor patients for misuse and abuse by: 

• Recognizing aberrant behavior
• Utilizing PDMPs to identify potential abuse where available
• Understanding the role of drug testing and performing drug screens as indicated
• Screening and referring for substance abuse treatment when indicated
• Performing medication reconciliation at each visit  

Prescribers maintaining patients on ER/LA opioids should over time reassess whether opioids continue to be necessary for management of the patient’s pain.  Prescribers should also: 

• Understand how to manage adverse events associated with ER/LA opioid products.
• Understand the need for reevaluation of patients’ underlying medical condition if symptoms change over time.  

Counseling Patients and Caregivers About the Safe Use of ER/LA Opioids

Prescribers should: 

• Give product-specific information about the prescribed opioid.
• Explain how to take the opioid as prescribed.
• Explain adherence to dosing regimen and how to handle missed doses.
• Warn that under no circumstances should an oral ER/LA opioid be broken, chewed or crushed, and patches should not be cut or torn prior to use, as this may lead to rapid release of the ER/LA opioid causing overdose and death.
• Caution that the use of other CNS depressants, alcohol, or illegal drugs with ER/LA opioids can cause overdose and death. Patients should only use other CNS depressants under the instruction of their prescriber.
• Discuss that withdrawal symptoms can occur if an ER/LA opioid is discontinued suddenly. Patients should discuss plans to stop the ER/LA opioid with their prescriber. Patients should discuss a tapering regimen with their prescriber.
• Explain that sharing ER/LA opioids with others may cause serious side effects including death, and that selling or giving away ER/LA opioids is against the law.
• Counsel patients to store their ER/LA opioid in a safe and secure place away from children and pets and to read the product-specific disposal information included with the ER/LA opioid product.
• Caution patients that ER/LA opioids can cause serious side effects that can lead to death. Patients should call their prescriber or get emergency medical help if they have symptoms of overdose or respiratory depression; symptoms of stomach or intestinal blockage; or allergic reactions. Patients should also be counseled on the most common side effects of ER/LA opioids and be cautioned about the risk of falls, working with heavy machinery, and driving.  

Patients should call their prescriber for advice about side effects.  Prescribers or patients are encouraged to report side effects to the FDA at 1-800-FDA 1088. 

General Drug Information for ER/LA Opioid Products  

Prescribers should be knowledgeable about general characteristics, toxicities, and drug interactions for ER/LA opioid products. For example: 

• Respiratory depression is the most serious adverse effect of opioids as it can be immediately life-threatening.
• Constipation is the most common long-term side-effect but can often be managed.
• Drug-drug interaction profiles vary among the products. Knowledge of particular opioid-drug interactions, and the underlying pharmacokinetic and pharmacodynamic mechanisms, allows for the safer administration of opioid analgesics.
  • Central nervous system depressants (sedatives, hypnotics, tranquilizers, tricyclic antidepressants) and alcohol can have a potentiating effect on the sedation and respiratory depression due to opioids. Alcohol consumption should be avoided entirely with some oral products (e.g. morphine, hydromorphone, oxymorphone) because ethanol increases the plasma concentration of the drug substance.
  • Opioids may enhance the neuromuscular blocking action of skeletal relaxants (e.g. pancuronium) and produce an increased degree of respiratory depression.
  • Using opioids with monoamine oxidase inhibitors (MAOIs) may result in possible increase in confusion, anxiety, and respiratory depression.
  • Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone (ADH).
  • Some opioids (methadone, buprenorphine) can prolong the QTc interval.
  • Some opioids interact with various cytochrome P450 enzyme inhibitors and inducers and thus may result in higher or lower than expected blood levels of the drug. See detailed drug information table.
  • Tolerance to sedating and respiratory-depressant effects is critical to safe use of certain products, certain dosage unit strengths, or certain doses of some products. Opioid tolerance must be demonstrated before using any strength of ER/LA fentanyl and ER/LA hydromorphone. For other ER/LA opioids the use of certain doses of the drug requires that the patient be opioid tolerant. See detailed drug information table.
  • Tablet and capsule dosage forms must be swallowed whole. The pellets from capsule dosage forms can be sprinkled on applesauce and swallowed without chewing.
  • For transdermal products, external heat, fever, and exertion can increase absorption, leading to fatal overdose. Transdermal products with metal foil backings are not safe for use in MRIs.  

Specific Drug Information for ER/LA Opioid Products 

Prescribers should be knowledgeable about specific characteristics of the ER/LA opioid products they prescribe, including the drug substance, dosage form/strength, dosing interval, key instructions, major drug interactions, use in opioid-tolerant patients, drug-specific adverse events, and relative potency to oral morphine.  For detailed information, prescribers can refer to prescribing information available online via DailyMed at dailymed.nlm.nih.gov or Drugs@FDA at www.fda.gov/drugsatfda .