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Some medications, such as narcotic pain relievers, inherently carry a high risk of dependency and overdose. With the approval of complex drug categories such as biologics, other risks associated with medication use (such as infection) are also heightened. Certain measures have been developed by the Food & Drug Administration (FDA) and the Drug Enforcement Administration (DEA)—along with healthcare providers and drug manufacturers—to control access to and potential misuse of certain high–risk prescription medications. The major measures include:

• 1) Controlled substance schedules, and
• 2) Risk Evaluation and Mitigation Strategies (REMS)

These measures have important implications in medication therapy management (MTM). Controlled substances carry additional restrictions for prescribing, dispensing, and record keeping. REMS programs may designate which physicians can prescribe certain drugs, limit the pharmacies that are allowed to dispense them, and require monitoring steps for patients (such as blood tests) to ensure safe use.

When supporting MTM services in the pharmacy setting, pharmacy technicians will want to take note of any controlled substances or medications with REMS programs on the patient’s Personal Medication List (PML). If so, certain extra steps may need to be considered when planning and executing MTM services. Some examples might be:

• Some drugs may need to be obtained via specialty pharmacies; some have specific storage requirements, including refrigeration
• Additional paperwork will be required for both controlled substances and REMS
• There may be specific steps related to follow–up and communication with prescribers and other healthcare providers. In addition, pharmacies, practitioners, or healthcare settings may be required to be registered to prescribe or dispense that agent.
• Patient education will need to address the specific instructions associated with using these medications, including safe storage
• Medication guides, written in non–technical terms, are required to be dispensed with the drug and must meet the standard formatting requirements from the FDA.¹

Controlled Substances

Controlled substances fall into Schedules I through V (or 1 through 5), as shown in Table 1. How controlled substances are stored, handled, and distributed in the pharmacy varies according to state laws, so technicians need to ensure they are familiar with the laws pertaining to their area.

Table 1. Controlled Substance Schedules2
Schedule	Description	Examples
I	No currently accepted medical use in the U.S.; lack accepted safety for use under medical supervision; high potential for abuse	heroin; lysergic acid diethylamide (LSD); peyote; methaqualone; 3,4-methylenedioxymethamphetamine ("Ecstasy").
II/IIN (2/2N)	High potential for abuse which may lead to severe psychological or physical dependence	Opioids/narcotics: hydromorphone (Dilaudid®); methadone (Dolophine®); meperidine (Demerol®); oxycodone (OxyContin®, Percocet®); fentanyl (Sublimaze®, Duragesic®); morphine, opium; codeine; hydrocodone. Stimulants: amphetamine (Dexedrine®, Adderall®), methylphenidate (Ritalin®) methamphetamine (Desoxyn®). Short-acting barbiturates: amobarbital, pentobarbital (Nembutal).
III/IIIN (3/3N)	Some potential for abuse, but less than substances in Schedules I and II. Abuse may lead to moderate or low physical dependence or high psychological dependence.	Narcotics: Products containing ≤ 90 mg codeine per dosage unit (Tylenol with Codeine®); buprenorphine (Suboxone®). Non-Narcotics: benzphetamine (Didrex®); phendimetrazine; ketamine; anabolic steroids (Depo®-Testosterone).
IV	Lower potential for abuse relative to substances in Schedule III	alprazolam (Xanax®); carisoprodol (Soma®); clonazepam (Klonopin®); clorazepate (Tranxene®); diazepam (Valium®); lorazepam (Ativan®); midazolam (Versed®); temazepam (Restoril®); triazolam (Halcion®); phenobarbital.
V	Lower potential for abuse relative to substances in Schedule IV. Preparations containing limited quantities of certain narcotics.	Cough preparations containing ≤ 200 mg of codeine per 100 mL or per 100 g (Robitussin AC®, Phenergan with Codeine®); ezogabine.
Source: U.S. Drug Enforcement Administration. Office of Diversion Control. Title 21 Code of Federal Regulations, Prescriptions: Controlled substances listed in Schedules III, IV, and V. Available at: http://www.deadiversion.usdoj.gov/21cfr/cfr/1306/1306_26.htm.2

When a patient participating in MTM has controlled substance/s on the Medication List, many questions may be evaluated during the MTM process, including:

• Is the patient taking the medication according to directions?
• Is the patient taking extra precautions for storing the medication as required by law? (And, does the patient understand these instructions?)
• Is there evidence of possible dependence on the medication? (See Table 2, Detecting Opioid Dependence)
• Is there evidence of possible abuse? (e.g., use of multiple pharmacies, “doctor shopping”)

Table 2. Detecting Opioid Dependence3
Drug category/Purpose	Examples	Possible signs of abuse
Opiates and opioids Pain relief	Hydrocodone, oxycodone, fentanyl, tramadol	Lack of response to pain, drowsiness, confusion, nausea, constipation, restricted pupils, slowed breathing, withdrawal symptoms when discontinuing drug
Benzodiazepines and barbiturates Anxiety and sleeplessness	Diazepam (Valium), alprazolam (Xanax), triazolam (Halcion), lorazepam (Ativan); pentobarbital (Nembutal), secobarbital (Seconal)	Drowsiness, poor memory, slurred speech, poor coordination, dilated pupils, signs of depression, dizziness, headaches, agitation, suicidal thoughts
Stimulants	Methylphenidate (Ritalin); amphetamine (Adderall); dextroamphetamine (Dexedrine)	anxiety, delusions, flushed skin and chest pain with heart palpitations, irregular sleep with long periods of wakefulness
Source: Narconon. Signs and Symptoms of Prescription Drug Use. Available at: www.narconon.org/drug–abuse/signs–symptoms–prescription–drug–use.html

According to the Centers for Disease Control and Prevention (CDC), about 80% of abused or misused controlled substances started out as legal prescriptions.⁴ To minimize nonmedical use, Medicaid has instituted “lock–in” programs in 46 states. These programs identify Medicaid recipients who exhibit behaviors consistent with seeking controlled substances and restrict them to a single prescriber and single pharmacy from which they can obtain these medications. Specific details of the programs vary by state.⁴

It is crucial that pharmacy technicians are aware of the opioid crisis and the current state laws governing the availability of naloxone to people with opioid addictions and their family members. As of June 25, 2015, 38 states permit a prescription for naloxone to be written and dispensed to a person other than the patient at risk. Also by that date, 28 states permit prescribing and dispensing of naloxone by healthcare professionals (such as pharmacists) who meet certain educational and professional criteria. In addition, 34 states provide immunity from liability to prescribers or dispensers of naloxone (the “Good Samaritan” Law). Although there is no overarching Federal statute at this time, it is important for pharmacy technicians to know the laws for naloxone distribution in the state where they practice.⁵

Pharmacy technicians may be responsible for many of the steps related to controlled substance record keeping and fact–finding for patients involved in MTM. For example, technicians may determine whether drugs on the controlled substances schedule are eligible for refills (or require a new prescription), whether limits in drug benefits may restrict the number of refills or duration of treatment, research past medical records or outside pharmacy records to detect patterns of controlled substance misuse, and help educate patients on storage and safe disposal of controlled substances. Specific controlled substance guidelines are available from the U.S. Drug Enforcement Administration (DEA) and are subject to state and local laws.⁶ Some general guidelines are outlined in Table 3.

Table 3. General Pharmacy Guidelines for Controlled Substances

Record-keeping: Establish a record-keeping system that tracks the receipt and disposition of all controlled substances Patient care facilities (hospitals, long-term care): keep separate medication records properly account for administration of controlled substances Storage: Pharmacies must keep controlled substances in a separate locked compartment or scattered throughout the drug inventory Faxed prescriptions: Some states prohibit faxes of prescriptions for Schedule II controlled substances as substitutes for the original Electronic prescriptions: The DEA has issued regulations for pharmacies that receive, dispense, and archive controlled substances electronically. Special software is required to fill electronic prescriptions for controlled substances, so not all pharmacies have agreed to accept them. Using this system, the prescription goes through an "intermediary" or third-party vendor which transmits the information to the pharmacy. There are special rules for communicating between pharmacies to ensure that a controlled substance prescription is not duplicated or filled at multiple pharmacies. 7 Disposal: Federal DEA regulations prohibit removal of controlled substances from a patient care facility for disposal without approval per the procedures of the regional DEA office. Some regulations require controlled substances to be destroyed by a licensed pharmacist or nurse practitioner with another licensed medical staff person as witness. Care facilities must submit specific records for the disposal of controlled substances. Controlled substances can never be returned to the pharmacy for re-use. Under Federal law, patients may not return unused controlled substances to the pharmacy, except in cases where a product has been recalled or has been prescribed/dispensed in error. The DEA has established a "take-back program" with centers connected with local law enforcement offices allowing patients to drop off unwanted medication to be destroyed.

Source: U.S. Drug Enforcement Administration. Office of Diversion Control. Questions and Answers. Available at: http://www.deadiversion.usdoj.gov/faq/index.html.

REMS Programs

REMS is an acronym for "Risk Evaluation and Mitigation Strategies." The intention of REMS is to identify certain high–risk drugs and to designate steps to ensure that their benefits outweigh their risks. Without REMS, the FDA has stated that certain drugs might otherwise have been removed from the market or have their approval delayed or refused (Table 4).⁸ The FDA can require drug manufacturers to develop a REMS before a drug is approved, or after a drug is already on the market. REMS may apply to a single drug, or an entire class. Each REMS program is drug–specific.

Table 4. Drug Risks and REMS Requirements8
Risk Example	Possible REMS Action
Serious infection	Patient receives education about initial warning signs of infection prior to obtaining prescription
Severe allergic reaction	Healthcare professional must be certified to administer or prescribe the agent
Liver damage	Liver function monitoring while the patient is taking the drug
Severe birth defects	Negative pregnancy test prior to prescribing, and patient is advised to use reliable methods of birth control.
Source: U.S. Food and Drug Administration (FDA). A Brief Overview of Risk Evaluation and Mitigation Strategies (REMS). www.fda.gov.

Some REMS programs may include additional responsibilities for pharmacists and technicians. At the simplest level, a Medication Guide (also called a MedGuide) must be delivered to a patient explaining the use of the drug in a clear and readable format. The majority of REMS programs currently in existence only require a MedGuide to be distributed to the patient. At higher levels of risk, the REMS program may restrict prescribing to physicians who have specific training in its use, and restrict dispensing to certified pharmacies (Table 5). Long–acting and extended–release opioid products (OxyContin^®, MS Contin^®) are required to have a REMS program.

Table 5. REMS programs may contain any of the following:

Medication Guide or Patient Package Insert (PPI) provided to the patient Communication Plan developed for healthcare providers Implementation System ETASU (Elements to Assure Safe Use), which may include: Certification and training of pharmacists and prescribers A system of restricted distribution Drug may only be used by patients who meet a list of conditions (e.g., lab results) A patient registration and monitoring program Pharmacist and prescriber registration

Medication guides

It is the pharmacist’s responsibility to distribute MedGuides to the patient. MedGuides must be distributed:

• When the patient requests a Medication Guide
• When a drug is dispensed in an outpatient pharmacy
• The first time a drug is dispensed to a healthcare professional for administration to a patient
• The first time a drug is dispensed after a Medication Guide is materially changed

Communication plan

This document is developed by drug manufacturers to communicate risks of a drug to healthcare providers, including physicians and pharmacists. These may include:

• Dear Healthcare Provider letters to communicate risks
• Information and tips to encourage REMS implementation or explain aspects of the REMS
• Distribution of information to professional societies and other organizations

Elements to Assure Safe Use (ETASU)

A REMS program may require any or all of the following steps to enhance safe use of a drug:

• Prescribers must have specific training/experience or special certifications
• Pharmacies, practitioners, or healthcare settings that dispense the drug must be specially certified
• Drug can be dispensed only in certain healthcare settings (e.g., infusion centers, hospitals)
• Drug must be dispensed with evidence of safe–use conditions (e.g., certain lab test results)
• Patients using the drug must complete required monitoring in order to continue using the agent
• Patients must be enrolled in a registry to track adverse effects, response to the drug

REMS example: Tysabri TOUCH Program

An example of a comprehensive REMS program is the TOUCH Prescribing program for the drug natalizumab (Tysabri), used for treatment of multiple sclerosis and Crohn’s disease.⁹ This drug is administered once a month via intravenous infusion, and carries a risk of a highly dangerous and often–fatal brain infection. The risk for this infection increases the longer a patient has used the drug, and for patients who have had certain chemotherapy or immunosuppressive treatments. It is possible to detect an increasing risk of the infection (called PML, for progressive multifocal leukoencephalopathy) by measuring antibodies in the blood. To ensure that monitoring protocols are followed and that patients are fully aware of the risks, only prescribers who are enrolled in the TOUCH program can prescribe Tysabri. In addition, only certified infusion centers can administer the drug. TOUCH prescribers must agree to a set of safety steps, including:⁹

• Educating patients about the benefits and risks of treatment (and distributing/reviewing the Medication Guide)
• With the patient, sign a Patient–Prescriber Enrollment Form
• Evaluate patients at specific intervals, including 3 months after first procedure and every 6 months thereafter
• Reauthorize treatment every 6 months and submit a reauthorization report to the manufacturer
• Complete required forms after a patient has discontinued the drug
• Report any cases of the infection (PML) to the manufacturer

Pharmacists’ Responsibilities in REMS

When the patient’s Personal Medication List is developed in medication therapy management (MTM), it is important to review and flag any medications that are subject to a REMS program. In MTM, the pharmacy staff should ensure that the goals of the specific REMS program are being met, or make a plan to address them. The technician might asked to: highlight steps in a particular REMS program, determine whether these steps have been followed, track down laboratory testing results or help patients make appointments for testing, and locate pharmacies, infusion centers, or other services to help the patient obtain the medication.

FDA recommendations for a pharmacist’s role in REMS include:

• Train staff pharmacists and technicians in the requirements associated with dispensing REMS drugs;
• Prominently display a list of REMS drugs and ensure that pharmacists and technicians are aware of the list and what is required for each;
• Document that MedGuides were given to patients;
• For REMS drugs that are restricted, keep a list on who can prescribe and which pharmacies are authorized to dispense;
• Keep a list of additional requirements for REMS drugs that require more than MedGuides.

During an MTM session, the pharmacist can take the opportunity to find out how the program is affecting the patient, whether any adverse effects are present that must be reported, and if the patient understands the medication risks that are identified in the REMS. The pharmacist can use the patient education opportunities that are provided in a one–on–one MTM session to better explain the specific REMS program, its purpose, and how these risks might apply to the patient’s individual condition.

References

1. Food and Drug Administration (FDA). Approved Risk Evaluation and Mitigation Strategies (REMS). Available at: https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm.
2. U.S. Drug Enforcement Administration. Office of Diversion Control. Title 21 Code of Federal Regulations, Prescriptions: Controlled substances listed in Schedules III, IV, and V. Available at: http://www.deadiversion.usdoj.gov/21cfr/cfr/1306/1306_26.htm.
3. Narconon. Signs and Symptoms of Prescription Drug Use. Available at: http://www.narconon.org/drug–abuse/signs–symptoms–prescription–drug–use.html.
4. Roberts AW, Skinner AC. Assessing the present state and potential of Medicaid controlled substance lock–in programs. J Manag Care Spec Pharm. 2014;20(5):439–446c.
5. Davis C. Addressing legal barriers to naloxone access. Food and Drug Administration. Available at: https://www.fda.gov/downloads/Drugs/NewsEvents/UCM454758.pdf.
6. Drug Enforcement Administration (DEA). Office of Diversion Control. Pharmacist's Manual: An Informational Outline of the Controlled Substances Act. Revised 2010. Available at: http://www.deadiversion.usdoj.gov/pubs/manuals/pharm2/.
7. U.S. Drug Enforcement Administration. Electronic Prescriptions for Controlled Substances (EPCS). Available at: https:www.deadiversion.usdoj.gov/ecomm/e_rx/faq/pharmacies.htm
8. U.S. Food and Drug Administration (FDA). A brief overview of Risk Evaluation and Mitigation Strategies (REMS). Available at: http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM328784.pdf.
9. Tysabri (natalizumab) [package Insert]. Cambridge, MA: Biogen; 2017.

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