Federal requirements for restricted drug programs e.g., pseudoephedrine, Risk Evaluation and Mitigation Strategies (REMS)

Restricted Drug Programs are special programs implemented to regulate the distribution, prescribing, and dispensing of certain high-risk medications. These programs are typically part of a Risk Evaluation and Mitigation Strategy (REMS) or other regulatory requirements to ensure patient safety.

Why Are Drugs Restricted?

Some medications have serious risks, such as:

Severe side effects (e.g., birth defects, organ toxicity)
Potential for misuse, abuse, or addiction
Strict monitoring requirements (e.g., lab tests, patient registries)

Types of Restricted Drug Programs

1. Pseudoephedrine Sales Restrictions (Combat Methamphetamine Epidemic Act – CMEA 2005)

The Combat Methamphetamine Epidemic Act (CMEA), passed in 2005, was designed to combat the rising production of methamphetamine, primarily by restricting access to certain over-the-counter (OTC) drugs that contain precursor chemicals used in meth production, like pseudoephedrine, ephedrine, and phenylpropanolamine.

Pseudoephedrine is a decongestant that can be used to illegally manufacture methamphetamine. The CMEA of 2005 imposes strict controls:

Regulated Drugs

Pseudoephedrine (PSE): Commonly found in decongestants (e.g., Sudafed).
Ephedrine: Found in some weight-loss and asthma medications.
Phenylpropanolamine (PPA): Formerly used in decongestants and appetite suppressants (now largely discontinued in OTC products due to safety concerns).

Sales Restrictions (Very Important)

Daily Purchase Limit: 3.6 grams per person.
Monthly Purchase Limit: 9 grams per person (7.5 grams if purchased through mail-order).
Mail-Order Purchases: Limit of 7.5 grams within 30 days.

Recordkeeping Requirements (Very Important)

Retailers must maintain a logbook of sales that includes:
Purchaser’s name, address, and the product/quantity purchased.
Date and time of the sale.
Buyers must show a valid photo ID (driver’s license, passport, etc.).
Sales records must be kept for 2 years.

Product Storage

Products containing these ingredients must be stored behind the pharmacy counter or in a locked display.
These products should not be freely accessible on store shelves.

Employee Training

Employees involved in the sale of these products must complete CMEA training on the law’s requirements.

2. Risk Evaluation and Mitigation Strategies (REMS)

REMS stands for Risk Evaluation and Mitigation Strategy. It is a drug safety program required by the FDA (Food and Drug Administration) for certain medications that have serious safety concerns.

The purpose of a REMS program is to ensure that the benefits of a drug outweigh its risks by implementing specific safety measures.

Components of REMS

Medication Guides or Patient Package Inserts – Information provided to patients about risks and safe use.
Communication Plans – Education for healthcare providers about drug risks and appropriate prescribing.
Elements to Assure Safe Use (ETASU) – Requirements such as:
- Special certification for prescribers or pharmacies.
- Restricted distribution (e.g., only available at certain hospitals or pharmacies).
- Patient monitoring through lab tests or enrollment in registries.
Implementation System – Ensuring compliance with REMS requirements.
Assessment Timelines – The FDA reviews the effectiveness of the REMS program periodically.

Examples of Drugs with REMS Requirements:

Isotretinoin (Accutane) – Requires enrollment in the iPLEDGE program due to birth defect risks.
Clozapine – Requires monitoring for agranulocytosis.
Opioids – Many opioids have REMS programs to reduce misuse and overdose risks.

Common Risk Evaluation and Mitigation Strategy (REMS) programs

1. iPLEDGE Program

Drug: Isotretinoin (Accutane®, Absorica®, Claravis®) (Very Important)

Use: Severe acne treatment

Key Restrictions:

Pregnancy prevention mandatory (teratogenic risk).
Females must:
- Undergo monthly pregnancy tests.
- Use two forms of contraception.
- Complete monthly surveys.
Prescribers, pharmacies, and patients must enroll in iPLEDGE.
No automatic refills—each prescription requires re-verification.
No more than 30 day supply at a time.

2. Clozapine REMS

Drug: Clozapine (Clozaril®, Fazaclo®, Versacloz®) (Very Important)

Use: Treatment-resistant schizophrenia

Key Restrictions:

Mandatory blood monitoring (weekly/monthly) for neutropenia (low white blood cells).
Prescribers & pharmacies must be certified.
Patients must be enrolled before dispensing.
Dispensing blocked if blood tests are not current.

3. Opioid Analgesic REMS

Drugs: Extended-release/long-acting (ER/LA) opioids (e.g., OxyContin®, MS Contin®, Duragesic®) (Very Important)

Use: Chronic pain management

Key Restrictions:

Prescriber education on risks of addiction, overdose, and misuse.
Patient counseling on safe use, storage, and disposal.
No formal patient registry, but strict monitoring encouraged.

4. TIRF REMS (Transmucosal Immediate-Release Fentanyl)

Drugs: Fentanyl buccal/sublingual (Actiq®, Fentora®, Subsys®)

Use: Breakthrough cancer pain (only for opioid-tolerant patients)

Key Restrictions:

Prescribers and pharmacies must be certified.
Patients must enroll and sign an agreement.
Strictly prohibited for acute or postoperative pain (high overdose risk).

Other REMS Programs

REMS Program	Drug(s)	Primary Use	Key Restrictions
iPLEDGE	Isotretinoin	Severe acne	Pregnancy prevention, monthly monitoring
Clozapine REMS	Clozapine	Schizophrenia	Mandatory blood tests for neutropenia
Opioid REMS	ER/LA opioids	Chronic pain	Prescriber training, patient counseling
TIRF REMS	Fentanyl (Actiq®, Subsys®)	Cancer pain	Only for opioid-tolerant patients
Mifepristone REMS	Mifeprex®	Medical abortion	Certified prescribers, patient agreement
Xyrem/Xywav REMS	Sodium oxybate	Narcolepsy	Centralized pharmacy, patient enrollment
Revlimid REMS	Lenalidomide	Multiple myeloma	Pregnancy prevention, restricted pharmacy
TOUCH Program	Tysabri®	Multiple sclerosis	PML risk monitoring

3. FDA & DEA Controlled Substances (Schedules II-V)

The FDA (Food and Drug Administration) and DEA (Drug Enforcement Administration) regulate restricted drug programs to ensure safe use, prevent abuse, and control the distribution of high-risk medications. These regulations primarily apply to Controlled Substances (Schedules II-V) under the Controlled Substances Act (CSA).

Schedule II (CII) – High Abuse Potential, Medical Use

Examples: Oxycodone, Morphine, Fentanyl, Adderall, Ritalin

Restrictions:

No refills allowed; a new prescription is required each time.
Must be stored in a locked cabinet in pharmacies. Some states policies differ about locked cabinets.
Electronic prescriptions must meet DEA security requirements.

Schedule III (CIII) – Moderate Abuse Potential

Examples: Buprenorphine (Suboxone), Tylenol with Codeine, Ketamine, Anabolic Steroids

Restrictions:

Can have up to 5 refills within 6 months.
Verbal and faxed prescriptions are allowed.
Pharmacists must be cautious about misuse.

Schedule IV (CIV) – Low Abuse Potential

Examples: Benzodiazepines (Xanax, Ativan, Valium), Tramadol, Zolpidem (Ambien)

Restrictions:

Can have up to 5 refills within 6 months.
Verbal and faxed prescriptions are allowed.
Pharmacists must be cautious about misuse.

Schedule V (CV) – Lowest Abuse Potential

Examples: Cough syrups with codeine (Robitussin AC), Pregabalin (Lyrica)

Restrictions:

Some available without a prescription in limited quantities in some states.
Must be recorded in a logbook by pharmacies.
Can have up to 5 refills within 6 months.
Verbal and faxed prescriptions are allowed.
Pharmacists must be cautious about misuse.

Federal Programs & Regulations for Restricted Drugs

1. Prescription Drug Monitoring Programs (PDMPs)

A state-run electronic database to track controlled substance prescriptions.
Helps prevent doctor shopping and prescription drug abuse.
Pharmacists and prescribers check PDMP before dispensing opioids.
Most states require pharmacies and prescribers to report within 24 hours of dispensing.
Some states allow 72 hours to 7 days, but stricter states (e.g., NY, CA) mandate same-day or next-day reporting.

2. DEA 222 Form (Schedule II Drug Ordering & Transfers)

Required to order, transfer, or return Schedule II drugs.
Must be stored for at least 2 years for DEA inspections.
Electronic version: CSOS (Controlled Substance Ordering System).

3. Combat Methamphetamine Epidemic Act (CMEA)

Regulates sales of pseudoephedrine, ephedrine, and phenylpropanolamine.
Limits daily and monthly purchases.
Requires ID verification and logs sales in a database.

4. Opioid Treatment Programs (OTPs) – Methadone & Buprenorphine

Methadone can only be dispensed at federally certified OTPs for addiction treatment.
Buprenorphine (Suboxone) requires a DEA X-waiver for prescribers but can be dispensed at retail pharmacies.

5. Secure & Responsible Drug Disposal Act

Establishes drug take-back programs to safely dispose of unused controlled substances.
Pharmacies and law enforcement agencies participate in DEA Take-Back Days.