MPJE - PA Review

What prompted the Federal Food, Drug and Cosmetic Act (FDCA) of 1938?

1937 - Sulfanilamide elixir (liquid) contained diethylene glycol (used as antifreeze), which led to severe kidney failure and death of over 100 people

What did the FDCA do?

Mandated drugs to be labeled with adequate directions for safe use. Also introduced the concept of premarket approval (manufacturers had to demonstrate safety to the FDA before marketing the drug)

Durham-Humphrey Amendment of 1951

Established 2 classes of drugs: prescription (AKA legend drugs) and OTC

Other than Durham-Humphrey Amendment do other than establishing 2 classes of drug?

• Authorized verbal Rx and Rx refills

• Mandated that Rx drug labels include the phrase: “Caution: Federal law prohibits dispensing without a prescription (now “Rx only”)”

What led to the Kefauver-Harris Amendments of 1962 (AKA drug efficacy amendment)?

Thalidomide Tragedy: Thalidomide was a sedative and sleeping pill marketed in Europe in the 1950s and 1960s for pregnant women to relieve morning sickness. Led to missing limbs (phocomelia).

What did the Kefauver-Harris Amendments do?

• Required new drugs to be safe AND effective for their claimed use.

• Increased safety requirements for drugs + established good manufacturing practices (GMPs) for manufacturing of drugs

• Gave FDA jurisdiction over Rx drug advertising

What is the purpose of Prescription Drug Marketing Act (PDMA) of 1987?

Ensure that drug products purchased by customers are safe and effective, and to avoid the risk to consumers from counterfeit, adulterated, misbranded, subpotent, or expired drugs

What does the PDMA of 1987 do?

• Bans the re-importation of Rx drugs and insulin products produced in the US

• Bans the sale, trade or purchase of Rx drug samples

• Mandates the storage, handling, and recordkeeping of Rx drug samples

• Prohibits (with some exceptions) the resale of Rx drugs purchased by hospitals or healthcare facilities

What did the drug quality and security act (DQSA) of 2023 do?

Amendments to the FDCA that addressed 2 primary topics:

1. Large-scale compounding by pharmacies

2. Establishing a framework for a uniform track-and-trace system for Rx drugs throughout the supply chain to prevent counterfeit drugs

What was the Drug compounding quality act (DCQA) passed in response to?

Fungal meningitis outbreak traced to contaminated injectable steroids produced by New England Compounding center. Death of > 60 patients in > 750 cases of infection.

What are outsourcing facilities

AKA 503B facilities

• Permitted to compound sterile products without receiving patient-specific prescriptions or medication orders. Regulated by FDA and subject to GMPs.

What are the requirements of a outsourcing facility (503 B facility)?

1. Have a RPh providing direct oversight over compounded drugs

2. Register as a outsourcing facility with the FDA

3. Report to FDA upon registering, and q6months, thereafter

4. Be inspected by FDA according to a risk-based inspection schedule and pay annual fees to support it

5. Report serious ADRs experiences FDA w/in 15 days and conduct a f/u investigation and reporting similar to current drug manufacturers

6. Label products with a statement identifying them as a compounded drug and other specified information about the drug

Outsourcing facilities may NOT compound a drug products that includes a bulk drug substance unless

1. Bulk drug substance appears on a list identifying bulk drug substances where there is a clinical need (503B bulk list) or

2. The drug product compounded from such bulk drug substance appears on FDA’s shortage list at the time of compounding, distribution, and dispensing

“Transaction data” includes

1. Transaction information: product same, strength, dosage form, NDC number, unique SNI, etc

2. Transaction history: paper or electronic statement that includes prior transaction info.

3. Transaction statement: statement by the seller

Transaction data must be maintained for 6 years

What is a product identifier?

Standardized graphic with 3 elements:

1. Product’s standardized numerical identifier (SNI)

   1. NDC + unique alphaneumeric serial number

2. Lot number

3. Expiration date

How many packages do you have to verify for the product indentifier?

3 or 10% (whichever is greater). If a product is illegitimate, must inform FDA by using form 3911 and notify trading partners w/in 24 hours

Adulteration

1. Contains any filthy, putrid, or decomposed substance

2. Prepared or held under insanitary conditions where it may have been contaminated

3. Methods of manufacturing don’t confirm to current GMPs

4. The manufacturing unit has not been inspected

5. Contains unsafe color additive

6. If claims to meet USP standards but its strength or purity does not

7. Even if it doesn’t claim to meet USP standards but the strength/quality differs from its label

Misbranding

1. Labeling is false or midleading

2. Prescription drug and the manufacturing label missing any of the following

   1. Name + address of the manufacturer, packer or distributor

   2. Brand and/or generic name of the drug/product

   3. Net quantity (weight, qty or dosage units)

   4. Weight of active ingredient per dosage unit

   5. “Rx only”

   6. IF not taken PO, the specific route of administration

   7. Storage instructions

   8. Lot #

   9. Exp date

   10. Adequate info for use (package insert + med guide)

3. OTC drug - fails to have any of the following:

   1. Principle display panel, including a statement of identity of product

   2. The name + address of manufacturer, packer or distributer

   3. Net qty of contents

   4. Cautions + warnings PRN

   5. Adequate directions for safe + effective use

   6. Content and format of OTC product labeling

      1. Active ingridient

      2. Purpose

      3. Use(s)

      4. Warnings

      5. Directions

      6. Other info.

      7. Inactive ingredients

      8. Questions? followed by #

4. Drug is liable to deterioration unless packaged or labeled accordingly

5. Container is made, formed, or filled as to be misbranding

6. Drug is an exact imitation of another drug or offered for sale under the name of another drug

Aduleration + misbranding as applied to pharmacies

1. Dispensing a Rx w/o authorization causes the drug to be misbranded even if its labeled correctly by the pharmacist.

2. Misfilling a Rx with the wrong dose, strength or directions for use = misbranding

3. If a misfilled Rx involves the wrong strength of the drug prescribed = adulterated

4. REMS drug prescribed w/o meeting REMS requirements = misbranding

5. Advertising or promotion of compounded drug that is false = misbranding

6. Exp drug in a MFR bottle = adulterated

7. Placing a beyond-use-date later than MFR EXP = misbranding

8. Counting med in a tray w/ residue from prior drug = adulteration

9. Incorrect storage (shelf instead of fridge) = adulteration

10. Failing to dispense in a child-resistant container when requried = misbranding

Abbreviated NDA (ANDA)

Provides for the review and ultimate approval of generic drugs

• Abbreviated because they don’t have to go through preclinical (animal) and clinical (human) data to establish safety + efficacy. They just have to demonstrate bioavailbility.

Orphan drugs

Rare diseases or conditions. Drug eligible for 7 years of market exclusivity.

Breakthrough therapy

Process designed to expedite the development and review of drugs that are intended to treat a serious condition and prilim clinical evidence indicates substantial improvement over current available therapy

Accelerated approval

Regulations that allow drugs for serious conditions that fill an unmet medical need for approval based on a surrogate endpoint

Fast track

Process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet need

Priority review

Take action within 6 months instead of 10 months (standard)

FDA recall classifications - 1

Reasonable probability product will cause either serious adverse effects on health or death

FDA recall classification - 2

May cause temporary or medically reversible adverse effects on health or where probability of serious ADRs is remote. (e.g., infusion pump w/ a minor software or hardware issue)

FDA recall classification 3

Not likely to cause adverse health consequences. (e.g., compliance w/ labeling or packaging regulations)

PA specific advertising rule

Prohibits pharmacies from advertising or promoting sale of controlled substances

PPIs requirement for hospitalized patients

PPIs are required to be given to hospitalized or institutionalized patients before the first drug administration and every 30 days thereafter. (Doesn’t happen in practice)

NDC number

First 4-5 digits: Labeler code

Next 3-4 digits: Specific drug, strength, dosage form

Last 1-2 digits: Package size

*should not appear on non-drug products, if on a supplement or medical device - it is misbranding. Medical devices have unique device indentifiers (UDIs)

Orange book

Use: determining generic equivalency (pharmaceutically and therapeutically equivalent to the brand drug)

Pharmaceutical equivalence

Identical dosage form and ROA that contain identical amounts of active drug incredient

Therapeutic equivalence

Bioequivalence has been demonstrated and expected to have the same clinical effect + safety profile

Orange book - lettering system

A = drug products that FDA considers to be pharmaceutically and therapeutically equivalent

B = drug products that FDA does NOT consider to be pharmaceutically and therapeutically equivalent

Codes for products with known or suspected bioequivalence issues

AA - conventional dosage forms

AN - solutions and powders for aerosolization

AO - injectable oil solution

AP - injectable aqueous solution

AT - topical products

Purple book

List of biological products that are considered “biosimilar” and provides interchangeability

“Biosimilar” or “bio similarity” defination

highly similar, with some difference in the inactive product and no clinically meaningful difference in safety, purity or potency

“Interchangeable product”

Product that has been shown to be biosimilar to the reference product and can be expected to have the same clinical effect as the reference patient in any given patient

“Biosimilar” vs “Interchangeable”

Designated “interchangeable” = PharmD can substitute for the reference product

“biosimilar” = requires prescriber intervention in order to substitute

substitution laws in PA (Orange and a purple book state")

PharmD can substitute products that are labeled “A-rated” generic products and “interchangeable” and biologic products. HOWEVER, excludes those with narrow therapeutic index

Poison prevention and packaging act of 1970 (PPPA)

Requires child-resistant containers for ALL Rx drugs and for some non-Rx drugs/classes/dietary supplements (below)

• Aspirin

• Methyl salicylate

• Controlled drugs

• Methyl alcohol

• Iron-containing drugs (exception = total elemental Fe 250 mg)

• Acetaminophen/ibuprofen (if > 1 gram in a single package)

• Benadryl > 66 mg

• Lidocaine (>/= 5 mg in single package)

• Loperamide (>/= 0.045 mg in a single package)

• Dibucaine >/= 0.5 mg

• Naproxen >/= 250 mg

• Ketoprofen >/= 50 mg

• Flouride

• Minoxidil > 14 mg

• Imidazolines

What is the exception to the PPPA act?

1. Request of patient or physician (**only the patient can provide a blanket request for all future prescriptions. Providers = only individual Rx, not legally required to have in writing)

2. Bulk container for household use

3. Specific Rx and non-Rx

   1. Oral contraceptives

   2. Medroxyprogesterone acetate tablets

   3. SL nitro

   4. ASA & Tylenol in effervescent tabs or granules

   5. K+ supplements

   6. Sodium fluoride containing 264 mg or less

   7. Anhydrous cholestyramine and colestipol packets

   8. Erythromycin granules for oral suspension (< 8 grams) or tablets (< 16 grams per package)

   9. Prednisone < 105 mg per package

   10. Mebendazole < 600 mg

   11. Betamethasone < 12.6 mg

   12. Preparations in aerosol containers for inhalation

   13. HRT

   14. Pancrealipase preps

   15. Sucrose preparations in a solution of glycerol and water

Federal hazardous substances act of 1966

Requires label on the immediate package of hazardous product and any outer wrapping or container that might cover up the label on the package with info on MFR name/business, name of product, “danger”, or “caution/warning” or other statements for warnings as appropriate"

Does the Federal hazardous substances act of 1966 apply to FDA regulated drugs

NO. But may apply to other products sold in the pharmacy such as bleach, cleaning fluids, antifreeze, etc

Can prescription drugs be mailed?

YES.

1. non-controlled drugs - yes, as long as no alcoholic beverages, poisons or flammable substances

2. Controlled substances. Yes, if meeting the following requirements

   1. Container meets labeling requirements

   2. Outer wrapper/container does not say the nature of the contents (including name of the pharmacy in the return address

HIPPA and HITECH (enforced the office of civil rights)

1. Notice and acknowledgement - provide notice of privacy practices upon first service delivery

2. Use and disclosure of PHI

   1. May use and disclose PHI to provide treatment for payment, governmental functions and for healthcare operations w/o patient authorization

   2. Use for marketing purpose requires patient authorization (refill reminders are not considered marketing)

3. Minimum necessary standard

   1. Pharmacy must make a reasonable effort to limit PHI to the minimum necessary to accomplish the intended purpose (does not apply to disclosure to HCP for treatment or when there is signed authorization)

4. Unintended “incidental” disclosures are okay

5. Patients have the right to get a copy of their PHI (within 30 days of request, with no more than 30 days extension)

6. Patients have the right to amend their records (within 60 days of request, with no more than 30 days extension)

7. Must have a contact person (e.g., privacy offical) to receive complaints

HITECH act

Amended HIPPA to strengthen many of its provisions.

1. Added a breach notification requirement that requires

   1. Notify individuals of breach w/ 60 days

   2. BAs must report any breaches of unsecured PHI to the covered entity and provide identifies of each affected individuals

   3. For breaches affecting < 500 individuals, must maintain a log of these breaches and notify HHS of these annually

   4. For breaches affecting > 500 individuals, secretary of HHS and prominent local media must be notified in addition to the affected individuals within 60 days of breach discovered

“Narcotic”

Drugs that are derivatives of opium, poppy straw, cocaine, or ecgonine. All narcotics are controlled substances but not all controlled substances are nacrotics.

“Listed chemicals”

Chemicals that, in addition to legitimate uses, can be used in manufacturing a controlled substance (e.g., OTC products containing ephedrine, pseudoephedrine, or phenylpropranoamine)

Scheduling of compounded controlled substances

Pharmacy may compound narcotic controlled substance pursuant to a Rx as long as the concentration is not greater than 20%. (Applies to aqueous or oleaginous solutions or solid oral dosage forms). It must also be compounded with 1+ non-narcotic therapeutic ingredients.

Scheduling of compounded controlled substances: over 20%

DEA may consider it to be manufacturing, which would require the pharmacy to be registered with DEA as a manufacturer.

Scheduling of compounded controlled substances - what if NOT mixed with another drug?

Automatically a schedule II (e.g., codeine or opium mixed with only water or simple syrup)

Codeine - concentration limits

Schedule V: 200 mg/100 mL

Schedule III: 1.8 grams/100 mL and 90 mg/dosage unit

anything above this = schedule II

Cheracol and Robitussin AC contain the maximum amount of codeine to be Schedule V.

Dihydrocodiene - concentration limits

Schedule V limit: 1 mg/mL

Schedule III limit: 1.8 grams/100 mL and 90 mg/dosage unit

Opium - concentration limits

Schedule V: 1 mg/mL

Schedule III: 5 mg/mL and 25 mg/dosage unit

Morphine - concentration limits

Schedule V: none (all are either III or II)

Schedule III: 0.5 mg/mL

Will a compounded narcotic Rx EVER be a schedule IV drug?

NO

How often must dispensers (pharmacy + practitioners) register w/ the DEA?

Every 3 years

What is the registration form for dispensers?

DEA 224

Renewal - DEA 224a

Dispenser registration numbers

All except mid-level practitioners start with: “A”, “B”, or “F” (“G” = department of defense contractors)

Mid-level practitioners = “M”

The second letter of the prefix will normally be the first letter of the last name or pharmacy/hosptial name

Does PA current consider pharmacists to be mid-level practitioners?

No

Verifying a DEA registration number

Step 1 - Add 1st, 3rd and 5th digits

Step 2 - Add 2nd, 4th, and 6th digits and multiply sum by 2

Step 3 - Add the sum of steps 1 and 2, and the last digit of the sum should correspond to the last digit of the DEA number

Application for DEA registration

step 1 - obtain a state pharmacy permit first

step 2 - submit application form electronically signed (applicant can authorize another individual to sign the application + renewals but must get a power of attorney with the DEA registration unit)

Different registration forms for different entities

DEA form 224 - dispensers (retail pharmacies, hospitals/clinics, practitioners, mid-level practitioners, and teaching institutions). Renewal form = 224A

DEA form 225 - manufacturers, distributors, researchers, analytical laboratories, importers, and exporters. Renewal form = 225A

DEA form 363 - narcotic treatment facilities. Renewal form = 363A

Who does not have to register with the DEA?

• Pharmacists working in a pharmacy and nurses working in a hospital or clinic

• Agent/employer of manufacturer

• Patient

• Officials of the US armed services, public health service of the Bureau of Prisons, acting in the course of their official duties.

Using the previous pharmacy owner’s DEA registration:

• Can be used for 45 days after the purchase if the all the following are met:

  • New owner must apply ASAP

  • Allowed by the previous owner

  • The previous owner acknowledges, as the registrant, that they will be held accountable for any violations

Ordering and transferring CS

DEA form 222

Is not valid for more than 60 days (partial supply are allowed with the remaining qty sent within 60 days)z

Electronic ordering of schedule II CS

DEA allows electronic ordering of CII through the controlled substances ordering system (CSOS)

expires when the DEA registration expires

2 types of CSOS certificates

1. CSOS administrative certificates are used to digitally sign communications with the DEA as well as with other participants in the CSOS community. Not valid for electronic ordering.

2. CSOS signing certificates are used for digitally signing CS ordering.Issued to approved registrant and power of attorney applicants.

Required elements on an invoice for a controlled substances (III-V)

1. Name of CS

2. Dosage form and strength

3. # of units per container (e.g., 100 tablet bottle)

4. Qty received (containers)

5. Date of receipt

6. Name, address, and DEA number of the registrant from which the CS was received

Transfers of CS b/w registrants - the 5% rule

A pharmacy does not have to register with the DEA as a distributer as long as the total number of dosage units transferred during a calendar year does not exceed 5% of all controlled substance dosage units that the pharmacy dispensed and distributed during that same year.

What is required for transfers of the CS within the 5% rule?

CII - DEA form 222

CIII-V: invoice provided by the supplier with all the required element as described elsewhere

Difference w/ CII and CIII-V

• CII - person receiving the product initiates and fills out the DEA form 222, which is sent to the supplier or seller

• CIII-V - invoice provided by the supplier or seller to the purchaser

Online centralized database for the reporting of suscious CII orders

Suspicious Orders Report Systems (SORS)

Theft or significant loss of CS

DEA form 106

• Must be reported in writing to DEA within 1 business day of discovering theft or significant loss. DEA recommendation = notifying the police.

• Although the initial notification must be made in writing within 1 business day, the actual DEA form does not need to be submitted (to the DEA theft and loss reporting system) until 45 days after the discovery.

ANY theft must be reported, but only “significant” losses must be reported

How to determine if a loss is “significant? - consider these factors

1. The actual qty of CS lost in relation to the type of business

2. The specific CS

3. Whether the loss of the CS can be associated with access to those CS by specific individuals or whether the loss can be attributed to the unique activities that take place involving the CS

4. Pattern of losses over a specific time period, whether the losses appear to be random or not, and the results of the efforts taken to resolve the losses

5. Whether the specific CS are likely candidates for diversions

6. Local trends and other indicators of the diversion potential of the missing CS

Reporting losses of listed chemicals (primarily pseudoephedrine pdt in a pharmacy)

1. DEA requires any unusual or excessive loss or disappearance (inc. theft) of a listed chemical to be reported to DEA at the earliest practicable oppourtunity

2. DEA form 107 w/in 15 calendar days

3. Must be filled out using the DEA’s theft and loss reporting (TLR) system

PA law for transfer warning

Federal law only requires it for CII-IV, but PA requires it for ALL, including C-V.

"Caution: Federal law prohibits the transfer of this drug to any person other than the pt for whom it was prescribed."

On-site destruction of CS in a pharmacy

DEA form 41. Requires

• NDC # of the drug + strength

• Dosage form

• Package size

• Qty. of the CS destroyed

• Method of destruction

• 2 signatures of employees as witnesses

What is the difference b/w destruction on the premises of a pharmacy and transferring CS to a DEA-registered reverse distributor for destruction

• Destruction on the pharmacy: requires DEA form 41

• Transfer to reverse distributer: requires DEA form 222 (CII) or invoice (CIII-V)

Waste of CS

“CS has been removed from inventory in accordance w/ a physician’s order for administration to a patient and is not entirely administered to the patient”

• Does not require DEA form 41. However, does need 2 witnesses and documentation of date, qty. wasted, and method of disposal.

Breakage or spillage of CS

• Doesn’t require notification to the DEA using form 106

CS inventories

• Initial inventory - required on the first day pharmacy is open for business

• Every 2-year inventory of CS (both federal and PA)

• Exact count required for CII

• Estimated count required for CIII-V (unless the container holds more than 1,000 tablets or capsules)

Inventory records must contain

• The date of inventory

• Whether the inventory was taken at the beginning or close of business

• Name of each CS inventories

• The finished form of each of the substances (e.g., 10 mg tablet)

• Number of dosage units of each finished form in the commercial container (e.g., 100-tablet bottle)

• Number of commercial container of each finished form (e.g., four 100-tablet bottles) AND

• Count of the substance

Is a perpeptual inventory of CS LEGALLY required?

No

How long must records of CS be maintained for?

2 years under both federal and PA CS acts

CS filing storage system

1. 3-file storage system

   1. File #1: CII only

   2. File #2: CIII-V

   3. File #3: Other (non-CS) drugs

2. 2-file storage system

   1. File #1: CII only

   2. File 2: CIII-V (and other non-CS)

only apply to written Rx and verbal Rx reduced to writing by a PharmD

Central recordkeeping

• Pharmacy wishing to maintain shipping and financial records at a central location other than the registered location must notify the nearest DEA Diversion Field Office.

• Unless denied, may begin maintaining central record 14 days after notification

• Central records EXCLUDES completed DEA form 222, or inventories. These must be maintainted in the pharmacy.

Explain corresponding responsibility between PharmD and MD in prescribing and dispensing of CS

• CS must be issued for a legit medical reason. This responsibility not only rests on the provider but also the pharmacist filling the Rx.

• PharmD who deliberately ignores a “high probability” that a Rx was not issued for a legit medical purpose may be prosecuted too.

Red flags that may require a PharmD to do further investigate to the legitimacy of CS Rx

• Multiple customers filling Rx written by the same prescriber for the same drugs in the same QTY

• Customers with the same last name and street address presenting similar Rx on the same day or within a short time span

• Two SA opiates prescribed together

• Patients traveling long distances to fill opioids

• Drug cocktails

• Payment by cash

• Unusually large QTY of CS

• Patter prescribing

• Irregular dosing instructions

• Lack of individualized therapy or dosing

• Early fills/refills

What practitioners does PA law authorize to prescribe CS?

• MD, Osteopathopic physicians, Dentists, Podiatrists, Vetrinarians

• Certified optometrists

  • Few CS for analgesic purposes for 72 hours

• PA

  • Must be delegated by supervising physician

  • C-II limited to a 72-hour dose for initial therapy and a 30-day supply for ongoing therapy clearly stated.

• CRNP

  • Must be delegated by supervising physician

  • CII: limited to 30 days per CPA

  • CIII or IV: limited to 90 days per CPA

• Nurse midwives

  • CII-V for woman’s acute pain delegated by a supervising physician.

  • CII - limited to 72 hours and may not be extended w/o approval from physician

  • CIII-V - up to 30 days supply and cannot be refilled w/o approval from physician

  • Psychotropic drugs may only be prescribed after consulting with physician

Can you legally accept a out-of state electronic Rx for a CS in PA?

Yes but you must verify the authenticity of it

Can you legally accept a out-of country Rx for a CS in PA?

No, as they cannot have a DEA registration

What are designated agents?

• They can communicate a prescription for a CIII-V but cannot authorize or prescribe.

• They can prepare a written Rx for the signature of a practitioner

• Can transmit a fax of the signed CS Rx to the pharmacy

Can a authorized agent of the prescriber verbally communicate emergency CII Rx to a PharmD?

No

Mandatory electronic Rx for CS

PA passed a law in 2018 requiring prescribers to issue all CS Rx electronically (“PA act 96 of 2018). Became effective in October, 2019.

What are exemptions for PA act of 96 of 2018 as the PA DOH is in the process of promulgating regulations in accordance with the law?

1. Rx issued by a vet

2. Temporary technological or electronical failure (practitioner has 72 hours to correct this)

3. Issued by a practitioner and dispensed by a pharmacy outside of PA

4. The practitioner or healthcare facility does not have internet access or an EHR system, or the pharmacy is not set up to process electronic Rx

5. Would be impractical or cause delay leading to adverse outcomes if sent electronically, as determined by MD

6. Hospice program or patient resides in a nursing home or residential health care facility

Requirements for a written CS Rx

1. Must be signed MANUALLY and dated on the date issued

2. Must contain

   1. Full name + address of patient

   2. Drug name, strength, and dosage form

   3. QTY prescribed

   4. Directions for use

   5. # of refills authorized, if any (not for CII)

   6. The name, address, and DEA # of the practitioner

   7. Earliest fill date if to be filled at a later date

   8. Rx #, dispensing PharmD initials, cautions communicated and the date filled