Delivering and Dispensing Drugs

Food and Drug Regulation in the US

“And pursue with eagerness the fortunes of hope”

1905

Pure Food and Drug Act of 1906 (Wiley Law) Promotes accurate labeling and

purity of food and drugs Defines two bases for seizing a

product Adulteration Misbranding

Ruth de Forest Lamb: An American Chamber of Horrors

                                                      

1937107 deaths. Could only be seized because it was labeled as an “elixir” but contained no alcohol.

Food, Drug and Cosmetic Act of 1938 Requires proof of safety prior to

marketing Requires pre-marketing approval by FDA Creates “new drugs” – those marketed

after 1938 Retains ability to seize drugs that are

Misbranded Adulterated

Carl Durham, R.Ph. Hubert Humphrey, R.Ph.

              

Caution: Federal law prohibits dispensing without prescription.

Phocomelia

Europe's deformed baby crop seen at 7,000

Sleeping pill deforms unborn child

Deformity drug's toll not final

Kefauver-Harris Amendments Improved informed consent for clinical

trials Established GMPs Teratology testing in animals Required proof of efficacy prior to

marketing DESI studies

FDA to control advertising of legend drugs

New Drugs

Drugs may not be introduced into commerce unless Proven safe and effective for intended

use Adequate labeling Meet current Good Manufacturing

Practices Produced by a registered

manufacturer

New Drug Development Process

Pre-clinical Testing• In vitro and in vivo animal testing

File IND (Investigational New Drug) Clinical Trials

• Phase I: healthy volunteers • Phase II: limited trials in patients with disease• Phase III: large-scale clinical trials

• Randomized• Double blind• Placebo-controlled

File NDA (New Drug Application)• Phase IV: post-marketing trials

Supplemental NDAs Prior approval supplement

Change in production or labeling Change being effected

Labeling changes that strengthen warnings

Limited changes to production Annual report

Minor changes

Abbreviated NDAs Used for generic drugs Demonstrate bioavailability and

bioequivalence May have different labeling than

innovator’s drug Doesn’t preclude dispensing for uses

not contained in the generic insert

FDA Ratings of New Drugs Chemical type

1. NCE2. New salt or ester3. New formulation4. New combination5. Duplicate of

another product6. Previously

marketed by same firm

Therapeutic PotentialP - Therapeutic

advance• No other effective

drugs• More effective or

safe• Other important

advantages

S - Similar to other drugs on market

FDA Jurisdiction Foods

Articles used for food or drink for man or other animals

Chewing gum Articles used for components of any

such article

FDA Jurisdiction Cosmetics

Applied to body Intended for cleansing, beautifying,

promoting attractiveness, altering appearance

Dalkon Shield 25 years of

litigation $2.6 billion

settlement trust

Demise of A.H.Robins Co.

FDA Jurisdiction Devices

Intended for diagnosis of disease or other conditions, or for cure, mitigation, treatment, or prevention of disease in man or animals.

Does not achieve its effect by chemical action or by being metabolized

FDA Jurisdiction

Drugs Listed in USP, NF, or HP Intended for diagnosis, cure, mitigation,

treatment, or prevention of disease in man or other animals

Articles (other than food) intended to affect the structure or function of body of man or animals

Intended to be used as component of the above

Adulterated Fails to conform to compendial

standards for purity, quality, strength, and appropriate assays

Failed to be stored under USP standards

Misbranded Incomplete labeling Misleading labeling

7-point OTC Label Name of Product Name and address

of manufacturer, packager, distributor

Net contents Active ingredients

and quantity of certain other ingredients

Name of any habit forming drug

Cautions and warnings

Adequate directions for use

Poison Prevention Packaging Act Requires child-resistant containers (CRCs)

on certain “household substances” Requires CRCs on all prescription drugs,

except for certain listed products Requires CRCs on specifically listed OTC

products Authorizes Consumer Products Safety

Commission to set standards for child-resistant packaging, or “special packaging” as its called in the Act

OTCs Requiring CRCs Aspirin, Acetaminophen NSAIDs Iron preparations >

250 mg elemental iron/pkg

Diphenhydramine > 66 mg/pkg

Lidocaine, Dibucaine

Minoxidil Methyl salicylate Ethylene glycol Methyl alcohol Hydrocarbons and

solvents NaOH, KOH

                                      

               

Tylenol in ChicagoExcedrin & Sudafed in WA

                          

                               

       

Tamper-resistant Packaging(Federal Anti-Tampering Act)

Indicator or barrier to entry If breached or missing provides visible

evidence of tampering Label statement describing barrier or

indicator Required for certain OTCs, devices, and

cosmetics Dentifrices, dermatologicals, lozenges,

and insulin are excluded

Dietary Supplement Health and Education Act New law - 1994 Allows certain claims to be made for

dietary supplements without violating FDCA

Dietary Supplements

Vitamin Mineral Herb or other botanical Amino acid

Dietary Supplements Substance to supplement diet by

increasing total dietary intake Concentrate, extract, metabolite,

constituent or combination of above

Dietary Supplements

Intended for ingestion Not represented for use as a

conventional food or sole item of a meal or diet

Labeled as a dietary supplement Deemed to be a food

Dietary Supplement Health and Education Act Pharmacists must use care in

making claims not otherwise allowed under this law

Labeling accompanying the product makes claims

Permitted Labeling under DSHEA

Label can claim benefit related to a classic nutritional

deficiency disease describe role of a nutrient intended to affect

structure or function of body characterize the mechanism of action describe general well-being gained from

consuming a nutrient Must state FDA has not evaluated claims

References and Nutrition Books

Articles, books, abstracts of peer-reviewed scientific publications may be sold or displayed Must be reprinted in their entirety Must be presented with other publications

to provide a balanced view Must be physically separate from product No information applied by sticker, etc.

Advertising and Labeling

May not make false, misleading, or unapproved claims for a product when you are the seller of the product

Specific assertions to purchasers may create warranties of fitness for a particular use

Information Required on Label of Legend Drug (Federal Law) the name and address of the dispenser the serial number date of the prescription or of its filling the name of the prescriber if stated in the prescription, the name of

the patient the directions for use and cautionary

statements, if any, contained in such prescription

21 USC 353 (b)(2)

Package Insert Warnings

CONTRAINDICATIONS

ADVERSE REACTIONS, PRECAUTIONS,WARNINGS

INDICATIONS

Patient Package Inserts Oral Contraceptives

Must supply both “brief” insert and complete insert with each dispensing

Must supply when requested On admission and q 30 d in hospital

Estrogen/Progestin Insert Same as for OCs

Other inserts/information should not be removed or covered over.

Patient may request professional package insert and is okay to give.

Unlabeled indications for approved drugs Labeling restricts manufacturers’ claims,

not prescribers’ use Labeling that CONTRAINDICATES a

particular use provides evidence that a pharmacist should not dispense the drug for that use or in that situation

It is permissible to dispense a generic for a use that is only in the labeling of the brand name drug

Information Required on Label of Legend Drug (WA) Complete directions for use (“UD” not valid) Expiration date Quantity dispensed Name and strength of drug Initials of pharmacist (can be in computer

system) “Warning: State or federal law prohibits

transfer of this medication to any person other than the person for whom it is prescribed.”

Prescriptions and Labeling by prescriber Valid Rx (69.41.040)

Authorized prescriber Legitimate medical use

Label, when dispensed by prescriber (69.41.050) Name of prescriber Complete directions for use Name of drug, strength Name of patient Date Samples – Name of patient and prescriber

Requirements of a valid Rx Written for a patient By an authorized prescriber In the due course of medical

practice Bona fide prescriber-patient

relationship Within scope of prescriber’s practice

For a legitimate medical purpose

Authority to Prescribe A matter of state law Cannot delegate authority to prescribe

Exceptions: laws authorizing collaborative practice agreements

Generally, authority to prescribe includes authority to dispense

Only pharmacists, with specific exceptions (eg, Physician Assistants) can dispense a prescription by another prescriber

Agent of physician may communicate instructions

Randle v. California State Board of Pharmacy(49 Cal Rptr 485 (1966))

Patient would bring in receipt for $7.50 for office visit

Pharmacist would call office nurse and ask for approval to fill prescription for 60 ampoules of Methedrine (desoxyephedrine; methampetamine – not a CSA in 1966)

On 21 occasions, it was proved that physician was out of town, and that the pharmacist knew it

Pharmacist: “Well, I assumed the nurse had authorization to do so or she wouldn’t have done it”

Practitioners with Prescriptive Authority in WA Physicians

MD Osteopath (DO) Podiatrist

Dentists Veterinarians

Mid-level practitioners Nurse Practitioner Physician’s

Assistant Naturopath* Optometrist (OD)* Pharmacist* Midwife*

Prescriptions must be legible in WA

Complete directions for use – “UD” not allowed in WA BC pills – “As directed on dialpak” Written schedules – “As instructed

on written schedule from Dr.” Keep copy with original Rx Estimate days’ supply carefully

Coumadin – “Take 1 daily or as directed by physician.”

Telephoned, and FAXed Rx Reduce oral Rx to writing FAX treated like telephoned Rx

Must show date, time, phone #, and location of FAX machine on FAX

Not printed on thermal paper Verify unclear or suspicious orders

with prescriber

Electronic prescribing Must meet standards for security and

integrity Must be approved by Board – approved

systems listed on web site Staff must sign and adhere to security

and integrity policy and procedures Must allow for communicating

preferences for substitution Pharmacist responsible to for accuracy,

validity, and authenticity of the order

Drug Product Selection Generic substitution

Same chemical entity Same dosage form Bioequivalent

• Same AUC• Same Peak

Therapeutic substitution Same class Equivalent therapeutic effect

Substitution “Formularies” Negative formulary

A list of drugs that cannot be generically substituted

Usually “narrow therapeutic index” drugs

Positive formulary A list of drugs that may be generically

substituted Based on bioavailability data

The Orange Book

The Orange Book Approved Drug Products

Doesn’t cover drugs without NDA Generics listed must have approved

ANDA Therapeutic Equivalence Evaluations

A = products considered therapeutically equivalent to “reference” product

B = products not considered therapeutically equivalent

Reasons for “B” rating BC: Extended release formulations BD: Particular active ingredients with

documented problems BE: Delayed-release formulations BN: Aerosols or nebulized formulations BP: Particular active ingredients with potential

problems BR: Rectal formulations BS: Drug standards difficulties BT: Topical products BX: Insufficient data B*: Questions remain to be resolved

Three-character Codes

Used when two or more “reference” drugs are available which are not bioequivalent to each other

Adalat CC = AB1 Procardia XL = AB2 Nifedipine generic rated AB1 can be

exchanged for Adalat CC, and so on.

Product Selection in WA

Two-line prescription blank, out of state ok to substitute unless “DAW” etc. is on Rx

Indicate on oral prescriptions if DAW or Substitution Permitted

Shall substitute unless patient requests otherwise

Must use therapeutically equivalent product of identical base or salt given in same regimen

May use any reliable information source to determine bioequivalence

Must pass on 60% of savings

Therapeutic Substitution in WA May do “Therapeutic Substitution” based

on prior authorization from prescriber Protocol, Exchange List, Formulary Per-prescription basis

Blanket prior authorization can be verbal, but are required to have documentation of authorization in the pharmacy

Substitution using prescriptive authority protocol is not really DPS, but prescribingRCW 69.41.100

Preferred Drug List: RxWashington.com Used for state-paid drug benefits plans Effective May 1, 2004 Pharmacists authorized to perform product

interchange using PDL on Rx’s from “endorsing prescribers” Prescriber may indicate DAW and non-PDL product

won’t need prior authorization Non-endorsing prescribers’ Rxs for non-preferred

drugs require prior authorization Refills of antipsychotics, antidepressants,

chemotherapy, HIV drugs, and immunosuppressive drugs exempt

Can you fill for quantities different than ordered? Cannot dispense more than the total

ordered including any refills Can use judgment for non-controlled drugs

Lipitor 10 mg #90, 1 daily• Insurance will only pay 30 days supply – ok to fill for 30,

and give 2 refills Lipitor 10 mg #30, 1 daily, Refill PRN

• Insurance will pay 90-day supply – ok to fill for 90 after first filling if patient tolerates drug

Elavil 10 mg #10, Refill 5x• Patient with history of suicide attempt – bad idea to

give more than 10 at a time

Not enough stock? Partial fill and order the rest – “Will call” Generally permitted by law

Restrictions for C-II drugs Problems with 3rd party payers and patient

doesn’t pick up remainder If put back in stock, must adjust patient profile May not be able to refund 3rd party General rule – don’t bill for full amount until it

has been given to the patient Problems with mailing unless patient has signed

a request

Secundum artem Circumstances may justify dispensing a

different strength or form than ordered Prednisone 10 mg #50, ½ tab daily Prednisone 5 mg #100, 1 tab daily

Levoxyl 225 mcg #30, 1 daily – doesn’t exist Levoxyl 113 mcg #60, 2 daily Levoxyl 200 mcg #30, 1 daily +

Levoxyl 25 mcg #30, 1 daily A wise pharmacist will inform prescriber of

these types of changes Be sure patient fully understands!

Refills of legend drugs All legend drugs expire after 1 year in WA Refill PRN = 1 year Refills must be consistent with directions If Rx expired, a refill should be treated as

a new Rx and given new number The full quantity of a prescription refill

may be dispensed up to the last day before the Rx expires

Legend Drugs Not Requiring CRCs Nitroglycerine SL SL, chewable

isosorbide 10 mg NaF 110 mg/pkg Cholestyramine and

colestipol powder Oral corticosteroids in

doses 105 mg of prednisone equiv.

Mebendazole 600 mg/pkg

K+ supplements 50 mEq/dose

EES granules 8 g/pkg, tabs 16 g

Aerosols for inhalation Pancrelipase OCs in memory aid

containers; MPG; other hormones

Sucrase solutions

Requirements for Containers At least 90% of adults, having been shown

how, can open within 5 minutes Not more than 20% of children < 5, having

been shown how, can open within 5 minutes Must meet USP standards for tightness, light

resistance May not be reused Because 1 in 5 children can open, by

design, never refer to these containers as “child-proof”

Exemptions and Waivers of CRC use Not required for institutionalized patients Prescriber may specify non-CRC on

individual prescriptions; no blanket waiver Patient or agent may request non-CRCs on

all prescriptions; blanket waiver Pharmacist may not designate him or

herself as patient’s agent Under federal law, waiver may be oral or

written WA: must be written

Liability Issues A child injured by a negligent act of a

pharmacist may be able to bring lawsuit after turning 18

Parents are not always legally able to waive child’s rights to sue

Some experts recommend that requests for non-CRCs include indemnification clauses

Accepting a waiver without warning patient of consequences to children may leave pharmacist exposed to liability

Some Realities Packages designed so that 90% of

adults can open IF SHOWN HOW Some packaging is particularly

suited to elderly Most common source of childhood

poisoning is a grandparent’s home or “Grandma’s purse”

Recalls

“Voluntary” for drugs FDA may initiate for devices or infant

formulas Wholesaler level Retail level Consumer level Product is considered misbranded or

adulterated - dispensing would violate FDCA

Recalls: Classes of Seriousness Class I - Likelihood of injury or death from

use of product; may include public warning

Class II - Temporary or reversible health problems from use of product

Class III - Use of product NOT likely to cause health problems

Market withdrawal - Minor health risk or minor FDA violation