Purple book review (section 1)

The FDA Orange Book's official name is...

"Approved Drug Products with Therapeutic Equivalence Evaluations" It is the primary source for determining generic equivalency of drugs. Available on FDA website

The FDA Purple Book's official name is...

"Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations"

Adulteration -- a drug is adulterated if...

1. Contains any filthy, putrid, or decomposed substance 2. It has been prepared of held under unsanitary conditions where it may have been contaminated 3. The methods of manufacture do not conform to current GMPs 4. It has been manufactured, processed, packed, or held in any factory, warehouse, or establishment and the owner, operator, or agent of such factory, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection 5. The container is composed of any poisonous or deleterious substance which may contaminate the drug 6. It contains an unsafe color additive 7. It purports to be a drug in an official compendium, and its strength differs from or its quality or purity falls below the compenium standard, unless the difference is clearly stated on the label (i.e., if the product claims to meet USP standards but its strength or quality does not meet those standards, it is adulterated) 8. It is not in a compendium, and its strength differs from or its quality falls below what it represents (i.e., what is on the label) 9. It is mixed or packed with any substance which reduces its strength or quality of the drug has been substituted in whole or in part. Note: if a product's strength is less than what is represented on its label, it could be both misbranded and adulterated

Adulteration and Misbranding as Applied to Pharmacies

1. Dispensing prescription without authorization causes the drug to be misbranded even if it is labeled correctly by the pharmacist. This is because a prescription drug product is only exempt from the MFG's labeling requirements when it is dispensed pursuant to a valid prescription 2. Misfilling a prescription with the wrong drug, strength, or directions for use will always cause the drug to be misbranded 3. If a misfilled prescription involves the wrong strength of the drug prescribed, it would also be adulterated. This is because the definition of adulteration includes when the strength differs from or quality falls below that which it represents

Special Warning Requirements for OTC Products in the FDCA

1. FD&C Yellow No. 5 (tartrazine) and No. 6 -- must disclose presence and provide warning in "precautions" section of label that may cause allergic reaction in certain susceptible persons 2. Aspartame -- must contain warning in "precautions" section of labeling to the following effect: Phenylketonurics: Contains phenylalanine ___ mg per ___ (dosage unit) 3. Sulfites -- prescription drugs containing sulfites (often used as a preservative) must contain an allergy warning in the "warnings" section of labeling 4. Mineral oil -- requires warning to only be taken at bedtime and not be used in infants unless under advice of a physician. Label also cannot encourage use during pregnancy 5. Wintergreen oil (methyl salicylate) -- any drug containing more than 5% methyl salicylate (often used as flavoring agent) must include warning that use other than directed may be dangerous and that article should be kept out of reach of children 6. Sodium Phosphates -- limits the amount of sodium phosphates oral solution to no more than 90 mL per OTC container. Also requires specific warning. 7. Isoproterenol Inhalation Preparations -- requires warning not to exceed dose prescribed and to contact physician if difficulty in breathing presists 8. Potassium Salt Preparations for Oral Ingestion -- requires warning regarding nonspecific small-bowel lesions consisting of stenosis, with or without ulceration, associated with the administration of enteric-coated thiazides with potassium salts 9. Ipecac syrup -- the following statement (boxed and in red letters) must appear: "For emergency use to cause vomiting in poisoning. Before using, call physician, the poison prevention center, or hospital ED immediately for advice." The following warning must appear: "Warning: Keep out of reach of children. Do not use in unconscious persons." The dosage of the medication must appear. The usual dosage is 1 tablespoon in individuals over 1 year of age. 10. Phenacetin (acetophenetidin) -- must contain warning about possible kidney damage when taken in large amounts or for a long period of time 11. Salicylates -- ASA and other salicylate drugs must have special warnings regarding Reye's syndrome. Retail containers of 1.25 grain (pediatric) ASA cannot be sold in containers holding more than 36 tablets 12. OTC Drugs for Minot Sore Throats -- Any OTC that states "For the temporary relief of minor sore throats" must include this warning: "Warnings -- severe or persistent sore throat or sore throat accompanied by high fever, HA, n/v may be serious. Consult physician promptly. Do not use more than 2 days or administer to children under 3 years of age unless directed by physician 13. Alcohol Warning -- Internal analgesics and antipyretics (APAP, ASA, ibuprofen, naproxen, ketoprofen, etc.) are required to have a warning for persons consuming 3 or more alcoholic beverages per day and to consult with a doctor before taking 14. OTC drugs for Vaginal Contraceptive and Spermicide Use Containing Nonoxynol 9 as the Active Ingredient -- these are subject to severel warning requirements, including one that states "Sexually transmitted diseases (STDs) alert: This product does not protect against HIV/AIDS or other STDs and may increase the risk of getting HIV from an infected partner" 15. Acetaminophen -- must have "acetaminophen" prominently displayed, must warn about liver toxicity, and must warn not to use other products containing APAP and to talk to a doctor or pharmacist before taking with warfarin 16. NSAIDs -- must include term "NSAID" prominently on label, and must contain "stomach bleeding" warning 17. OTC Products Containing Iron in Solid Oral Dosage Form -- must provide the following warning: "Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of an accidental overdose, call a doctor or poison control center immediately"

Outsourcing facilities must have/do all of the following

1. Have a licensed pharmacist who provides direct oversight for the drugs compounded; 2. Register as an outsourcing facility. The FDA website provides a list of the names of each outsourcing facility along with the state where the facility is located, whether the facility compounds from bulk drug substances, and whether drugs compounded from bulk are sterile or nonsterile; 3. Report to the Secretary of HHS upon registering, and every 6 months thereafter, the drugs sold in the previous 6 months; 4. Be inspected by FDA according to a risk-based inspection schedule and pay annual fees to support it; 5. Report serious adverse event experiences within 15 days and conduct a follow-up 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

Example of REMS includes -- Isotretinoin (Accutane) iPLEDGE Program

1. Only doctors registered in iPLEDGE can prescribe isotretinoin. Doctors registered with iPLEDGE assume the responsibility for pregnancy counseling of female patients of childbearing potential (need negative pregnancy test) 2. Patients need to be registered in iPLEDGE to be prescribed isotretinoin (also complete consent form, obtain counseling about risks and requirements for safe use of drug, complying with negative pregnancy test, and use contraception) 3. Only pharmacies registered in iPLEDGE can dispense isotretinoin (ipledgeprogram.com). To register, a pharmacy must select a Responsible Site Pharmacist who must obtain iPLEDGE program information and registration materials, sign and return the completed registration form. 4. The Responsible Site Pharmacist must attest to: a) I know the risk and severity of fetal injury/birth defects from isotretinoin b) I will train all pharmacists on the iPLEDGE program requirements c) I will comply and seek to ensure al pharmacists comply with iPLEDGE program requirements d) I will obtain isotretinoin from iPLEDGE registered wholesalers e) I will return to the MFG (or delegate) any unused product f) I will not fill isotretinoin for any party other than a qualified patient

FDA requires Medication Guides for drugs when...

1. Patient labeling could prevent serious adverse effects 2. Product has serious risks relative to benefits 3. Patient adherence to directions is crucial

Elements to assure safe use (REMS) may include...

1. Special training, experience, or certification of health care practitioners prescribing the drugs; 2. Special certification for pharmacies, practitioners, or healthcare settings that dispense the drug; 3. Dispensing drugs to patients only in certain healthcare settings such as hospitals; 4. Dispensing drugs to patients with evidence or other documentation of safe use conditions such as lab test results; 5. Monitoring patients using the drug; or 6. Enrolling each patient using the drug in a registry

Additional OTC Requirements

1. Tamper-Evident Packaging -- MFG and packagers of OTC drugs (except dermatological, dentifrice, insulin, or lozenge products) for sale at retail must package products in a tamper-evident package 2. Repackaging of OTC Products -- A pharmacist that repackages OTC products would be subject to cGMP requirements and would have to meet all additional requirements including tamper-evident packaging if offered for sale to the public When an OTC product is prescribed and filled as a prescription, the OTC labeling requirements do not have to be followed. The prescription drug labeling requirements would apply and would include the prescriber's directions for use. If an OTC is filled as a prescription, any instructions for refills would apply as would expiration dates (valid for one year)

Outsourcing facilities may not compound a drug product that includes a bulk drug substance unless...

1. The bulk drug substance appears on a list indentifying bulk drug substances for which there is a clinical need (the 503B bulks list) 2. The drug product compounded from such bulk drug substance appears on FDA's drug shortage list at the time of compounding, distribution, and dispensing Note: FDA issued an Interim Policy on Compounding Using Bulk Drug Substances under Section 503B of the FDCA which is in place while the FDA develops the 503B bulks list. See compounding section of FDA's website for more.

Misbranding -- a drug is misbranded if...

1. The labeling is false or misleading in any particular way 2. It is a prescription drug and the MFG's label fails to contain the following information: a) the name & address of the MFG, packer, or distributor b) Brand and/or generic name of the drug or drug product c) The net quantity (weight, quantity, or dosage units) d) The weight of active ingredient per dosage unit e) The federal legend "Rx only" f) If not take orally, specific route(s) of admin g) Special storage instructions if appropriate h) MFG's control number (lot number) i) Expiration date j) Adequate information for use (package insert and medication guide or patient package insert if required); this includes other info (e.g., black box warning for benzos, opioids, etc.) 3. It is an OTC drug and fails to contain the following: a) A principal display panel, including a statement of identity of the product b) The name and address of MFG, packer, or distributor c) Net quantity of contents d) Cautions and warnings needed to protect user e) Adequate directions for safe and effective use (for layperson) (note: OTC must have adequate directions for use while Rx products must have adequate information for use [i.e., the package insert]) f) Contents and format of OTC product labeling in "Drug Facts" panel format including: aa) Active ingredient bb) Purpose cc) Use(s) -- indications dd) Warnings ee) Directions ff) Other info gg) Inactive ingredients (in alphabetical order) hh) Questions? (optional) followed by phone number 4. It is a drug liable to deterioration unless it is packaged or labeled accordingly 5. The container is made, formed, or filled as to be misleading 6. The drug is an exact imitation of another drug or offered for sale under the name of another drug 7. It is dangerous to health when used in the dosage or manner suggested in the labeling 8. It is packaged or labeled in violation of the Poison Prevention Packaging Act

The advertising of prescription drug prices (including by pharmacists) is considered reminder advertising under FDA regulations. However, such advertising is exempt from FDA advertising regulations provided that the following conditions are met:

1. The only purpose of the advertising is to provide information on price, not information of the drug's safety, efficacy, or indications for use 2. The advertising contains the proprietary name of the drug (if any), the generic name of the drug, the drug's strength, dosage form, and the price charged for a specific quantity of the drug 3. The advertising may include other information, such as the availability of professional or other types of services, as long as it is not misleading 4. The price stated in the advertising shall include all charges to the consumer; mailing and delivery fees, if any, may be stated separately

Exceptions to having a distribution license and passing transaction data are as follows:

1. When distriution is between two entities that are affiliated or under common ownership; 2. When dispenser is provding product to another dispenser on a patient=specific basis; 3. When dispenser is distributing under emergency medical reasons; 4. When dispenser is distributing "minimal quantities" to a licensed practitioner for office use

Compounding pharmacies that are not registered with the FDA as an "outsourcing facility" are often referred to as ___

503A facilities/pharmacies and may only compound products pursuant to an individual prescription or medication order; they are permitted to do limited anticipatory compounding, primarily regulated by the states, and subject to USP 797 quality standards for sterile compounding

Orange Book uses a 2-letter coding system to indicate equivalency with first letter being the key:

A = Drug products that the FDA considers to be pharmaceutically equivalent and therapeutically equivalent B = Drug products that the FDA considers NOT to be pharmaceutically equivalent and therapeutically equivalent

Risk Evaluation and Mitigation Strategies (REMS) are strategies to manage...

A known or potential serious risk associated with a drug, drug class, or biological product

A REMS can include...

A medication guide, Patient Package Insert, a communication plan, elements to assure safe use, and an implementation system

Transaction statement includes...

A paper or electronic statement by the seller that the seller is authorized (licensed), received the product from an authorized (licensed) person, received the transaction information and transaction history from the prior owner if required, did not knowingly ship a suspect or illegitimate product, has systems and processes to comply with verification requirements, and did not knowingly provide false transaction information

Transaction history includes...

A paper or electronic statement that includes prior transaction information for each prior transaction back to the manufacturer

The National Drug Code is...

A unique 10-character number that identifies a particular drug my MFG or packager (labeler), product, and package size

Orange Book: products with no known or suspected bioequivalence issues...

AA - conventional dosage forms AN - solutions and powders for aerosolization AO - injectable oil solutions AP - injectable aqueous solutions AT - topical products

Orange Book: products with actual or potential bioequivalence problems, but for which adequate scientific evidence has established bioequivalence for these products, are given a rating of...

AB

While nearly all drug products have an NDC number...

An NDC code does not indicate a drug is approved by the FDA FDA has proposed to standardize the NDC format and move to an 11-digit code, but that proposed change has not yet been adopted

To dispense isotretinoin, the pharmacists must obtain...

Authorization from iPLEDGE via internet/phone signifying the patient is registered, has received counseling and education, and is not pregnant

Prescription Drug Marketing Act of 1987 (PDMA)

Bans the reimportation of prescription drugs and insulin products produced in the US (except by the manufacturer); bans the sale, trade, or purchase of prescription drug samples; mandates the storage, handling, and recordkeeping requirements for prescription drug samples; prohibits, with exceptions, the resale of prescription drugs purchased by hospitals or healthcare facilities (intended to prevent diversion of drugs due to price differentials because hospitals generally receive lower prices for drugs than community pharmacies

Food, Drug, and Cosemetic Act of 1938

Because of the deaths caused by the sulfanilamide elixir in 1937, Congress passed the first legislation that required new drugs to be proven safe prior to marketing

Isotretinoin products are dispensed in...

Blister packages which cannot be broken, and a 30-day supply is the maximum quantity that can be dispensed -- NO REFILLS ALLOWED

The DSCSA applies to prescription drugs for human use in finished dosage form, but certain products are exempted, including...

Blood and blood components, radioactive drugs, imaging drugs, certain IV products for fluid replacement, dialysis solutions, medical gases, compounded drugs, medical convenience kits containing drugs, certain combination products, sterile water, and products for irrigation

FDA Drug and Device Recall Classifications

Class I: reasonable probability product will cause either serious adverse effects on health or death Class II: may cause temporary or medically reversible adverse effects on health or where probability of serious adverse effects is remote Class III: not likely to cause adverse health consequences

Durham-Humphrey Amendment of 1951

Created a distinction between OTC and prescription; authorized verbal prescriptions and prescription refills

The Federal Hazardous Substances Act of 1966 does not apply to...

Drugs regulated by the FDA but may apply to other products sold in a pharmacy such as bleach, cleaning fluids, antifreeze, etc.

The Food, Drug, and Cosmetic Act of 1938 also...

Established the FDA and is the primary law dealing with food, drug, cosmetic, and medical device safety

Outsourcing facilities that meet the Act's requirements are...

Exempt from the new drug provisions, adequate directions for use, and drug track and trace provisions

Prescription drug advertising is regulated by...

FDA

FDA requires REMS if...

FDA finds that it is necessary to ensure that the benefits of the drug, drug class, or biological product outweigh the risks of the product

If a product is illegitimate, pharmacies must notify...

FDA using Form FDA 3911 and notify trading partners within 24 hours. Pharmacies should also work with the MFG to prevent illegitimate products from reaching patients

503B facilities are primarily regulated by the ___ and are subject to ___

FDA; FDA's current Good Manufacturing Practices (cGMPs)

OTC drug advertising is regulated by...

FTC

A pharmacy that compounds products may advertise that it provides compounding services including that it compounds specific products. However...

If a pharmacy makes any therapeutic claims regarding those products, it would be subject to FDA's rules on advertising

The Drug Quality and Security Act (DQSA) of 2013 addressed which two primary topics?

Large-scale compounding by pharmacies and establishment of a framework for uniform track and trace system for prescription drugs through the supply chain

FDA Purple Book...

Lists biological products that are considered biosimilar and provides interchangeability evaluations for these products; only biological products that have been designated "interchangeable" may be substituted for original product in Texas

Drug Compounding Quality Act (DCQA) [part of the DQSA]

Maintains regulation of traditional compounding with states under Section 503A, but establishes Section 503B in the FDCA that allows facilities that are compounding sterile pharmaceuticals that are not based on patient-specific prescriptions to register with the FDA as an "Outsourcing Facility"

The DSCSA made effective on November 27, 2020, that pharmacies...

May only receive drugs with product identifiers. Pharmacies are not yet required to authenticate (scan) those product identifiers. Note: a product identifier is a stanardized graphic with 3 elements: the product's SNI, which comprises of the NDC plus a unique alphanumerical serial number, a lot number, and an expiration date

Failure to provide a PPI for these drugs would cause them to be...

Misbranded

MFG must obtain FDA approval before distribution of MedGuides and are responsible for ensuring that a sufficient number of MedGuides are provided to pharmacies. Many include MedGuides at the bottom of the PI, but...

Most pharmacy computer systems also print MedGuides for the products that need them at the time of dispensing

For hospitalized/institutionalized patients, a PPI...

Must be provided to a patient prior to the first administration of the drug and every 30 days thereafter

PPIs are required to be given to patients when prescriptions for certain products are dispensed. Currently required for...

Oral contraceptives and estrogen-containing products

FDA maintains a searchable MedGuide database on its website, and there are...

Over 1000 products that now require a MedGuide

NDC: last 1 to 2 digits are...

Package size

Under DSCSA, manufacturers are required to...

Provide "Transaction Data" for each product sold, and pharmacies are required to receive transaction data and pass this information along if they further distribute the product

The Drug Supply Chain Security Act (DSCSA) (Track and Trace)...

Provides for a uniform national framework for an electronic track and trace system for prescription drugs as they move through the supply chain and sets national standards for states to license drug wholesaler distributors

Exemptions to PPA include...

Request of patient or physician Bulk containers not intended for household use Drugs distributed to institutionalized patients Specific Rx and non-Rx drug exemptions: oral contraceptive, conjugated estrogens, and norethindrone acetate in MFG's dispenser package; medroxyprogesterone acetate tabs; SL NTG and Sl and chewable isosorbide dinitrate of 10 mg or less; ASA and APAP in effervescent tabs or granules; potassium supplements in unit-dose packaging; sodium fluoride containing no more than 264 mg of sodium fluoride per package; anhydrous cholestyramine and colestipol packets; erythromycin ethylsuccinate granules for oral suspension and oral suspensions in packages containing no more than 8 g erythromycin; erythromycin ethylsuccinate tabs in packages containing no more than 16 g erythromycin; Prednisone tablets containing no more than 105 mg per package Methylprednisolone tablets containing no more than 84 mg per package Mebendazole tablets containing no more than 600 mg per package Betamethasone tablets containing no more than 12.6 mg per package Preparations in aerosol containers intended for inhalation Pancrelipase preparations Sucrose preparations in a solution of glycerol and water Hormone replacement therapy products that rely solely upon the activity of one or more progesterone or estrogen substances

Kefauver-Harris Amendment of 1962

Required new drugs to be proven safe and effective for their claimed use; increased safety requirements for drugs and established Good Manufacturing Practices (GMPs) for manufacturing of drugs; gave FDA jurisdiction over prescription drug advertising

Poison Prevention Packaging Act of 1970 (PPPA)

Requires use of child-resistant containers for prescription and the following nonprescription drugs: ASA methyl salicylate (oil of wintergreen)-- liquid preparations containing more than 5% by weight of methyl salicylate unless packaged in pressurized spray containers methyl alcohol (methanol)-- containing more than 4% or more by weight unless packaged in a pressurized spray container, iron-containing drugs (exception- animal feeds used as vehicles for the admin of drugs noninjectable animal and human drugs providing iron for therapeutic or prophylactic purposes, which contain a total amount of elemental iron equivalent to 250 mg dietary supplements containing iron (250 mg elemental iron or more) APAP (more than 1 g APAP in a single package); exemptions: APAP-containing effervescent tabs or granules containing less than 10% APAP with a median lethal dose greater than 5 g/kg of body weight and that release of at least 85 mL carbon dioxide per grain of APAP when placed in water; unflavored APAP-containing preparations in powder form, other than those intended for pediatric use, that are packaged in unit doses with no more than 13 grains of APAP per unit dose and that contain no other substance subject to the special packaging requirements Diphenhydramine HCl -- preparations for human use in oral dosage forms containing more than the equivalent of 66 mg of diphenhydramine base in a single package Ibuprofen -- preparations for human use in oral dosage forms containing more than 1 gram or more of ibuprofen in a single package Loperamide -- preparations for human use in oral dosage forms containing more than 0.045 mg of loperamide in a single package Lidocaine -- products containing more than 5 mg lidocaine in a single package (all dosage forms) Dibucaine -- products containing more than 0.5 mg dibucaine in a single package (all dosage forms) Naproxen -- containing 250 mg or more of naproxen in a single package Ketoprofen -- containing more than 50 mg ketoprofen in a single package Fluoride -- more than 50 mg elemental fluoride and more than 0.5% fluoride in a single package Minoxidil -- more than 14 mg minoxidil in a single package (includes topical products) Imidazolines -- packages containing 0.08 mg or more in a single package (includes tetrahydrozoline, naphazoline, oxymetazoline, xylometazoline) Any drug switched from Rx to OTC status

Medication Guides (MedGuides)

Similar to PPI but without requirements for institutionalized patients

NDC: next 3 to 4 digits are...

Specific drug, strength, and dosage form

Patient Package Inserts (PPIs) are...

Supplied by the MFG and written for a layperson

The DSCSA states that pharmacies must investigate and properly handle...

Suspect and illegitimate products. Suspect products are products that one has reason to believe are potentially counterfeit, diverted, stolen, subject of a fraudulent transaction, intentionally adulterated, or appear otherwise unfit for distribution such that they would result in serious adverse health consequences or death to humans;

The Federal Hazardous Substances Act of 1966 is administered by...

The Consumer Product Safety Commission; they enforce this act which is intended to protect consumers from hazardous and toxic substances

The Federal Hazardous Substances Act of 1966 requires...

The label on the immediate package of a hazardous product and any outer wrapping or container that might cover up the label on the package to have the following information in English: 1. The name and business address of the MFG, packer, distributor, or seller; 2. The common or usual or chemical name of each hazardous ingredient; 3. The signal word "Danger" for products that are corrosive, extremely flammable, or highly toxic; 4. The signal word "Caution" or "Warning" for all other hazardous products 5. An affirmative statement of the principal hazard or hazards that the product presents (e.g., "Flammable," "Harmful if Swallowed," "Causes burns," "Vapor Harmful," etc.) 6. Precautionary statements telling users what they must do or what action they must avoid to protect themselves 7. Where it is appropriate, instructions for first aid treatment if the product injures someone 8. The word "Poison" for a product that is highly toxic, in addition to the signal word "Danger" 9. If a product requires special care in handling or storage, instructions for consumers to follow to protect themselves 10. The statement "Keep out of reach of children." If a hazardous product such as a plant does not have package, it still must have a hang tag that contains the required precautionary information

NDC: first 4 to 5 digits are...

The labeler code

Transaction information includes...

The product's name, strength, and dosage form, NDC number, container size and number of containers, date of transaction, and name and address of the person from whom ownership is being transferred and to whom ownership is being transferred. A unique product identifier or serialized numerical identifier (SNI) will also be required that identifies an individual bottle or unit of sale

NDC numbers are required for a drug MFG to list its product with FDA. Although FDA suggests NDC numbers be included on the drug's label...

They are technically not required. However, nearly all drug MFG include NDC numbers because they facilitate automated processing of drug data by government agencies, third-part payers, wholesalers, and MFG

"Transaction Data" includes...

Transaction information; transaction history; transaction statement

Pharmacies must investigate any suspect or illegitimate product. As part of the investigation, a pharmacy must...

Verify the product identifier of at least 3 products or 10% of the suspect product, whichever is greater, or all of the packages if fewer than 3. Pharmacies must also verify any illegitimate product in response to a notification of illegitimate product from FDA or a trading partner (this requirement was scheduled to go into effect on November 23, 2020 but has been delated until November 23, 2023)

Pharmacies that are "distributing" must have a...

Wholesale distribution license and must pass DSCSA transaction data with that distribution

Outsourcing facilities, aka 503B facilities, are permitted to compound sterile products...

Without receiving patient-specific prescriptions or medication orders

MedGuides must be...

Written in a standard format and in language suitable for patients