Chapter 1.13-27.edited.docx

Ill. Other Provisions or the FDCA and Federal Regulations Special Warning Requirements for OTC Products in the FDCA STUDY TIP: These are special labeling requirements under federal regulations for products containing the following ingredients or for specific drug categories. Normally, the manuf...

Ill. Other Provisions or the FDCA and Federal Regulations Special Warning Requirements for OTC Products in the FDCA STUDY TIP: These are special labeling requirements under federal regulations for products containing the following ingredients or for specific drug categories. Normally, the manufacturer's label would include these warnings, but you should be familiar with these requirements. 42 Copyright O 2023 Gary Cacciatore FD&C Yellow No. 5 (tartrazine) and No. 6 (21 CFR 201.20)— Must disclose the presence and provide a warning in the “precautions” section of the label that the drug may cause an allergic reaction in cer tain susceptible persons. z. Aspartame (21 CFR 201.21)—Must contain a warning in the "pre cautions” section of labeling to the following effect: Phenyl-ketonuria: Contains phenylalanine mg per (dosage unit). Sulfites (21 CFR 201.22)—Prescription drugs containing sulfites (often used as a preservative) must contain an allergy warning in the “warnings” section of the labeling. Mineral Oil (21 CFR 201.302)—Requires warning to only be taken at bedtime and not be used in infants unless under the advice of a physician. The label also cannot encourage use during pregnancy. Wintergreen Oil (methyl salicylate) (21 CFR 201.303 and 201.314(g)(1))—Any drug containing more than 5% methyl salicylate (often used as a flavoring agent) must include a warning that use other than directed may be dangerous and that article should be kept out of reach of children. Sodium Phosphates (21 CFR 201.307)—Limits the amount of sodium phosphates in oral solution to no more than 90 ml per OTC container. Also requires specific warnings. Isoproterenol Inhalation Preparations (21 CFR 201.305)— Requires warning not to exceed the dose prescribed and to contact physician if difficulty in breathing persists. Potassium Salt Preparations for Oral Ingestions (21 CFR 201.306)—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. Ipecac Syrup (21 CFR 201.308) The following statement (boxed and in red letters) must appear: “For emergency use to cause vomiting in poisoning. Before using, call the physician, the poison prevention center, or the hospital emergency room immediately for advice.” The following warning must appear: “Warning: Keep out of reach of children. Do not use in unconscious persons.” 43 Copyright O 2023 Gary Cacciatore The dosage of the medication must appear. The usual dosage is 1 tablespoon (15 ml) in individuals over one year of age. It may only be sold in 1 oz. (30 ml) containers. Phenacetin (acetophenetidin) (21 CFR 201.309)—Must contain a warning about possible kidney damage when taken in large amounts or for a long period of time. Salicylates (21 CFR 201.314)—Aspirin and other salicylate drugs must have special warnings for use in children, including a warning regarding Reye's syndrome. Retail containers of1'Z‹ grain (pediatric) aspirin cannot be sold in containers holding more than 36 tablets. OTC Drugs for Minor Sore Throats (21 CFR 201.315)—Any OTC product that states “For the temporary relief of minor sore throats” must include this warning: “Warning—Severe or persistent sore throat or sore throat accompanied by high fever, headache, nausea, and vomit- ing may be serious. Consult a physician promptly. Do not use more than 2 days or administer to children under 3 years of age unless directed by a physician." ]3. Alcohol Warning (21 CFR 201.322)—Internal analgesics and antipyretics, including acetaminophen, aspirin, 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. ]4. Over-the-Counter Drugs for Vaginal Contraceptive and Spermicide Use Containing Nonoxynol 9 as the Active Ingredient (21 CFR 301.325)—These are subject to several 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.” OTC Pain Relievers (21 CFR 301.326) Acetaminophen. Must have “acetaminophen.” prominently displayed. Must warn about liver toxicity. Must warn not to use with other products containing acetaminophen and to talk to a doctor or pharmacist before taking with warfarin. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). Must include the term “NSAID” prominently on the label. Must contain “stomach bleeding” warning. 44 Copyright B 2023 Gary Cacciatore J6. OTC Products Containing Iron in Solid Oral Dosage Form (21 CFR 310.518(a)) 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 accidental overdose, call a doctor or poison control center immediately.” This warning requirement also applies to dietary supplements containing iron, as indicated in 21 CFR 101.17(e). Additional OTC Requirements Tamper-Evident Packaging Manufacturers and packagers of OTC drugs for sale at retail must package OTC products in a tamper-evident packaging. Certain products are exempted, including dermatologi- cals, dentifrices (e.g., toothpaste), insulins, and lozenges. OTC products not packaged in tamper-evident packaging would be considered adulterated and misbranded. 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 manufacturer labeling and tamper-evident packaging, if offered for sale to the public. STUDY TIP: If a patient wishes to purchase an OTC drug in a smaller package size than what is commercially available, a pharmacist cannot break open a commercialOTC product and sell the lesser quantity by placing it in a vial and labeling it. The only way this can be done is if the patient has a prescription for the smaller quantity and the OTC drug is filled as a prescription, as discussed below. 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 drug is filled as a prescription, any instructions for refills would apply, as would beyond-use dates (valid for one year). FDA Drug and Device Recall Classifications L Class I—Reasonable probability that the product will cause either serious adverse effects on health or death. 45 Copyright O 2023 Gary Cacciatore Class II—May cause temporary or medically reversible adverse effects on health or where the probability of serious adverse effects is remote. Class III—Not likely to cause adverse health consequences. Advertising and Promotion of Prescription Drugs Prescription drug advertising is regulated by the FDA. Over-the-counter (OTC) drug advertising is regulated by the Federal Trade Commission (FTC). Advertising of Prescription Drug Prices (including by pharmacists)—The advertising of prescription drug prices is considered reminder advertising under FDA regulations (21 CFR 200.200). However, such advertising is exempt from FDA advertising regulations provided that the following conditions are met: The only purpose of the advertising is to provide information on price, not information on the drug's safety, efficacy, or indications for use. The advertising contains the proprietary name of the drug (if any), the generic name of the drug, the drug's strength, the dosage form, and the price charged for a specific quantity of the drug. The advertising may include other information, such as the availability of professional or other types of services, as long as it is not misleading. The price stated in the advertising shall include all charges to the consumer; mailing and delivery fees, if any, may be stated separately. 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 the FDA's rules on advertising, which are complex and beyond the scope of this book. Patient Package Inserts (PPIs) Supplied by the manufacturer and written for a layperson. Required to be given to patients in the community setting when new and refill prescriptions for certain products are dispensed. Currently required for: Oral contraceptives (21 CFR 310.501). Estrogen-containing products (21 CFR 310.515). — 46 - Copyright B 2023 Gary Cacciatore Hospitalized or Institutionalized Patients—A PPI must be provided to a patient prior to the first administration of the drug and every 30 days thereafter. STUDY TIP: This may not happen in practice, but you need to know it is legally required. Failure to provide a PPI for these drugs would cause them to be misbranded. Medication Guides (MedGuides) J. Similar to the PPI program but with amended requirements for institutionalized patients. FDA requires Medication Guides for all new and refill prescriptions dispensed in the community setting when: Patient labeling could prevent serious adverse effects. Product has serious risks relative to benefits. Patient adherence to directions is crucial. Medication Guides must be written in a standard format and in language suitable for patients. Manufacturers must obtain FDA approval before distributing Medication Guides and are responsible for ensuring that a sufficient number of Medication Guides are provided to pharmacies. Many manufacturers include the Medication Guide at the bottom of the package insert, but most pharmacy computer 5ystems also print Medication Guides for the products that need them at the time of dispensing. FDA maintains a searchable Medication Guide database on its website, and there are hundreds of products that now require a Medication Guide. Some of the drugs, drug classes, and biologicals requiring Medication Guides include: Accutane‘ (isotretinoin) Antidepressants in children and teenagers Coumadin (warfarin sodium) Epogen‘ (epoetin alfa) Forteo‘ (teriparatide, rDNA origin) Lindane shampoo and lotion Lotronex‘ (alosetron hydrochloride) Nolvadex‘ (tamoxifen) Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Remicade‘ (infliximab) Trizivar‘ (abacavir sulfate, lamivudine, and zidovudine) 47 Copyright B 2023 Gary Cacciatore Opioid analgesics and cough products m. Benzodiazepines Failure to provide a Medication Guide when dispensing a drug that requires one would cause the drug to be misbranded. STUDY TIP: Consumer Medication Information (CMI), which is often provided to community pharmacy patients for all new and refill prescriptions dispensed, is written patient information that is not equivalent to or substitutable for FDA-regulated and mandated PPls and MedGuides. Prescription Drugs: Side Effects Statement To enable consumers to report the side effects of prescription drugs to the FDA, pharmacies and pharmacists are required to distribute a side effects statement to patients when dispensing all new and refill prescriptions in the outpatient setting. The side effects statement provided with each prescription drug must read, “Call your doctor for medical advice about side effects. You may report side effects to the FDA at I-800-FDA-1088.” The side effects statement can be distributed on a sticker attached to the pharmacy container, on a preprinted pharmacy prescription vial cap, on a separate sheet of paper, or found within CMI or MedGuides. Risk Evaluation and Mitigation Strategies (REMS) REMS are strategies to manage a known or potentially serious risk associated with a drug, drug class, or biological product. FDA requires a REMS if it finds that it is necessary to ensure that the benefits of the drug, drug class, or biological product outweigh the risks of the product. A REMS can include a Medication Guide, a Patient Package Insert, a communication plan, elements to ensure safe use, and an imple mentation system. It must also include a timetable for the assessment of the REMS. Elements to as5ure safe u5e may include: Special training, experience, or certification of healthcare practitioners prescribing the drugs; Special certification for pharmacies, practitioners, or healthcare settings that dispense the drug; Dispensing drugs to patients only in certain healthcare settings such as hospitals; 48 — Copyright O 2023 Gary Cacciatore Dispensing drugs to patients with evidence or other documentation of safe use conditions such as laboratory test results; Monitoring patients using the drug; or Enrolling each patient using the drug in a registry. s. A complete list of products with approved REMS can be found on the FDA's website and may include an entire drug class, such as the Opioid Analgesic REMS. Note: In 2022, the FDA sought public comments on modifying the REMS for opioid analgesics to require that mail-back envelopes be dispensed and education on safe disposal be provided with opioid analgesics dispensed in an outpatient setting. This was not finalized at the time of publication of this book but could become a requirement if implemented. Example of a REMS—Isotretinoin (Accutane) iPLEDGE Program. Only doctors registered in iPLEDISE can prescribe isotretinoin. Doctors registered with iPLEDGE must agree to assume the responsibility for pregnancy counseling of female patients of childbearing potential. Prescribers must obtain and enter into the iPLEDGE system negative test results for those female patients of childbearing potential prior to prescribing isotretinoin. Only patients registered in iPLEDGE can be prescribed isotretinoin. In addition to registering with iPLEDGE, patients must comply with a number of key requirements that include completing an informed consent form, obtaining counseling about the risks and requirements for the safe use of the drug, and, for women of childbearing potential, complying with required pregnancy testing and use of contraception. Only pharmacies registered in iPLEDGE can dispense isotretinoin. To register in iPLEDGE, a pharmacy must select a Responsible Site Pharmacist who must obtain iPLEDGE program information and registration materials via the internet pwww.ipledgeprogram.com) or telephone (1-866-495-0654) and sign and return the completed registration form. To activate registration, the Responsible Site Pharmacist must access the iPLEDGE program via the internet (www.ipledgeprogram.com) or 49 Copyright 0 2023 Gary Cacciatore telephone (1-866-495-0654) and attest to the following points: I know the risk and severity of fetal injury/birth defects from isotretinoin. I will train all pharmacists on the iPLEDGE program requirements. I will comply and seek to ensure that all pharmacists comply with iPLEDGE program requirements. f4) I will obtain isotretinoin from iPLEDGE-registered wholesalers. I will return to the manufacturer (or delegate) any unused product. I will not fil1 isotretinoin for any party other than a qualified patient. To dispense isotretinoin, pharmacists must obtain authorization from iPLEDGE via the internet (www .ipledgeprogram.com) or telephone (1-866-495-0654), signifying the patient is registered, has received counseling and education, and is not pregnant. Product is dispensed in blister packages, which cannot be broken, and a 30-day supply is the maximum quantity that can be dispensed. No refills are allowed. Example REMS—Thalomid (Thalidomide) REMS Prescriber Requirements The prescriber enrolls and becomes certified with Celgene for the Thalomid REMS program. The prescriber counsels the patient on the benefits and risks of thalidomide. The prescriber provides contraception and emergency contraception counseling. The prescriber verifies negative pregnancy tests for all female patients of reproductive potential. The prescriber completes a Thalomid Patient-Physician Agreement Form with each patient and sends it to Celgene. The prescriber/patient completes applicable manda- tory confidential survey. The prescriber obtains an authorization number from Celgene and writes it on every prescription along with the patient risk category. 50 Copyright 0 2023 Gary Cacciatore The prescriber writes no more than a 4-week (28-day) supply, with no automatic refills or telephone prescriptions. The prescriber sends a Thalomid prescription to the certified pharmacy. Pharmacy Requirements The pharmacy must be certified in the Thalomid REMs program with Celgene. Prescriptions can only be accepted with an authorization number and patient risk category. Authorization numbers are valid for 7 days from the date of the last pregnancy test for females of reproductive potential and 30 days from the date issued for other patients. The pharmacy must obtain a confirmation number prior to dispensing via a toll-free number or online. The confirmation number is valid for 24 hours and must be entered on the prescription. This means the prescription must be dispensed within 24 hours of obtaining the confirmation number. No automatic refills or telephone prescriptions are permitted. Prescription must be written for a 4-week (28-day) supply or less. No refills are allowed, and subsequent prescriptions may be dispensed only if there are 7 days or less remaining on the existing prescription. A certified Thalomid REMS counselor must counsel the patient, and counseling must be documented. I9) prescription must be dispensed with a medication guide. (10JPrescriptions cannot be transferred to another pharmacy without prior authorization from Celgene. National Drug Code (NDC) Number A unique 10-character number that identifies a particular drug by manufacturer or packager (labeler), product, and package size. NDC numbers will have one of the following configurations: 4-4-2, 5-3-2, or 5-4-1. First 4 to 5 digits = labeler code. Next3 to 4 digits = specific drug, strength, and dosage form. Last 1 to 2 digits = package size. 51 CopyBright 2023 Gary Cacciatore 2» NDC numbers are required for a drug manufacturer to list its product with the FDA. Although the FDA suggests NDC numbers be included on the drug's label, they are not technically required. Nearly all drug manufacturers include NDC numbers because they facilitate automated processing of drug data by government agencies, third-party payers, and wholesal e manufacturers. STUDY TIPi NDC numbers should not appear on non-drug products. If a dietary supplement or medical device has an NDC number on its label, it would be misbranded. Medical devices have unique device identifiers (UDls) instead of NDC numbers. Any product that implies it is an FDA-approved drug when it is not would also be misbranded. While nearly all drug products have an NDC number, an NDC code does not indicate a drug is approved by FDA. Although the NDC is 10 digits, the standard for billing and claims submissions is an 11-digit NDC. This is accomplished by inserting a leading zero into one of the segments: first segment if it is four numbers, second segment if it is three numbers, or added to the beginning of the third segment if it only has one number. On July 25, 2022, the FDA published a proposed rule to change the NDC to 12 digits in length with three distinct and consistent segments and one uniform format. This rule is only proposed, and even when finalized, there will be a transition period before it is fully implemented. FDA Orange Book The official name is Approved Drug Products with Therapeutic Equivalence Evaluations. Available on the FDA's website. The primary source for determining the generic equivalency of drugs. To be considered generically equivalent, a drug must be both pharmaceutically equivalent and therapeutically equivalent to the reference drug product (normally the brand-name drug). Definitions: “Pharmaceutical equivalents” are drug products in identical dosage forms and route(s) of administration that contain identical amounts of the identical active drug ingredient. 52 Copyright O 2023 Gary Cacciatore “Therapeutic equivalents” are approved drug products that are pharmaceutical equivalents for which bioequivalence has been demonstrated, and they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling. Note: This means the drug is bioequivalent to the refer- ence drug product. Uses a 2-letter coding system to indicate equivalency, with the 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. STUDY TIP: The first letter of the 2-letter code tells you if the product is considered equivalent. It is recommended that the reader look up an Orange Book listing in the FDA Orange Book database online and be familiar with its format. 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. Products with actual or potential bioequivalence problems but for which adequate scientific evidence has established bioequivalence for those products are given a rating of AB. There are situations where there may be multiple pharmaceutically equivalent reference drugs that have not been determined to be bioequivalent to each other. For these products, the FDA implemented a three-character code such as AB1, AB2, and AB3. If a generic drug product establishes bioequivalence to one of the reference drugs, it will receive the same three-character code as the reference drug. An example includes Adalat CC (ABI) and Procardia XL (AB2), which are both reference drugs with the same dosage form and active ingredients, but they are not rated as bioequivalent to one another. 53 Copyright G› 2023 Gary Cacciatore FDA Purple Book The official name is LiStS OfLicensed Biological Product5 with Reference Product Lxclusivit y and Biosimilarit y or Inter- changeabilit y Evaluations. z. Lists biological products that are considered biosimilars and provides interchangeability evaluations for these products. Biosimilar or biosimilarity means that the biological product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product. An interchangeable product is a product that has been shown to be biosimilar to the reference product and can be expected to produce the same clinical result as the reference product in any given patient. Only biological products that have been designated "interchangeable” may be substituted for the original reference product by a pharmacist in Texas. Biosimilar products would require prescriber intervention in order to substitute. Note: While there are several biosimilar products on the market (e.g., adalimumab, bevacizumab, and epoetin alfa), IDA has only designated a few of them as interchangeable. The first interchangeable biological was approved by the FDA in July 2021 when Semglee (insulin glargine-yfgn) was designated by TDA as interchangeable with (and can b8 SH 5tltuted at the pharmacy level for) its reference product, Lantus‘ {insulin glargine). Medical Devices The FDA regulates companies that manufacture and repackage medical devices. A medical device includes instruments, apparatuses, machines, implants, or other related articles intended to treat or prevent disease but, unlike drugs, does not achieve its primary purpose through chemical action within or on the body and does not depend on being metabolized. The FDA classifies medical devices based on the risk associated with the device. 54 Copyright 8 2023 Gary Cacciatore Class I devices are deemed to be low risk and are, therefore, subject to the least regulatory controls. Dental floss is an example. Class II devices are at higher risk and require greater regulatory controls. Syringes are an example. Class III devices are generally the highest-risk devices and are subject to the highest level of regulatory control, and those that pose a significant risk of illness or injury require premarket approval by the FDA. Replacement heart valves are an example. Not all medical devices require a prescription, but many do (e.g., contact lenses). S. Certain Class I and Class II devices are exempt from premarket approval and GMPs but typically must still comply with other regulatory requirements unless they are exempt. Animal Drugs I. The FDA regulates drugs intended to be used by animals. Animal drugs have to be approved by the FDA as safe and effective. The FDA determines if an animal drug must be sold as a prescription or OTC drug. Animal prescription products can be dispensed only by or upon the lawful written order of a licensed veterinarian. The manufacturer's label of an animal prescription drug product must bear the legend “Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian.” Veterinarians can legally prescribe approved human drugs for animals in certain circumstances (this is called extra-label or off-label use). Therefore, pharmacies and pharmacists may receive and dispense such prescriptions. The FDA has released guidance regarding the compounding of animal drugs, which allows pharmacies to compound animal drugs under specific circumstances. Emergency Contraception (Plan B) When single-pill levonorgestrel (Plan B One-Step) was first made available without a prescription, it had age restrictions. It was initially only available without a prescription for women aged 17 and older. There was also confusion, political controversy, and lawsuits surrounding the age limitations for Plan B One-Step that are beyond the scope of this book. — — ss Copyright 0 2023 Gary Cacciatore Since 2013, Plan B One-Step and similar generic versions of single-dose levonorgestrel have been available without a prescription to anyone of any age. These products are often still kept behind the counter. Next Choice, the two-pill emergency contraceptive option, does have an age restriction. It is available behind the counter without a prescription for women 17 and older. Women under 17 still need a prescription. No states currently restrict the sale of Plan B, but given the overturning of Roe v. Wade in Dohfis vs. Jackson Women's Health Organization, new legislation may be introduced to do so in some states, and there may be legislation to strengthen or expand access in other states. 56 Copyright 0 2023 Gary Cacciatore Scanned with CamScanner