Compounded Medications

Prescriber Considerations

What are the concerns with compounded formulations?

• Compounded drugs pose a higher risk to patients than FDA-approved drugs because they do not undergo FDA premarket review for safety, effectiveness, or quality (US Food and Drug Administration, 2023).
• Liability risks are associated with adverse outcomes from drugs that are not FDA-approved. Therefore, it is prudent from medical and legal perspectives for prescribers to employ FDA-approved products for patients whenever possible. If commercially available products are inadequate, compounding could be an effective alternative, provided that the prescriber fully understands the legal and regulatory ramifications of such practices (Kircik L, 2023). If non-FDA treatments are needed to provide optimal care to a patient, there are risk mitigation strategies a prescriber can consider to ensure patients receive safe and effective care.
• The FDA cautions, not all products sold as “semaglutide” contain an identical active ingredient as the FDA-approved semaglutide and may include salt formations that have not been demonstrated to be safe or effective (US Food and Drug Administration, 2024). In some patients, the salt formations may be contraindicated to underlying diagnoses.
• The most recent alert from the FDA elucidated that patient overdosing of semaglutide is the primary contributing factor to complications associated with compounded formulations of the medication. According to their analysis of adverse event reports, dosing errors – often resulting in significant overdoses – have emerged as the most prevalent issue among patients using compounded semaglutide products (US Food and Drug Administration, 2024).

The FDA outlines when compounded medications are appropriate:

• During drug shortages when the drug is listed on the FDA Drug Shortages List (US Food and Drug Administration, 2023).
• To fulfill the needs of patients whose medical needs cannot be met by an FDA-approved drug (US Food and Drug Administration, 2023).

The FDA established two distinct categories of compounding pharmacies to regulate drug compounding practices, 503A and 503B. 503A pharmacies, also known as traditional compounding pharmacies, prepare patient-specific medications based on individual prescriptions (US Food and Drug Administration, 2022). 503B pharmacies, or outsourcing facilities, can produce larger batches of compounded medications without specific prescriptions for office use or healthcare facilities. Both must comply with USP <795> and <797> in addition to state pharmacy regulations. 503B pharmacies must also comply with Title 21 Code of Federal Regulations Part 210 and 211 (Current Good Manufacturing Processes) in addition to several other regulations and guidelines.

What can prescribers do?

Discuss, document, and obtain informed consent

If a prescriber identifies that a patient might benefit from a medical formulation that is not available commercially, they should thoroughly discuss the potential risks and benefits with the patient, document the reasons for choosing the compounded formulation over existing commercial products, and obtain the patient's informed consent (Kircik L, 2023). Patients should be made aware of the differences between the FDA-approved and nonapproved versions of medications (for example, compounded GLP-1 agonists versus commercially prepared, compounded hormone therapies, pellets versus commercially prepared). While standard risks comparable to those associated with FDA-approved therapies may be covered during an informed consent conversation, therapies with higher-than-normal risks or those requiring a more thorough informed consent process might necessitate a signed consent form after the discussion. Discussions during the informed consent process should acknowledge that results and outcomes may vary, and although thorough patient workups are indicators that the patient will have a favorable outcome from the therapy, there is no guarantee an adverse outcome may not result from the treatment.

Select patients appropriately and implement protocols for ongoing patient monitoring

For example, for patients with both obesity and cardiovascular disease, a compounded version of semaglutide might offer cardiovascular benefits that outweigh the risks of other FDA-approved antiobesity drugs or not using any treatment at all (Einav, 2024). Patient selection should rely on qualitative and quantitative clinical data that follow established criteria or practice protocols for prescribing as well as serve as a baseline for ongoing evaluation. Evaluation of medical history, comorbidities, and current medications, in addition to necessary diagnostic values, assist in providing evidence-based care, avoidant of contraindications, potential drug interactions, or other clinical indications the treatment may harm the patient.

Protocols detailing the plan of care to continuously monitor the patient's response to the medication and adjust the treatment plans are necessary for patient safety (Einav, 2024). Systematically assess the patient's response to the medication and modify the treatment plan as needed, ensuring consistent follow-up appointments to assess for efficacy and manage any adverse reactions to treatment (Einav, 2024). Maintaining regular follow-ups, diagnostics, and appointments should be a term and expectation of treatment, detailed in the conditions to treat agreed upon at the onset of therapy.

Write the prescription correctly

A critical safety mechanism in the prescribing process of semaglutide is the utilization of prefilled autoinjector devices, which effectively mitigate the risks associated with dosage conversion errors and patient related dosing errors from the utilization of multi-dose vials of medications. However, this robust safeguard is absent when prescribing compounded formulations. The FDA has identified incorrect dose calculations and unit conversions between milliliters, milligrams, and units as the predominant prescriber errors leading to semaglutide overdoses (US Food and Drug Administration, 2024). The FDA further cautions prescribers and dispensers to provide clear instructions as many patients are unfamiliar with self-injection, withdrawing and administering medications from a multi-dose vial, and experience confusion among the various units of measure (US Food and Drug Administration, 2024). Adherence to guidelines and recommendations from the Institute for Safe Medication Practices and application of human factors principles are of paramount importance to ensure patient safety and minimize risk of medication errors.

• Specify the exact formulation, avoiding generic names (US Pharmacopeial Convention, 2023)
• Indicate the absence of additives (US Pharmacopeial Convention, 2023)
• Include specific instructions for preparations (US Pharmacopeial Convention, 2023)
• Prescribe the correct quantity
• Provide precise and clear directions for use that align with the specific compounded preparation (US Food and Drug Administration, 2024)

Prescribing, Administering, Procuring, and Dispensing for Advance Practice Providers

States vary vastly in their specific practice acts as to who may prescribe, administer, dispense, and procure medications. Validate the scope of practice of your licensure in each jurisdiction in which you are licensed to determine any limitations. The following definitions are generalizations and should be validated in each state as defined in statute.

Prescribing: The authority to write prescriptions for medications that are sent to a professional pharmacy to be filled. May be independent or subject to oversight by a collaborating/supervising physician.

Administering: The direct application of a medication or treatment to a patient. In some states, Advance Practice Providers may be limited regarding the prescription of scheduled medications. In the case of hormone pellets, the provider may require an order from an authorized prescriber for testosterone pellets; however, they may be able to administer them, depending on that state’s practice laws.

Dispensing: The provision of prescribed medications to patients for future doses. Some states only allow dispensing of professionally prepared pharmaceutical samples only for medications already prescribed to a patient. Some states do not allow dispensing in any form. Dispensing is hotly debated between states. The advance practice provider should know with certainty if dispensing is allowed in their practices acts prior to dispensing a medication to a patient for future dosing.

Procuring: The ability to obtain medications or substances necessary for patient care. Some states require a doctor of medicine, osteopathic medicine, or pharmacy to procure medications for utilization in a practice setting.

Procuring and dispensing medications within a practice introduces additional risk exposures for the provider. This process implies liability, as it suggests that the provider endorses the method of preparation and formulation of the medication. Furthermore, it establishes a duty for the provider to ensure proper administration of the medication to the patient. By prescribing the medication to a pharmacy, the provider shifts this liability to the third-party preparer and dispenser of the medication.

Adopt specialty-specific professional organization best practices

Certification through your credentialing body can provide you with the best practices for prescribing compounded medications at your level of licensure specific to the population you serve.

Accreditations are available for compounding pharmacies, providing a comprehensive assessment of a pharmacy's quality and safety standards, including the Pharmacy Compounding Accreditation Board (PCAB). PCAB accreditation aligns with USP compliance for sterile and non-sterile preparations. However, this designation does not imply the pharmacies are classified as FDA 503A or 503B entities.

A Compounding Prescriber’s Checklist for Success

• Evaluate necessity, first considering FDA-approved options for treatment. Assess if the patient’s medical needs justify the use of a compounded drug.
• Understand legal and regulatory requirements and the implications of prescribing compounded medications. Familiarize yourself with 503A and 503B designations and relevant standards USP <795>, <797>, and CGMP for 503B pharmacies.
• Consider risks associated with compounding drugs and implement risk mitigation strategies to prioritize patient safety and prevent dosing errors.
• Evaluate the patient’s complete medical history, comorbidities, and current medications to avoid contraindications and interactions.
• Obtain informed consent ensuring to include:
  • Risks and benefits of compounded medications
  • Potential alternatives for the medication
  • Potential adverse outcomes or failure of treatment regimen
  • Differences between FDA-approved and compounded drugs
• Document rational for utilization of compounded medications over FDA-approved products and the conversation of informed consent with the patient regarding this plan of care.
• Prescribe medications detailing the exact formulation, indicating the absence of additives and providing clear instructions for preparation and use.
• Provide patient education on administration techniques, detailing the process for multi-dose vials, injection practices, infection prevention measures, and identification of adverse reactions including when to follow up with a provider or emergency care.
• Adhere to a protocol for follow up assessments, diagnostics, and response to the medication.
• Consult professional guidance from professional organizations for prescribing.
• Ensure your practice aligns with your personal scope of practice, licensure, and state and federal regulations.

A Guide to the Informed Consent Process for Compounded Medications

OmniSure Consulting recommends that a legal counselor review all patient consent forms.

Explanation of Compounded Medications: Compounded medications are custom-prepared formulations that are not reviewed by the FDA for safety, effectiveness, or quality. They are used when commercially available drugs are not suitable for a patient's specific needs.

Potential Risks and Benefits:

• Benefits:
• Customization to meet individual patient needs.
• Availability during drug shortages or when FDA-approved options are not suitable.
• Risks:
  • List all possible adverse reactions or outcomes up to and leading to death specific to the regimen prescribed.
  • _____________________________________________________________________________________
• Lack of FDA premarket review.
• Potential for dosing errors or quality issues.
• Possible adverse reactions or interactions with other medications.

Patient Acknowledgment: I acknowledge that my healthcare provider has discussed the following with me:

1. The reasons for recommending a compounded medication over an FDA-approved product.
2. The potential risks and benefits associated with the compounded medication.
3. The results of my response to these therapies may vary. There is no guarantee I will experience the desired outcomes of this treatment.
4. The differences between FDA-approved and compounded medications.
5. The plan for monitoring and follow-up to assess the medication's effectiveness and manage any adverse reactions.

I understand that while compounded medications can offer benefits, they also carry risks that may not be present with FDA-approved drugs. I have had the opportunity to ask questions and have received satisfactory answers.

References

Einav, M. E. (2024, March 26). The Truth About Compounded GLP-1s That Doctors Need to Know. Retrieved from MedEdge.

Kircik L, S. D. (2023). Clinical and Legal Considerations in Pharmaceutical Compounding. Journal of Clinical and Aesthetic Dermatology, S23-S28.

US Food and Drug Administration. (2022, June 9). Compounding and the FDA: Questions and Answers. Retrieved from US Food and Drug Administration: https://www.fda.gov/drugs/human-drug-compounding/compounding-and-fda-questions-and-answers

US Food and Drug Administration. (2023, March 24). Drug Compounding and Drug Shortages. Retrieved from US Food and Drug Association: https://www.fda.gov/drugs/human-drug-compounding/drug-compounding-and-drug-shortages

US Food and Drug Administration. (2024, July 26). FDA Alerts Health Care Providers, Compounders and Patients of Dosing Errors Associated With Compounded Injectiable Semaglutide Products. Retrieved from US Food and Drug Administration: https://www.fda.gov/drugs/human-drug-compounding/fda-alerts-health-care-providers-compounders-and-patients-dosing-errors-associated-compounded

US Food and Drug Administration. (2024, January 10). Medications Containing Semaglutide Marketed for Type 2 Diabetes or Weight Loss. Retrieved from US Food and Drug Administration: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/medications-containing-semaglutide-marketed-type-2-diabetes-or-weight-loss#

US Pharmacopeial Convention. (2023). USP chapter <795>: Pharmaceutical compounding—Non-sterile preparations. Retrieved from United States Pharmacopeia and National Formulary (USP-NF).