CLINICAL, OPERATIONAL, AND SAFE USE OF MANIPULATED DRUG PRODUCTS AND ALTERNATE ADMINISTRATION ROUTES

To support clinically appropriate, evidence-based use of manipulated drug-products or alternate drug administration routes when it supports optimal patient care; further, 

To promote research that includes pharmaceutics, pharmacokinetics, pharmacodynamics, safety, and efficacy of drugs when manipulated or when given through alternate administration routes; further, 

To encourage manufacturers to develop drug products in ready-to-use devices and diverse formulations; further,

To foster pharmacist-led interdisciplinary teams to provide institutional guidance, best practices, and safety recommendations regarding drug products that are manipulated or administered through alternative routes.

Rationale

Administration of drug products through alternative routes of administration including intranasal, nebulization, intrathecal, intraosseous, and enteral routes that deliver medications to alternate sites of absorption are increasingly more prominent in practice as patient needs evolve. For example, novel delivery mechanisms through the nebulization of antibiotics and antifungals that are formulated for intravenous (IV) administration are used adjunctively to treat pulmonary infections in critically ill patients. Intranasal administration is often the route of choice in the emergency department due to access issues, safety concerns, and the characteristics of specific patient populations (e.g., children). Soluble drugs such as naloxone can be converted for intranasal administration without altering the substance simply by use of an aerosolizer. The intranasal route is frequently used to treat pain when oral and intravenous routes are not available or optimal, and intranasal midazolam is often used for sedation in the pediatric population, although that route of administration has not been approved by the Food and Drug Administration.

Manipulation of a drug product can include crushing, splitting, or suspending it in a solvent, which can alter the pharmaceutical properties of the original dosage form. These manipulations are often performed for various reasons including when a patient a) requires the medication administered enterally but is unable to take the medication by mouth, b) requires a dose that is not readily available and so a specific dose requires it to be compounded, or c) is unable to swallow or has a feeding tube placed necessitating manipulation. For patients who lose the ability to swallow easily (e.g., due to stroke or cancer), it is sometimes quite difficult to provide drugs as liquid formulations because they may not be available, thus necessitating crushing them.

Studies reveal that oral drug products pass through the stomach, exposing them to a specific set of pH conditions. The stomach may be bypassed when drug products are administered via feeding tube to organ systems in the body that may have a different pH, affecting the adsorption, metabolism, or distribution of the drug. In addition, the physical properties of the manipulated formulation may also cause obstruction and clogging of enteral tubes used for feeding and medication administration, leading to undesirable outcomes, including supra- or subtherapeutic concentrations in the body, which could lead for example to organ rejection in transplant patients, loss of viral suppression in HIV-positive patients, or toxicities when manipulating an extended-release tablet. When drug products are manipulated or administered through alternative sites or means, consideration for the properties of formulations, including but not limited to drug molecule size, viscosity, surface tension, solubility, stability, osmolality, tonicity, and pH must also be included as these can affect pharmacokinetics and pharmacodynamics.

It is important to recognize that the need to manipulate or administer drug products through an alternate route is because there is not a commercially available formulation and as such, need may require compounding with both sterile and nonsterile ingredients. Due to this variability and potential source for sterile compounding and administration errors, manufacturers should be encouraged to create commercially available formulations to meet clinical needs where there is evidence that supports the use of manipulated drug products or alternate administration methods.

There is also a lack of resources that provide guidance on how manipulation and alternative sites of drug administration may affect the bioavailability of the drug product or whether the manipulated drug product remains bioequivalent with the original dosage form. There is even less research or publicly available information on the clinical effects of manipulated drug products and those administered via alternate routes or delivery systems. ASHP encourages clinical and practice-based researchers to conduct studies on these subjects and to disseminate this information via journal articles and other easily accessible resources. ASHP also encourages education of the pharmacy workforce and other healthcare providers regarding the basic principles of drug dosing for manipulated drug products. Given that the frequency that some of these medications are manipulated or administered is often based on small case studies, consideration for the potential role of artificial intelligence in advancing model development and validation should also be explored.

Manipulation of drug products and alternate administration are also not without risk. Nebulized drugs that are not commercially available may be compounded with both sterile and nonsterile ingredients and that, when possible, should be compounded with preservative- and additive-free formulations to improve patient tolerability and considerations for drug stability, safety for patient and personnel administering nebulized drug products, and methods for preparation and delivery. Drug products administered intranasally often vary in pharmacokinetic and pharmacodynamic properties due to the presence of preservatives and viscosity of the agents and efficacy may depend on the use of additional devices such as atomizers. There are also exposure risks to caregivers preparing or administering manipulated drug products that are carcinogenic or teratogenic. Medications compounded for administration in the epidural space or intrathecal administration also bear consideration for the presence of preservatives. To this end, ASHP strongly recommends that when medications are manipulated or being considered for alternative administration, a multidisciplinary team that includes a pharmacist is convened to assess clinical, safety and operational needs and provide institutional guidance.