The importance of attention to appropriate safety precautions in handling hazardous drug (HD) preparations in the clinic setting cannot be overemphasized. The veterinarian is legally and ethically obligated to educate staff regarding safe handling of chemotherapeutic drugs. Lack of staff communication and training in chemotherapy protocols could lead to an Occupational Safety and Health Administration investigation, fines, and lawsuits. Staff should have access to relevant Safety Data Sheets and be made aware of the toxicity of any chemotherapeutic agent that is used in the practice.

For the purposes of these guidelines, HDs will be used interchangeably with chemotherapeutic agents. A complete list of HDs has been compiled by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health (NIOSH). Improper handling can lead to unintended exposure to cytotoxic agents that are mutagenic, teratogenic, or carcinogenic. For example, exposure of healthcare workers to HDs has been confirmed by the presence of HD metabolites in urine. For this reason, safety is a paramount consideration for everyone involved with chemotherapy.

Personnel safety considerations

There are several routes of exposure to HDs. HDs can enter the body via inhalation, accidental injection, ingestion of contaminated foodstuffs, hand-to-oral contact, and dermal absorption. While HD exposure is always a constant threat when chemotherapeutic agents are used, proper procedures and policies can minimize the risk. The United States Pharmacopeia (USP) has developed an enforceable “General Chapter” practice standard devoted to the handling of HDs, which outlines standards regarding personnel protection for preparation and handling of HDs. Because an in-depth discussion of HD controls is beyond the scope of these guidelines, readers can refer to USP for more detailed information on this topic.

Veterinary practices will ordinarily not be involved in chemotherapeutic drug compounding. However, it is helpful for the healthcare team personnel to have a general awareness that direct contact with HDs, either by handling, reconstituting, or administering HDs, represents an exposure risk. Many HDs have also been found to have drug residue on the outside of drug containers, which creates another opportunity for exposure of individuals who receive drugs and perform inventory control procedures. Personal protective equipment (PPE) should be used to protect personnel from exposure during handling of HDs. PPE includes gloves, gowns, goggles for eye protection, a full face shield for head protection, and respiratory barrier protection.

Regular exam gloves are not recommended for use as standard protocol for handling chemotherapeutic agents. However, as an expedient, wearing two pairs of powder-free nitrile or latex gloves can be used as a last resort. Vinyl gloves do not provide protection against chemotherapy. Ideally, gloves should be powder free and rated for chemotherapy use by the American Society for Testing and Materials (ASTM). For receiving HDs, one pair of ASTM-tested chemotherapy gloves may be worn. When administering, managing, and disposing of HDs, two pairs of ASTM-tested chemotherapy gloves may be worn. The inner glove should be worn under the gown cuff and the outer glove over the cuff. Disposable gowns made of polyethylene-coated polypropylene or other laminate materials offer the best protection.

Eye, face, and respiratory protection is mandatory when working with HDs outside of a clean room or isolator cabinet, or whenever there is a probability of splashing or uncontrolled aerosolization of HDs. A full face mask is a suitable alternative to goggles, although it does not form a seal or fully protect the eyes. A NIOSH N95 respirator mask is suitable for most situations, with the exception of large spills that cannot be contained by a commercially available spill kit.

PPE should be removed in the following order:

1. chemotherapy gown (touching the outside of the gown, then rolling the outside inward to contain HD trace contamination),
2. goggles and face shields (touching only the outside without making contact with the face),
3. chemotherapy gloves (touching the outside of the gloves away from the exposed skin while attempting to roll the glove outside-in).

If a glove becomes contaminated or if there is a breach in the glove, it should be removed and discarded promptly, while carefully avoiding contamination of the handler’s skin or nearby surfaces.

Closed-system transfer devices (CSTDs) are another type of PPE that can be used for any cytotoxic chemotherapy agent (although not necessarily for all HDs) during preparation and administration. In the case of non-cytotoxic agents that are not on the NIOSH list of HDs, for example, asparaginase, a CSTD, is not required. FDA approval of CSTDs requires the following capabilities: no escape of HDs or vapor, no transfer of environmental contaminants, and the ability to block microbial ingress. CSTDs can greatly reduce the potential for HD exposure to clinical personnel and should always be used concurrently with other PPE.

Traditional needle and syringe techniques for mixing HDs create the potential for droplet or aerosol contamination. CSTDs prevent mechanical transfer of external contaminants and prevent harmful aerosols that are created by mixing HDs from escaping and exposing personnel. CSTDs are commercially available from a number of companies.

The following additional safety precautions will help minimize the potential for exposure of personnel handling HDs:

• Male and female employees who are immune-compromised or attempting to conceive and women who are pregnant or breastfeeding should avoid working with chemotherapy agents.
• Employees or pet owners who will be exposed to the patient’s waste (urine, feces, vomit, blood) within 72 hr of chemotherapy administration (sometimes longer for some drugs) should wear proper PPE.
• Chemotherapy pills (tablets and capsules) are best handled within a biological safety cabinet (BSC) if available. If no BSC is available, a ventilated area or a respirator should be used to avoid inhalation of HD particles or aerosols.
• Separate pill counters should be used for chemotherapy pills. Counters labeled for chemotherapy use will help avoid inadvertent use with conventional medications. The counters should be stored either within the BSC (not to be removed) or in a sealed container (e.g., a plastic box with a secure lid) dedicated to that pill counter and any other items that may come in contact with HD pills.

Environmental safety considerations

Environmental controls are an important part of risk mitigation. The recommended location for chemotherapy preparation and administration is a quiet, low-traffic room that is dedicated to chemotherapy purposes, free from distractions, and easy to clean. Because HD spill events represent the greatest risk of personnel exposure, it is important to use extreme care when cleaning spills. Commercially available spill kits are useful in containing and cleaning HD spills. Absorbent pads or pillows can be used to immediately contain larger spills. When managing a spill, it is recommended to start from the outer edges of the spill and work your way toward the middle to prevent spreading HD residue. An HD-spill management sequence (Table 4, see the full guidelines) has been developed and is a suitable basis for a veterinary practice protocol. Spill kits should contain instructions for use and be located in areas where HDs are located and administered. Only trained personnel should clean up HD spills, and they should wear appropriate PPE, including double chemotherapy gloves and respiratory masks. HD agents are best stored in a dedicated, closeable cabinet or refrigerator. Following administration, discard HDs, administration materials, and gloves and other PPE into chemotherapy waste receptacles. It is important that staff members who have touched chemotherapy vials or potentially contaminated areas NOT touch anything or anyone else until they have removed their PPE and washed their hands.

Patient safety considerations

Chemotherapeutic agents have a narrow therapeutic index and can lead to significant or fatal toxicity if overdosed. Errors in dose calculations and labeling as well as breed-specific sensitivities can lead to adverse events. Errors in dose calculations are responsible for a large portion of mistakes made in chemotherapy. In veterinary medicine, agents may be dosed in terms of milligrams/kilogram (mg/kg) or milligrams per meter squared (mg/m2). These are easily confused and can lead to drastically different dose calculations. Prior to mixing chemotherapy drugs, calculations should be done by two individuals. The two calculated doses can then be compared and serve as a double check. The concentration of drug in mg/ml should also be double-checked.

The Washington State University College of Veterinary Medicine has extensively investigated the ABCB-1 gene (formerly known as MDR1), which is responsible for breed-specific variability in susceptibility to adverse events. The ABCB-1 gene codes for the production of p-glycoprotein (Pgp) pumps, which act to remove drugs from individual cells. The Washington State University College of Veterinary Medicine has published a list of breeds that have a high probability of an ABCB-1 gene mutation (Table 5, see the full guidelines). Many chemotherapy drugs, notably vincristine and vinblastine, are substrates for Pgp pumps and require a dose adjustment for that reason.

When administering chemotherapy to an animal, proper restraint is very important in order to prevent drug extravasation. Staff members assisting with restraint should wear chemotherapy gloves and other appropriate PPE. Frequent monitoring of the injection site should be performed throughout the injection or infusion. Placement of a small-gauge IV catheter (e.g., 24 g, 22 g) will preserve vein viability and provide secure access. Although winged infusion sets are not as secure as IV catheters, they can be used for bolus injections of drugs such as vinca alkaloids, cyclophosphamide, and carboplatin. Winged infusion sets should never be used for severe vesicants, such as doxorubicin, or for lengthy infusions.

Venipuncture should entail a nicely seated, one-stick technique in order to avoid creating multiple holes within the vein wall that would allow the chemotherapy drug to leak into surrounding tissue. After chemotherapy administration is complete, apply gauze or an alcohol swab to the injection site when removing the needle or catheter from the patient. This can help stabilize sudden movements of the exiting cannula as well as absorb possible residual chemotherapeutic agents contained within. 

Because heparin can cause precipitation or inactivation of some chemotherapy agents, non-heparinized flushes are recommended. A 0.9% NaCl preparation is a standard fluid choice. Prime any lines with the 0.9% NaCl or other fluid prior to the addition or administration of chemotherapy.

Extravasations

Extravasation is the process of liquid leaking into surrounding tissue, typically near the insertion site of a peripheral catheter. Drugs
are classified according to their potential for causing damage asvesicant, irritant, or a nonvesicant. Table 6 (see the full guidelines) lists the extravasation potential for five injectable chemotherapies used in veterinary medicine. 

Most extravasation events can be prevented by a systematic, standardized, evidence-based approach to administration techniques. A trained and experienced staff will greatly decrease procedure-related extravasation risk factors. Fidalgo et al. outline a preventative protocol that may help minimize the risk of extravasations. 

The most common signs of extravasation are discomfort, pain, swelling, and redness at the injection site. Prolonged symptoms often progress to tissue ulcerations, blistering, and necrosis. Indications of an extravasation event include the absence of blood return from the catheter, bolus administration resistance, and failure of the infusion. If an extravasation event does occur, do not immediately remove the catheter. Rather, attempt to aspirate as much drug as possible and do not inject any fluid into the catheter. An extravasation mitigation protocol should be implemented as soon as possible. (For more information on extravasasions, see pp. 18–21.)

Labeling of hazardous drugs

Labeling of HDs is an extremely important aspect of personnel safety. Without adequate HD labeling, personnel are placed at risk of accidental exposure to HDs. All HDs should be labeled clearly with chemotherapy warning labels. Injectable HD agents should be labeled as “opened” or “reconstituted” on a specific date and the concentration of the reconstituted agent should be indicated. 

“Look-alike, sound-alike” describes drugs that are spelled and pronounced similarly but are different. The term came about in response to errors involving inadvertent misfills of drugs, for example, vincristine being confused with vinblastine. A simple practice that many pharmacies now follow is arranging their medication stock alphabetically by generic name using a “Tall Man Lettering System.” This is a simple way to emphasize spelling and pronunciation differences between drugs (e.g., vincristine is written as vinCRIStine and vinblastine is written as vinBLAStine). 

Appropriate labeling of mixed chemotherapies can also reduce errors and allow for another double check prior to administration. Diluted drugs should be labeled with the amount of drug in milligrams contained in the syringe or minibag. For drugs that are not diluted, it is good practice to label the syringe with the concentration of the drug as it comes from the vial. These labeling techniques allow for another double check prior to administration. 

The Institute for Safe Medical Practices has developed several strategies to prevent simple errors. Naked decimal points and trailing zeros have been implicated in many errors in healthcare and have been designated as unapproved abbreviations. An example of a naked decimal point is when “0. 2 mg” is written as “. 2 mg,” easily leading to a 10-fold overdose if “. 2 mg” is read as “2 mg.” Similarly, a trailing zero notation is when “10 mg” is written as “10. 0 mg,” which can easily be mistaken for “100 mg.”