Safe use of cytotoxic drugs (Proceedings)

In the therapy of neoplastic infections with cytotoxic drugs, there is little basis for the selective killing of the abnormal cells as opposed to the healthy cells in the body. There are only a few known differences in receptors and metabolism that are suitable drug targets at the present time. Instead, the major difference between neoplastic cells and healthy cells is in the rate and timing of cell growth, as neoplastic cells exhibit excessive, uncoordinated growth. Therefore, most anticancer drug therapies target all rapidly growing cell populations. Some phase of DNA synthesis and mitosis may be specifically targeted by cytotoxic therapy, or a critical step in the metabolism of rapidly dividing neoplastic cells may be targeted. Because these targets are minimally selective for neoplastic cells, many normal cells in the body will also be killed or damaged by cytotoxic drugs. The rapidly growing, renewing populations of cells are most susceptible to toxicity, and include: gametes, blood stem cells, epidermis, and gastrointestinal epithelium. Ironically, whereas the use of the cytotoxic anticancer drugs are intended to kill cancer cells, an important potential side effect of their administration is the generation of new populations of cancerous cells, as a result of damage to DNA that does not result in cell death. Reproductive toxicity can be considered an extension of the pharmacological effects of toxicity to rapidly dividing cells, as the healthy gametes and embryo also undergo rapid cell division. Due to these concerns, it is most prudent for women who are pregnant or attempting to become pregnant to avoid unnecessary contact with cytotoxic agents, especially during the first trimester of pregnancy when the developing embryo is particularly susceptible to teratogens.

Preparation of Cytotoxic Drugs: The likelihood of drug exposure must be taken into account when considering the safety of personnel who will handle cytotoxic drugs and patients during or after drug administrations. Although the cytotoxic agents are used therapeutically, and most chemotherapy protocols are well-tolerated by veterinary patients, the cumulative toxicity to personnel that arises from repeated contact with these drugs can cause health problems in the nursing staff that are beyond those expected in the patient. The main routes of personnel exposure to cytotoxic drugs are by aerosolization or by absorption through skin. Both types of exposure can occur when preparing drugs for administration. The act of withdrawing cytotoxic drug from the vial into a syringe is generally the step that presents personnel with the greatest potential for exposure to a high concentration of drug. Ideally, personnel are protected from drug exposure and patients are protected from contamination of the product by the use of a Class 11, Type B or C laminar flow biosafety cabinet during drug preparation. Class 11 biosafety cabinets provides HEPA filtration of incoming air, a feature that is designed to protect the product and personnel from large particulates, such as bacteria and viruses. However, many biosafety cabinets, or laminar flow hoods, are Class 11, Type A hoods, which are usually set up to exhaust HEPA filtered air back into the room. As HEPA filters cannot efficiently filter small, volatile compounds, most Type A hoods are not appropriate for preparation of cytotoxic drugs. In contrast, the Class 11, Type B2 biosafety cabinet vents all exhausted air to the atmosphere, protecting personnel from exposure to volatile chemicals, and is therefore preferred over the Class 11, Type A biosafety cabinet. However, the NIH Division of Occupational Health and Safety (DOHS) permits the use of a Class 11, Type A biosafety cabinet that is equipped with a canopy that exhausts air from the cabinet to the outside. For the practitioner, the need for protection of personnel during preparation of cytotoxic drugs presents the most significant obstacle to the safe provision of chemotherapy, as most practices are not equipped with the appropriate biosafety cabinet. For the practitioner without a Class 11, Type B2 biosafety cabinet, some suggested means of preparing cytotoxic drugs for administration include having a pharmacy or hospital prepare doses of cytotoxic drugs, or using personal protective equipment and a dedicated clean room to prepare drug doses. There are obvious advantages to using a pharmacy or hospital to dispense the cytotoxic dose. Many pharmacies have appropriate biosafety cabinets in order to meet regulations concerning both the handling of cytotoxic agents and the compounding of injectable drugs. Several veterinary compounding pharmacies now advertise this service. In addition, human hospitals and outpatient cancer clinics may regularly dispense cytotoxic medications for human patients and may be willing to prepare drug doses for veterinary patients as well.

If a veterinary practice decides to prepare doses of cytotoxic drugs on the premises without an appropriate biosafety cabinet, then the personnel should be aware that they are stepping outside of accepted protocols for personnel safety. If a product is dispensed at such a practice, then a respirator mask must be used in lieu of a biosafety cabinet, and the preparation of cytotoxic drugs should be rare, rather than routine. Current National Institute of Occupational Safety and Health (NIOSH) recommendations are for the use of a powered, air-purifying respirator with a high-efficiency filter. It should be noted that surgical masks are not appropriate, as they cannot filter volatile chemicals and can even trap cyototoxic drugs in close proximity to inspired air. If a biosafety cabinet is not available, then a modified cleanroom should be used. The area should be free of distractions, extraneous personnel, clutter, and food or drink. A plastic-backed, absorbent liner should be placed on a solid surface table and all necessary supplies collected. The recommendations stated below regarding the use of personal protective equipment should be followed, with the addition of a suitable respirator.

Before preparing drugs, personnel should don a polyethylene gown with cuffed sleeves and eye protection. Double layers of patient examination gloves may be worn, with one glove under the gown cuff and the second pair over the cuff of the gown. Two layers of gloves are worn because some drugs can quickly penetrate the latex glove, and because the second layer affords some protection in case of a manufacturing defect. Powder-free gloves are necessary as cytotoxic drugs can adsorb to powder and then be dispersed throughout the room. Chemotherapy gloves are sold specifically as a single layer for chemotherapy use, are thicker and longer than exam gloves (minimal thickness of 0.10 mm, minimal length of 270 mm), and have been tested for their permeation to common cytotoxic agents. Such testing indicates that nitrile gloves are at least as effective as latex gloves in slowing permeation of cytotoxic drugs through the gloves. Hands are washed before and after applying gloves, and gloves are changed immediately when contaminated, or at least hourly.

The work surface should be protected with a plastic-backed, absorbent liner. When preparing a dose of a cytotoxic drug from a vial, personnel should make every attempt to avoid aerosolization of the product, even when working in an appropriate biosafety cabinet. A luer-lock syringe should be selected that is of sufficient volume that it will never be more than 1/2-2/3 full. A chemotherapy pin is used to help prevent the contents of the drug vial from becoming pressurized. In addition, if a diluent must be added, a careful adjustment of pressure can made by aspirating air into the syringe containing diluent before adding a small amount of diluent to the vial, followed by aspirating air into the syringe, etc. A newer product, PhaSeal®, offers an improvement on the traditional use of the chemotherapy dispensing pin and the pumping technique. This system is completely closed, providing a double-membraned, sealed line of connection from the drug vial to the syringe and the IV line.

Many injectable cytotoxic drugs are vesicants, and can cause severe tissue necrosis if extravasated. Therefore, personnel should be very cognizant of the drug that may be present on the needle. For that reason, infusion lines should be used and needles should not be capped, or a one-handed technique should be used. The infusion line may be prefilled with an appropriate priming solution, such as normal saline solution, prior to preparation of the cytotoxic drug dose. Heparinized solution generally should not contact the cytotoxic agent as precipitation of some drugs can occur. The syringe containing the drug dose can then be attached to the infusion line, without the use of an injection cap, which would again necessitate the use of a needle. Any contamination of the outer syringe surfaces can be cleaned with 70% isopropyl alcohol on a gauze sponge. When oral cytotoxic therapy is to be used, similar precautions should be followed when handling this medication. Pills should never be split or crushed, to prevent airborne exposure to drug. Once the dose has been prepared, it may be placed in a bag that will protect against spills, such as a ziplock bag, and labeled with the date, dose, patient's name, and responsible personnel's initials. Some cytotoxic drugs (e.g., cisplatin and 5-fluorouracil) are light sensitive and should be stored in amber bags. Other drugs may be thermally labile and should be placed with a cold pack if they will not be immediately used.

Disposal: Once the drug dose has been prepared, paper towels should be used to clean the work surface with water followed by a 70% isopropyl alcohol solution. The paper towels are disposed of as cytotoxic waste. Ideally, the gown and gloves used to prepare the drug should also be discarded before leaving the preparation area. Procedures for the disposal of cytotoxic waste are similar to those for the disposal of biohazardous materials, except that as regulated waste, cytotoxic drugs must be disposed of in accordance with Federal, state, and local laws. In the U.S., yellow bags, containers, or stickers are used to distinguish cytotoxic waste from red biohazardous waste. Sharps and soft material are placed in hard plastic containers or bags, respectively, in a manner analogous to the disposal of biohazardous materials. Biohazardous and cytotoxic waste should be mixed as little as possible, as the disposal requirements for cytotoxic waste (e.g., incineration) are more stringent and costly than those for biohazards. However, any biohazardous waste that may also contaminated with cytotoxic drugs (such as blood and urine from treated animals) should be treated as cytotoxic waste.

Administration of cytotoxic drugs: Personnel should wear personal protective equipment for administration of cytotoxic drugs that is similar to that described above for preparation of drug. Use of a plastic-backed, absorbent mat underneath the patient and the general administration area is desirable. For administration of cytotoxic drugs, surgical masks may be acceptable to capture splatters, but should be immediately removed and discarded if contamination is suspected. Face shields are preferred. Polyethylene gowns, double latex gloves or chemotherapy gloves, and eye protection as described above are also recommended. The use of luer lock connections and use of needles only for the connection of the saline primed infusion set to the injection port is again prudent. Placing a pad or cotton ball soaked in 70% isopropyl alcohol over the injection port will also assist in preventing aerosolization. The injection port is then flushed with normal saline and then with heparinized saline, if the catheter is to remain. All injection materials that were in contact with the cytotoxic drug are then placed in a sealable (e.g., "ziplock") bag and discarded appropriately.

Spills: Accidents should be anticipated and proactive steps taken to mitigate unnecessary exposure of personnel to spilled materials. Nonessential personnel should stay away from the contaminated area. Chemotherapy spill kits are available and generally include: absorbent pads or pillows, gloves, a polyethylene gown, and sealable bags. A NIOSH-certified respirator (e.g., N-95 or cartridge respirator with HEPA filters) should be used in spills that include volatilized liquid or powders. Liquids are gently blotted with the pillow and powders are covered with gauze pads moistened with water. The area of the spill is also cleaned with a detergent solution (not bleach) and paper towels. The material is placed in the sealed bag and transferred to an appropriate waste receptacle. If cytotoxic drugs are accidentally splashed onto the skin or eyes, then the area should be copiously flushed with water, skin gently washed with detergent, and medical attention secured.

Handling of Treated Patients: Both the owners and veterinary personnel responsible for a patient's care should be aware that cytotoxic drugs were given and that protective measures are to be taken. The same considerations that dictate whether the most susceptible populations of personnel should handle cytotoxic drugs also apply to the care of the treated patient. After drug therapy, all body fluids should be treated as contaminated material for several days to one week after drug administration. Therefore, personnel who must clean heavily contaminated cages or kennels should follow the same guidelines as described above for the treatment of spills. Feces may be flushed down the toilet or double-bagged and disposed of as household waste when at home. Dogs should be encouraged to urinate on grass and the area should not be sprayed down where possible, again to avoid aerosolization. Cat litter boxes should be cleaned frequently and the waste double-bagged. Gloves should be dispensed to the owners with appropriate instructions on management of pet wastes. Soiled linens should be separated from other laundry, and an extra rinse cycle after washing can help to prevent cross-contamination.

Resources:

1. OSHA Technical Manual (OTM). Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

2. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication 92-2621. http://dohs.ors.od.nih.gov/publications.htm#biosafety

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