Rpharmy Rhazdrugs • leflunomide

Preparation Administration Receiving and Storage Disposal Transport PPE Additional Information Assessment of Risk Exposure Risk Supplemental Information Mechanism of Action Safety Data Sheet(s) Black Box Warning Approval

leflunomide

Trade Name(s): Arava; Leflunomide
Group 2: Non-Antineoplastic Hazardous	AHFS Class: Monocarboxylic Acid Amide Agents; Immunomodulatory Agents

Preparation:

Oral - 2&3

Oral - 2&3

Activity	Gloves	Gown	Eye/Face	Mask	Notes/Instructions
Dispensing prepackaged formulations					PPE not required if dispensed in manufacturer packaging with no counting or manipulation needed.
Counting/Repackaging tablets and capsules		Recommended if pregnant, breast feeding, or trying to conceive		If risk of dust inhalation	Do not split, crush, open, or otherwise manipulate tablets or capsules. Manually prepack and count in designated HD area with dedicated equipment. Do not use Automated Repackaging equipment. Only the minimum number of tablets or capsules necessary to accomplish the task should be emptied from the bottle onto the counting tray. Reasonable efforts should be made to minimize the production of powder/dust and aerosolization of any particulate as well as residual dust present in the tray. Deactivate, decontaminate, clean and disinfect area and equipment after use and between hazardous drugs.
Repackaging oral liquids			If risk of spill or splash	If risk of inhalation	Repackage in designated area with dedicated equipment Deactivate, decontaminate, clean, and disinfect area and equipment after use and between hazardous drugs.

Administration:

Oral - 2&3

Oral - 2&3

Formulation

Gloves

Gown

Eye/Face

Mask

Notes/Instructions

Tablet or capsule - from unit dose package

Gloves Single

Gloves Double

Recommended if pregnant, breast feeding, or trying to conceive.

Do not crush, cut, open or manipulate hazardous drugs.

Liquid - oral or feeding tube

Gloves Double

Recommended if pregnant, breast feeding, or trying to conceive.

Gown

Recommended if pregnant, breast feeding, or trying to conceive.

Face Shield

If potential for splash, vomit or spit up.

Eye and face protection is recommended for patients who are unruly, predisposed to spitting out, have difficulty swallowing or if the formulation is hard to swallow.

Reference: NIOSH 2016, USP <800>

Receiving and Storage:

Storage & Handling

Storage & Handling

Type of Instance	Gloves	Gown	Mask	Eye/Face	Notes/Instructions
Receiving undamaged HD shipping container					Hazardous drugs should be received in impervious plastic to segregate them from other drugs and to allow for safety in the receiving process. HDs must be delivered to the HD storage area immediately after unpacking.
Receiving damaged HD shipping container		If container must be opened	If container must be opened	If container must be opened	If possible, do not open the container. Instead, segregate the container in a segregated area and mark "hazardous." Alert other staff and contact the supplier for direction. If the container is to be returned, leave in the segregated area until the return is complete. If the damaged HD container must be opened, don the appropriate PPE and transport the container to the designated HD area. Remove undamaged items, cleaning the outside of each with alcohol or hydrogen peroxide. Enclose the damaged HD item(s) in a hazardous plastic bag, seal in a small shipping box marked "hazardous," and place in a segregated area. Clean the designated HD area where the container was handled. Contact the supplier for direction. If the supplier declines return, dispose of as hazardous waste. If the damaged HD in the shipping container constitutes a large volume spill, report to the USP 800 Specialist.
Spill Cleanup			Large volume	Large volume	Clear the area of the spill and restrict access, if necessary. Small Volume Spills: Powder or liquid spills of 5 grams/ml or less. Clean spill using a cloth, towel or wipe dampened with alcohol or hydrogen peroxide. Do not spray cleaning product directly on to surface or spill. Large Volume Spills: Powder or liquid spills of 5 grams/ml or more. Use a Chemo Spill Kit and the cleaning agents included, following the instructions in the kit. Contain liquid spills by covering with absorbent sheets. If the spill is a powder, use a cloth, towel or wipe dampened with alcohol or hydrogen peroxide. Report large volume spills to the USP 800 specialist. Dispose of all contaminated materials in the appropriate hazardous drug waste container. After removing PPE, wash hands, arms, and face.

Reference: USP <800>

Disposal:

Disposals - All

Disposals - All

Hazardous Pharmaceutical

Trace Chemo

Biohazardous and Sharps

1. Non-returnable hazardous, chemo and EPA regulated drugs.
(Patient specific prescriptions, partially used blister packs, containers with more than 3% medication remaining)

2. Empty bottles or packaging of P-Listed drugs.
(Warfarin, nicotine, epinephrine, nitroglycerin, physostigmine)

3. PPE with visible contamination from hazardous drug.

1. Waste contaminated through contact with chemotherapeutic agents.

(Empty vials, IV bags, syringes and tubing)

2. PPE worn while handling hazardous drugs with NO visible contamination.

(Gowns, gloves and masks)

3. Used CSTD devices.

1. All sharps capable of cutting or piercing the skin.
(Needles/syringes, broken ampules, lancets)

2. Items contaminated with blood or other potentially infectious materials.
(Tubing, bags or dressings containing blood, contaminated waste from isolation patients)

Transport:

Transporting

Transporting

Dosage Form	Ship to Institution or Pharmacy	Ship to Locations Outside of ODOC
Tablets and Capsules	Transport in appropriate resealable clear plastic bag with "Hazardous Drug" labeling or sticker. Place bagged HD in a small shipping box labeled "Hazardous" and seal. Place sealed box inside larger shipping container or box and seal.	Transport in appropriate resealable clear plastic bag with "Hazardous Drug" labeling or sticker. Place bagged HD in a small shipping box labeled "Hazardous" and seal. Place sealed box inside larger shipping container or box and seal. Include storage, disposal, and HazD category information.
Liquid, Topical, and Transdermal	Transport in appropriate resealable clear plastic bag with "Hazardous Drug" labeling or sticker. Place bagged HD in a small shipping box labeled "Hazardous" and seal. Place sealed box inside larger shipping container or box and seal.	Transport in appropriate resealable clear plastic bag with "Hazardous Drug" labeling or sticker. Place bagged HD in a small shipping box labeled "Hazardous" and seal. Place sealed box inside larger shipping container or box and seal. Include storage, disposal, and HazD category information.

PPE:

PPE Standards

PPE Standards

PPE	Standards
Shoe Covers	To avoid spreading HD contamination and exposing other healthcare workers, shoe covers worn in HD handling areas must not be worn to other areas.
Gowns	Gowns must be changed per the manufacturer's information for permeation of the gown. If no permeation information is available, change them every 2-3 hours or immediately after a spill or splash. Gowns are not reusable and must be disposed of after use. Must close in the back (no open front) Gowns worn in hazardous drug handling areas must NOT be worn to other areas
Gloves	Must be worn when handling all HDs Inspect for physical defects before use. Gloves should be changed every 30 minutes (unless otherwise recommended by the manufacturer) and immediately when torn, punctured, or contaminated. Gloves must be changed in between patients when administering different HDs. Wash hands with soap and water after removing.
Face Shields	Face shields should be worn in situations where eye, mouth, or nasal splashing is possible Face shields can be worn with goggles to provide a full range of protection against splashes to the face and eyes.
Goggles	Goggles must be used when eye protection is needed. Eye glasses, safety glasses and face shields do not provide adequate eye protection. Must be worn when there is a risk for spills or splashes of HDs or HD waste materials.
N95 Masks	Personnel who are unpacking HDs that are not contained in plastic should wear an N95 mask until the drug can be identified. Surgical masks do not provide respiratory protection from HD exposure and must not be used. N95 respirators offer no protection against gases and vapors and little protection against direct liquid splashes. Follow all requirements in the Occupational Safety and Health Administration (OSHA) respiratory protection standard (29 CFR 1910.134).
Removal and Disposal	All PPE worn when handling HDs is considered contaminated. Remove gloves first, grasping the outside of the glove with the opposite gloved hand. Hold the removed glove in the gloved hand. Slide the fingers of the ungloved hand under the remained glove at wrist. Peel second glove over the first glove. If wearing double glove, remove the outer gloves one at a time, turning them carefully inside out to avoid touching the outside. Leave inner gloves on. The face shield, if worn, should be removed next, while avoiding contact with the front. Remove the gown, using care to pull it away from the body, not pulling it over the head, to avoid transfer of contamination to clothes and skin. Turn the gown inside out, fold it tightly, and discard it. Remove the mask (if worn), avoiding touching the face-piece. Remove inner gloves (if double gloved) and discard in the disposal container. Immediately wash hands with soap and water. . PPE must be placed in an appropriate waste container and further disposed of per local, state, and federal regulations.

Reference: USP <800>

Additional Information:

ODOC Formweb

Assessment of Risk:

AoR

Exposure Risk:

Toxic if swallowed.
Causes skin irritation.
Causes serious eye irritation.
May cause respiratory irritation

Reference: SDS - Cayman Chemical

Supplemental Information:

Teratogenic in laboratory studies at 1/10 HD; Marked postnatal survival at 1/100 HD; Severe liver injury reported in patients; Carcinogenicity observed at doses below HD

Mechanism of Action:

Leflunomide is a prodrug that is rapidly and almost completely metabolized following oral administration to its pharmacologically active metabolite, A77 1726. This metabolite is responsible for essentially all of the drug's activity in-vivo. The mechanism of action of leflunomide has not been fully determined, but appears to primarily involve regulation of autoimmune lymphocytes. It has been suggested that leflunomide exerts its immunomodulating effects by preventing the expansion of activated autoimmune lymphocytes via interferences with cell cycle progression. In-vitro data indicates that leflunomide interferes with cell cycle progression by inhibiting dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine ribonucleotide uridine monophosphate (rUMP)synthesis) and has antiproliferative activity. Human dihydroorotate dehydrogenase consists of 2 domains: an α/β-barrel domain containing the active site and an α-helical domain that forms a tunnel leading to the active site. A77 1726 binds to the hydrophobic tunnel at a site near the flavin mononucleotide. Inhibition of dihydroorotate dehydrogenase by A77 1726 prevents production of rUMP by the de novo pathway; such inhibition leads to decreased rUMP levels, decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest. It is through this action that leflunomide inhibits autoimmune T-cell proliferation and production of autoantibodies by B cells. Since salvage pathways are expected to sustain cells arrested in the G1 phase, the activity of leflunomide is cytostatic rather than cytotoxic. Other effects that result from reduced rUMP levels include interference with adhesion of activated lymphocytes to the synovial vascular endothelial cells, and increased synthesis of immunosuppressive cytokines such as transforming growth factor-β (TGF-β). Leflunomide is also a tyrosine kinase inhibitor. Tyrosine kinases activate signalling pathways leading to DNA repair, apoptosis and cell proliferation. Inhibition of tyrosine kinases can help to treating cancer by preventing repair of tumor cells.

Reference: Drug Bank

Safety Data Sheet(s):