Objectives 5/19/2017. Hazardous Drugs Sunnybrook Health Sciences Centre s Experience. Hazardous Drug Committee at Sunnybrook

Transcription

1 s Sunnybrook Health Sciences Centre s Experience Romina Marchesano Drug Information Pharmacist Sunnybrook Health Sciences Centre Objectives Review: SHSC approach to NIOSHs list of s and USP <800>/ NAPRA Standards Proposed Algorithm for Classifying NIOSH Group 2 and 3 Drugs Risk Assessment of NIOSH Group 2 and 3 Drugs Plan for implementation Committee at Sunnybrook Director of Pharmacy Manager of Odette Cancer Centre Manager of the Acute Care Pharmacy Oncology Pharmacist Drug Information Pharmacists Coordinator IV and Chemotherapy Preparation Training and Certification Program 1

2 SHSC Criteria for Classifying Drugs as Hazardous A drug is considered hazardous if 1 or more of these criteria are met: 1. A Table 1 drug on the NIOSH 2016 List of s (antineoplastic drugs, including those with manufacturer s safe handling guidance (MSHG). 2. A Table 2 drug on the NIOSH 2016 List plus one or more of the following: IARC Group 1 or 2A Carcinogen Manufacturer s Safe Handling Guidance (MSHG) FDA Pregnancy Category X Black Box safety warning in the product monograph. 3. A Table 3 drug on the NIOSH 2016 list with a FDA Pregnancy Category X and/or Black Box safety warning in the product monograph. 4. Oncology drugs classified as Hazardous by British Columbia Cancer Agency (BCCA) which have been approved since the most recently published NIOSH HD list*. 5. If a new drug has a structure and toxicity profile that mimic existing drugs determined hazardous by the above criteria. * manual Drugs marketed prior to the publication of the 2016 NIOSH list and not deemed hazardous by NIOSH will not be considered HD abiraterone acitretin AFAtinib amsacrine anastrozole arsenic trioxide axitinib azacitidine azathioprine BCG (intravesical) bendamustine bicalutamide bleomycin bortezomib bosentan bosutinib brentuximab busulfan cabazitaxel capecitabine CARBOplatin carfilzomib carmustine ceritinib chlorambucil chloramphenicol Consolidated List CISplatin cladribine clofarabine clomiphene crizotinib cyclophosphamide cyclosporine cytarabine dabrafenib dacarbazine DACTINomycin dasatinib DAUNOrubicin decitabine degarelix dexrazoxane dienogest diethylstilbestrol (DES) DOCEtaxel DOXOrubicin dronederone dutasteride entecavir enzalutamide epirubicin eribulin erlotinib estramustine estrogens etoposide everolimus exemestane finasteride fingolimod floxuridine fludarabine 5-fluorouracil flutamide fulvestrant ganciclovir gemcitabine goserelin histrelin hydroxyurea ibrutinib IDArubicin idelalisib ifosfamide imatinib irinotecan isotretinoin ixabepilone ixazomib leflunomide lenalidomide letrozole leuprolide lomustine mechlorethamine Medroxy- PROGESTERone megestrol melphalan mercaptopurine methotrexate misoprostol mitomycin mitotane mitoxantrone mycophenolate nelarabine nilotinib nivolumab osimertinib oxaliplatin PACLitaxel paliperidone panitumumab pazopanib pembrolizumab pemetrexed PERTuzumab Pomalidomide ponatinib pralatrexate procarbazine Progesterone (compounding) progestins raloxifene raltitrexed regorafenib reovirus serotype 3 dearing strain ribavarin risperidone romidepsin ruxolitinib sirolimus SORAfenib streptozocin SUNItinib tacrolimus tamoxifen temozolomide temsirolimus teniposide terflunomide testosterone thalidomide thioguanine topotecan trametinib trastuzumab emtansine tretinoin triptorelin ulipristal valganciclovir valrubicin vandetanib vemurafenib vinblastine vincristine vinorelbine vismodegib vorinostat ziv-aflibercept What about the other Drugs on the NIOSH list? The cost of classifying the remaining drugs on the NIOSH list as hazardous would cost a minimum of ~$100,000/year based on our usage data and our in-house study on the cost of packaging. This does not account for the time/ppe required to prepare oral solutions and injectables under the BSC and the PPE required by Nursing to administer the medication. 2

3 Economic Evaluation of Adding A Drug To The Hospital's List Ma N, Kulchycki A, Hayes J, Carating H, Walker SE. Department of Pharmacy, Sunnybrook Health Sciences Centre, and Leslie Dan Faculty of Pharmacy, University of Toronto. Toronto, Ontario. Objective To determine the incremental cost of unit dose (UD) packaging a drug as a hazardous product based on NIOSH standards. Methods Labor, material and personal protective equipment (PPE) costs for packaging both hazardous and nonhazardous drugs was determined for various methods including blister packaging, Ziploc bag over wrap, PACMed, Cadet, and AutoBag. Costs were then used to estimate the cost of adding three drugs, clonazepam, phenytoin, and warfarin, to the hospital's hazardous drug list. Results: The cost to package non-hazardous drugs using either the Cadet or PACMed ranged from $ /UD. Two primary methods for packaging intact tablets and capsules as hazardous drugs were identified. The first method, manually blister packing followed by overwrapping with a Ziploc bag, cost $0.77/UD. The second was to package the drug with the Cadet, followed by an AutoBag overwrap, which cost $0.54/UD. In the previous fiscal year, 108,193 doses of clonazepam, phenytoin, and warfarin were dispensed. The total cost to package and administer all doses using the Cadet packaging method was estimated as $58, annually, Conclusion Packaging and administering hazardous drugs cost about $0.50/UD more than non-hazardous oral dosage forms. USP <800> USP allows for other s (HDs) to be handled differently under specific circumstances. The only HDs that can be considered for alternative handling are: Antineoplastic drugs listed in Table 1 that will not be manipulated (i.e. counting or packaging) Non-antineoplastic drugs listed in Table 2 (Group 2) that are not Active Pharmaceutical Ingredients Reproductive risk drugs listed in Table 3 (Group 3) These types of HDs can be treated in one of two ways: 1) Handle all as HDs and use all the containment strategies in USP <800> 2) Assess risk and determine which specific dosage forms may be handled with alternative strategies and/or work practices that maintain staff protection. USP <800>; Patricia C. Kienle and Kate Douglass Pharmacy Purchasing & Products March 2017; Eric Kastango USP Chapter <800> and Assessment of Risk NIOSH Group 1 Drugs Antineoplastic drugs - we follow USP <800> or NAPRA guidelines for safe handling and containment All manipulations are done in pharmacy Splitting, crushing, injectables 3

4 NIOSH Group 2 Drugs For each medication in Group 2 (available in Canada), a review of hazardous risk from the following resources was undertaken: NIOSH List of s International Agency for Research on Cancer (IARC) of the World Health Organization National Toxicology Program (NTP) Product Monograph and Manufacturing Safe Handling Guidelines Safety Data Sheets Literature Studies in humans Studies in animals Other institution s approach to safe handling Algorithm for classification An algorithm for classification of Group 2 and Group 3 Drugs was proposed A drug would be classified as: A OR A Reproductive Risk Drug REPRODUCTIVE RISK ALERT If you are pregnant, trying to conceive, or are breast-feeding, observe special handling, administration, and disposal Reproductive Risk Drug De-list 4

5 NIOSH Group 2 Drugs IARC 1: azathioprine cyclosporine estrogen(s) IARC 2A: chloramphenicol Other risperidone paliperidone* HD Carcinogenic Drugs Agents that have evidence supporting human carcinogenicity: International Agency for Research on Cancer (IARC) Group 1 Carcinogen = known human carcinogen, OR IARC Group 2A Carcinogen = probable human carcinogen, OR Other indication of potential human risk o Animal model studies positive for tumors while receiving less than the equivalent maximum recommended human dose, AND o Same tumor/cancer in animal model to also be found in humans, AND o Human tumor/cancer must be reported by a pharmacovigilance study. *metabolite of risperidone NIOSH Group 2 Drugs mycophenolate sirolimus tacrolimus Biologic Response Modifier fingolimod leflunomide lenalidomide thalidomide tofacitinib Immunosuppressive Immunomodulator teriflunomide* HD Immune Modulators Agents used for the treatment of certain types of cancers, autoimmune diseases, and preventing organ transplant rejections. All agents carry the risk for immunosuppression which increases the risk for developing malignancies or serious infections. Agents with one of the following AHFS classification: o Immunosuppressive agents (92:44) o Biologic response modifiers (92:36) o Immunomodulatory agents (92:20) *metabolite of leflunomide; AHFS = American Hospital Formulary Service NIOSH Group 2 Drugs Estrogens, Estrogens Agonist/ Antagonist estradiol estrogens raloxifene Progestins medroxyprogesterone progesterone Combination estrogen/ progesterone contraceptives HD Hormone or Hormone Receptor Modulators Agents with one of the following AHFS classification: o Estrogens (68:16:04) o Estrogen Agonist-Antagonist (68:16:12) o Progestins (68:32) o Contraceptives (68:12) 5

6 NIOSH Group 2 Drugs cidofovir (SAP) dexrazoxane ganciclovir valganciclovir HD Drugs with Manufacturers Safe Handling Guidance (MSHG) Agents that have received the manufacturers safe handling guidance NIOSH Group 2 and 3 Drugs Reproductive Risk Drugs NIOSH Group 2 FDA Pregnancy Risk D and X carbamazepine deferiprone divalproex fosphenytoin phenytoin propylthiouracil NIOSH Group 3 FDA Pregnancy Risk D and X See table on next page RRD Reproductive Risk Drugs These agents pose a risk to men and women who are actively trying to conceive and women who are pregnant or breast feeding. Agents must be either NIOSH Group 2 drugs with FDA Pregnancy Risk D or X, or NIOSH Group 3 drugs with FDA Pregnancy Risk D or X Medications that are FDA Pregnancy Risk B and C are not included in the list of drugs that require special handling as there is no human data to suggest that these medications cause harm. NIOSH Group 3 Drugs with FDA Pregnancy Risk D and X Group 3 Drugs NIOSH Classification Group 3 Drugs NIOSH Classification acitretin NIOSH 3; Black Box; Preg X misoprostol (Arthrotec ) NIOSH 3; Preg X alitretinoin NIOSH 3; Preg D nafarelin NIOSH 3; Preg X NIOSH 3; Black Box; paroxetine NIOSH 3; Preg D ambrisentan Preg X pamidronate NIOSH 3; Preg X NIOSH 3; Black Box; plerixafor NIOSH 3; Preg D bosentan Preg X ribavirin NIOSH 3; Preg X cetrorelix NIOSH 3; Preg X riociguat NIOSH 3, Preg X choriogonadotropin NIOSH 3; Preg X temazepam NIOSH 3, Preg X clomiphene NIOSH 3, Preg X testosterone NIOSH 3; Preg X NIOSH 3; topiramate NIOSH 3; Preg D clonazepam Preg D; first trimester NIOSH 3; Black Box; dronedarone NIOSH 3; Preg X tretinoin Preg X dutasteride NIOSH 3; Preg X ulipristal NIOSH 3; Preg X finasteride NIOSH 3; Preg X NIOSH 3; Black box; ganirelix NIOSH 3; Preg X valproic acid Preg D lomitapide NIOSH 3, Preg X voriconazole NIOSH 3; Preg D macitentan NIOSH 3, Preg X warfarin NIOSH 3; Preg D mentropins NIOSH 3; Preg X zoledronic acid NIOSH 3; Preg D 6

7 NIOSH Group 3 Drugs with FDA Pregnancy Risk B and C NOT INCLUDED due to lack of human evidence for reproductive risk Group 3 Drugs Cabergoline Colchicine Dinoprostone Ergonovine/methylergonovine Eslicarbazepine Fluconazole Gonatotropin, chorionic Icatibant Oxytocin Pasireotide Pentetate calcium trisodium Telavancin Vigabatrin Ziprasidone Cabergoline NIOSH Classification NIOSH 3; Preg B NIOSH 3, Preg C NIOSH 3, Preg C NIOSH 3; Black box (fetal risk, reproductive outcomes); Preg C NIOSH 3; Preg B Reproductive Risk Drug De-list NIOSH Group 2 Drugs abacavir entecavir liraglutide nevirapine oxcarbazepine rasagaline spironolactone zidovudine Remove from list 7

8 NIOSH Group 2 Drugs to De-List NIOSH Group 2 Drug NIOSH Rationale for listing Route Our Findings abacavir Preg C Oral entacavir Preg C Oral liraglutide recombinant Preg C SC nevirapine Preg B Oral oxcarbazepine Preg C Oral rasagiline Preg C Oral Black Box; spironolactone Preg C Oral IARC 2B; zidovudine Preg C Oral Not Available in Canada Drug Not Available NIOSH Rationale for in Canada listing altretamine NIOSH 1; Preg D bexarotene NIOSH 1; Preg D gemtuzumab ozogamicin omacetaxine pentostatin thiotepa toremifene trimetrexate alefacept apomorphine NIOSH 1; Preg D NIOSH 1; Preg D NIOSH 1; Preg D NIOSH 1; IARC 1; Preg D NIOSH 1; Preg D NIOSH 1; Preg D Preg B Preg C Drug Not Available in Canada NIOSH Rationale for listing Black Box; estropipate Preg X fluoxymesterone Preg X palifermin Preg C IARC 2B; phenoxybenzamine Preg C pipobroman Preg D uracil mustard Preg D mipomersen Preg B ospemifene Preg X methyltestoterone NIOSH 3; Preg X peginesatide NIOSH 3, Preg C zonisamide Determine Risk of Exposure The actual risk to healthcare workers depends on toxicity of the drugs, how the drugs can enter the body (e.g., dermal, inhalation, or ingestion), and how the drugs are handled how they are manipulated, how often they are handled, and the exposure controls in place, such as the type of engineering controls and personal protective equipment (PPE). (NIOSH 2016) For example, Low Risk Higher Risk Highest Risk Dispensing a single tablet Single pair of gloves may be adequate Repeatedly counting, cutting, or crushing tablets Contamination to workplace if exposure controls are not in place If a containment device such as a BSC (Class II biological safety cabinet) or CACI (compounding aseptic containment isolator) is not available, then double gloves, a protective gown, respiratory protection, and a disposable pad to protect the work surface should be used. Preparing several intravenous doses of an antineoplastic drug In addition to double gloving and a protective gown, an engineering control such as a BSC or CACI, possibly supplemented with a CSTD (closed system drug-transfer device), is necessary to protect the drug, environment, and healthcare worker. 8

9 Assessment of Risk and Stratification Identify and use alternative containment strategies and/or work practices for specific dosage forms of HDs that are not antineoplastic agents or are not active pharmaceutical ingredients (API) Example: Oxytocin nurses wear PPE in their 2 nd and 3 rd trimester of pregnancy USP Chapter 800 and Assessment of Risk Webinar by Eric Kastango ( Patricia C. Kienle and Kate Douglass. Perform an Assessment of Risk to Comply with USP <800>. Pharmacy Purchasing & Products March 2017 Assessment of Risk (AoR) Documentation Drug Name: Data Assessment of Risk (AoR) Initially Performed: Date of AoR Reviewed: HD Drug Category: Antineoplastic Non-antineoplastic Reproductive Risk Only Delist Dosage form (select one): Sterile dosages compounded by a vendor and not requiring additional manipulation Dosage forms of conventionally manufactured product that require only packaging or counting Other: Describe Packaging: Rationale for not requiring all <800> containment Specific Alternative Administrative, Engineering strategies and Work Practice Control Strategies Document rationale here: Literature: IARC: MSHG: SDS: Document specific alternative strategies below or N/A (see below) Based on Assessment of Risk will proceed as follow: Follow alternative strategies documented above Follow all USP <800> requirements Assessment of Risk written by RPh Date: Reviewed by Pharmacy Manager: RPh Date: Patricia C. Kienle and Kate Douglass Pharmacy Purchasing & Products March 2017 Alternative containment strategies Alternative containment strategies can be used for Group 2 and 3 drugs. Examples include: Closed system transfer device Dissolve a medication in an oral syringe Must consider time to dissolve Personal Protective Equipment (PPE) Ensure nursing is aware of proper PPE when preparing a Reproductive Risk Drug for administration Pre-prepare common units of use Prepare syringes of oral solution in advance for the common doses phenytoin 300 mg valproic acid 250 mg Prepare in-house suspensions in bulk (e.g. finasteride) Auto-substitution for similar product (e.g. temazepam would be substituted to lorazepam) Patricia C. Kienle and Kate Douglass Pharmacy Purchasing & Products March

10 Plan for Implementation All of table 2 drugs that were deemed to be Hazardous will be treated as a. The HD policy and procedures must be followed. For the Reproductive Risk Drugs Involve Nursing from the beginning - a working group to determine alternative containment strategies for different drug formulations. Occupational Health and Safety endorsement Policy for Reproductive Risk Drugs Education for all staff (learning modules) Packaging and labelling with Reproductive Risk Alert, notification of Reproductive Risk on the MAR Policy for Reproductive Risk Drugs Policy for Reproductive Risk Drugs will be separate from Policy Staff is responsible for taking necessary precautions if they are: Actively trying to conceive Pregnant, breastfeeding Planning to have children in the near future Yearly acknowledgment of the policy and expectations of appropriate precautions Packaging and Labelling of Reproductive Risk Drugs Medications will be supplied as unit-dose, ready-toadminister tablets, capsules, liquid oral or injectable preparations in sealed plastic bags. USP <800> prohibits the use of unit dose packaging machines for antineoplastic drugs. For Group 2 and 3 drugs, machines can be used. Cleaning should occur with the appropriate agent (germicidal, sporicidal, decontamination) Reproductive Risk Alert auxiliary label will be placed on the plastic bag REPRODUCTIVE RISK ALERT If you are pregnant, trying to conceive, or are breast-feeding, observe special handling, administration, and disposal MAR entry will indicate the drug has a reproductive risk 10

11 Evaluate dosage form for each drug NIOSH Group 2 Drugs carbamazepine Tablet Capsule Oral solution Injectable Immediate release tablet SR tablet deferiprone divalproex fosphenytoin methimazole Enteric coated tablet IV, SC phenytoin IV propylthiouracil Evaluate dosage form for each drug NIOSH Group 3 Drugs acitretin alitretinoin ambrisentan bosentan cetrorelix choriogonadotropin clomiphene clonazepam dronedarone dutasteride finasteride ganirelix lomitapide macitentan menotropins misoprostol (Arthrotec) PFS=prefilled syringe Tablet Capsule Oral solution Injectable Hard gelatin Soft cap Film coated Film coated SC (vial) SC (vial) Film coated Soft gelatin Film coated SC (PFS) Film coated SC (vial) Enteric coated Other Continued. NIOSH Group 3 Tablet Capsule Oral Injectable Other Drugs solution nafarelin nasal paroxetine Film coated pamidronate IV plerixafor SC (vial) ribavirin Coated riociguat Film coated temazepam Soft gelatin IM Patch, testosterone gel topiramate Film coated Soft gel Cream, tretinoin, isotretinoin gel ulipristal valproic acid IV Film coated Powder for IV voriconazole suspension warfarin zoledronic acid IV 11

12 Handling/Manipulation and PPE required for Administration Route of Administration Instructions to Nursing Personal Protective Equipment required Tablet/ capsule to be administered whole Split tablet Tablet to be crushed for oral/enteral tube administration Capsule for dysphagic patient or enteral tube administration IM/SC IV Administer whole pill Split in pharmacy Nurse only administers If oral solution available, pharmacy to dispense in oral syringe OR Nurse to dissolve/crush a dose in a syringe To be determined Prefilled syringe or Prepared in Pharmacy Nurse only administers Single pair chemo gloves Single pair chemo gloves Single pair chemo gloves Gown Absorbent pad Mask (if potential for splashing) Eye protection (if potential for splashing) To be determined Double Chemo gloves Gown Absorbent pad Eye protection (if potential for splashing) Road Ahead Our goal is to implement RRD in the next several months Policy approval and endorsement by Nursing, Occupational Health and Safety Education of all staff Operationalizing the change Questions & Feedback? romina.marchesano@sunnybrook.ca I admit we may have missed one or two of the regulations in USP <800> 12

13 References NIOSH 2016 USP <800> NAPRA Model Standards for Pharmacy Compounding of Hazardous Sterile Preparations USP Chapter 800 and Assessment of Risk Webinar by Eric Kastango ( Patricia C. Kienle and Kate Douglass. Perform an Assessment of Risk to Comply with USP <800>. Pharmacy Purchasing & Products March 2017 Power LA, Polovich M. Safe Handling of s: Reviewing Standards for Worker Protection. Pharmacy Practice News. Sept Connor TH, Celano P, Frame JN, Zon RT. Summary of the Workshop on the Safe Handling of Hazardous Drugs Cohosted by the NIOSH and American Society of Clinical Oncology. Am Soc Clin Onc. 2017: 13(3); NIOSH Group 2 Drug abacavir entacavir liraglutide recombinant nevirapine Summary of our Findings for Table 2 Drugs to De-list NIOSH Rationale for listing Preg C Preg C Preg C Preg B Summary of our Findings No studies have demonstrated in humans. All laboratory studies, including those performed in mice, rats and in vitro, used doses equivalent greater than 6x the expected human systemic exposure. No human carcinogenicity studies. All animal studies exposed model to >35x maximum expected human doses Animal studies showed male and female rats developing thyroid C- cell tumors at doses of 0.075mg/kg/day (=0.5x human dose based on AUC). Rodents were found to have greater concentrations of GLP-1 receptors located on C-cells, which is the likely explanation for proliferation and tumorigenicity. Comparatively, humans have much lower levels of expression of GLP-1 receptors on C-cells. A subsequent study demonstrated there was no increase in calcitonin when patients were administered liraglutide. Thus, the potential tumorigenicity of liraglutide remains minimal in humans. No human studies completed. Animal models suggest hepatocellular adenomas are species specific. Continued. NIOSH Group 2 Drug oxcarbazepine rasagiline NIOSH Rationale for listing Preg C Preg C Summary of our Findings No evidence for teratogenicity, mutagenicity or carcinogenicity. Oxcarbazepine may merit Pregnancy Risk given its structural similarity to carbamazepine and the teratogenic effect of anticonvulsants No compelling evidence for carcinogenicity or toxicity in humans. One report of increased incidences of Parkinson s dementia patients receiving rasagiline developing skin cancer. However, other reports have noted that Parkinson s dementia patients generally have higher incidences of skin cancer compared to that of the general population. Only 1 of 2 animal models developed cancer at doses of ~75x greater than the MRD for humans. 13

14 NIOSH Group 2 Drug spironolactone zidovudine NIOSH Rationale Black Box; Preg C IARC 2B; Preg C Summary of our Findings Continued. The Black Box warning is based on laboratory studies where male and female rats developed thyroid adenomas and male rats developed interstitial-cell adenomas in testis. Numerous studies have looked at the association between spironolactone or other potassium sparing diuretics, and were unable to identify a relationship with thyroid, renal cell, breast, ovarian, or uterine cancer. The IARC has since issued a statement that there is inadequate evidence in humans for the carcinogenicity of spironolactone. IARC Summary There is inadequate evidence in humans for the carcinogenicity of spironolactone. There is limited evidence in experimental animals for the carcinogenicity of spironolactone. Overall evaluation: Spironolactone is not classifiable to its carcinogenicity to humans. The IARC cites several early studies that looked at the association of zidovudine with non-hodgkin lymphoma (NHL), an AIDS-defining cancer. The initial report by Pluda et al. (1990) raised concerns over potentially increased rates of NHL among patients enrolled in longterm Phase I trials of zidovudine. Although the results of the report indicate patients had a median CD4 + count of 6cells/mm 3 (range, 4-21cells/mm 3 ) at the time of NHL diagnosis, the authors did not discount the potential of zidovudine as the cause. Subsequent studies, including a randomized, placebo-controlled trial, have failed to demonstrate a relationship between zidovudine and NHL. 14