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Hazards in determining whether a drug is hazardous

Nadine Badry, Joan Fabbro and Mario L de Lemos J Oncol Pharm Pract published online 20 August 2013 DOI: 10.1177/1078155213496675 The online version of this article can be found at: http://opp.sagepub.com/content/early/2013/08/20/1078155213496675

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Commentary

Oncology Pharmacy Practice

J Oncol Pharm Practice 0(0) 14 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155213496675 opp.sagepub.com

Journal of

Hazards in determining whether a drug is hazardous

Nadine Badry, Joan Fabbro and Mario L de Lemos
BC Cancer Agency, Vancouver, BC, Canada

Abstract The US National Institute for Occupational Safety and Health list and evaluation criteria have provided an important foundation to help institutions identify and create a list of hazardous formulary drugs. However, further guiding principles were needed to make the adoption feasible at our organization. First, we developed separate directives for determining the inherent hazardous toxicity of a drug and for the requirements for safe handling based on dosage forms (exposure risks) of these drugs. Secondly, we created a systematic approach in determining the scope of the drugs reviewed by US National Institute for Occupational Safety and Health. Thirdly, we streamlined our review process by defining which drugs needed to be evaluated by our organization. Finally, we considered the pros and cons of creating a tiered system for classifying hazardous drugs beyond those recommended by US National Institute for Occupational Safety and Health.

Keywords Hazardous substances, occupational exposure, pharmaceutical preparations, consensus, personnel, hospital

Background
Many antineoplastic agents require special precautions because their inherent toxicity poses hazards to the workers who handle these drugs. The US National Institute for Occupational Safety and Health (NIOSH) has published a list of drugs that it considers to be hazardous, initially in 20041 and updated in 20102 and 2012.3 Given the large number of marketed drugs, the NIOSH list clearly cannot be all-inclusive. Therefore, institutions are supposed to supplement it by assessing formulary drugs to develop their own list of hazardous drugs. To help determine if a drug is hazardous, NIOSH has also published assessment criteria13 based on the 1990 American Society Health-System Pharmacists (ASHP) denition of hazardous drugs.4 The development of an institutional list of hazardous drugs at the BC Cancer Agency, British Columbia, Canada has evolved since 2005. British Columbia is the westernmost province of Canada, with a population of about four million and an area equivalent to the countries of France, Germany and Switzerland combined (or the American states of Texas and New Mexico combined). The Agency is a governmentfunded, non-prot, integrated care organization which

delivers cancer drug therapy over the province of British Columbia to approximately 35,000 patients annually via six regional centres and more than 30 hospitals. Annually, the Agency and its partner hospitals handle approximately 300,000 cancer drug prescriptions. During the preparation of the list, we encountered several issues that could not be easily addressed from the list of hazardous drugs or assessment criteria developed by NIOSH. We would like to share some of these issues and the suggested approach to resolve them.

Hazard of inherent toxicity vs. risk of occupational exposure

Unlike the therapeutic use of hazardous drugs in patients, healthcare workers are exposed to the risk of drug toxicity without the clinical benets. NIOSH denes a hazardous drug based on its inherent toxicity then goes on to state: Some drugs dened as hazardous may not pose a signicant risk of direct occupational
Corresponding author: Mario L de Lemos, BC Cancer Agency, 600750 West Broadway, Vancouver, BC V5Z 1H1, Canada. Email: mdelemos@bccancer.bc.ca

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2 exposure because of their dosage formulations.3 This denition would allow safe handling policies to be driven by workers protection from the unchangeable risks (inherent drug toxicity) rather than the resource-dependent hazards (operational needs to minimize occupational exposure). Therefore, we created our list of hazardous drugs by assessing a drugs inherent toxicity and then developed safe handling policies based on the potential for occupational exposure due to the form of the hazardous drug. For example, some drugs dened as hazardous may pose less risk of direct occupational exposure because of their dosage formulation (coated tablets, capsules), or because the dose remains inside the manufacturers original packaging while being handled by pharmacy sta (pre-lled unit-dose syringes, blister-packaged tablets, sachets). These assumptions are consistent with the NIOSH guidance which specically mentions coated tablets and capsules as examples of dosage formulations which may not pose a signicant risk of exposure as long as the dosage form is not manipulated.3 To address these two separate issues, our institution has created two separate directives one to address the inherent hazardous potential of a drug (Supplementary material, Appendix 1) and another to describe the safe handling practice requirements based on the dosage forms of the hazardous drugs (Supplementary material, Appendix 2).

Journal of Oncology Pharmacy Practice 0(0) the NIOSH List 2004 was described as a sampling of major hazardous drugs, it was compiled from lists provided by several major organizations, including the NIH Clinical Center, the Johns Hopkins Hospital, and the Pharmaceutical Research and Manufacturers of America.1 Therefore, it is likely to include most antineoplastic drugs available in the US up to 2004. Second, NIOSH specied that it reviewed drugs marketed in the US between 2004 and 2007 for the 2010 list2 and between 2007 and 2009 for the 2012 list.3 Finally, NIOSH also published several proposed lists between 2004 and 2012: 1. New FDA drugs and warnings tting NIOSH criteria for hazardous drugs (2006)5 2. New FDA drugs and warnings not tting NIOSH criteria for hazardous drugs (2006)6 3. Draft proposed additions and deletions to appendix A of NIOSH alert on hazardous drugs (6 April 2009)7 4. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2012: proposed additions and deletions to the NIOSH hazardous drug list8 We assumed that a drug has been reviewed by NIOSH if it was: . available in the US before 2004, or . included in one or more of the proposed lists mentioned above. Therefore, our list of hazardous drugs is made up of two components (Supplementary material, Appendix 3):

Determining which drugs were reviewed by NIOSH (Figure 1)

There are three major sources for information on the drugs that were reviewed by NIOSH. First, although

Reviewed by NIOSH? Yes No BCCA review

Hazardous?

Hazardous?

No

Yes

Yes

No

BC Cancer Agency Hazardous Drugs List

Figure 1. Review process of hazardous drugs.

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Badry et al. 1. Drugs listed in the most current NIOSH list 2. Drugs assessed by the BC Cancer Agency for their hazardous risks because we could not be certain of their inclusion from the NIOSH reviews.

Refining the risk level

Some groups have attempted to further dene the level of risk associated with exposure to a drug by stratifying the levels of inherent toxicities beyond the criteria recommended by NIOSH. This would lead to a tiered list (e.g. high, low) of hazardous drugs. For example, it has been suggested that certain characteristics (e.g. carcinogenicity, genotoxicity, organ toxicity at low doses) may represent higher risks when compared to others (e.g. teratogenicity, reproductive toxicity).10,11 Therefore, drugs with reproductive toxicity would be assigned with low risk of inherent toxicity. It is not clear, however, how reproductive toxicity from clinical observation should necessarily be more acceptable to the workers than say, genotoxicity from in vitro data. Another approach, recommended by the ASHP,12 is to assign risk level based on a combination of inherent toxicity and estimated level of occupational exposure. Hence, the hazard risk for all intact solid-dosage medication forms is classied as low because occupational exposure is not deemed to be signicant.11,12 Similarly, the ASHP suggests that the hazard risk for monoclonal antibodies would be low because their larger molecular weights limit their dermal absorption. This approach assumes that dermal absorption rather than inhalation is the primary route of exposure13; however, no threshold on the molecular weight has been clearly established. The biotechnology industry proposes 50150 kDa14 based on the observation that allergens and topical dermatological drugs are usually less than 0.5 kDa.15 One consensus guideline used 100 kDa, although some drugs above this threshold were still assigned as high-risk (141 kDa for asparaginase and pegaspargase).10,11 In any case, there is no particular data to suggest that larger molecules would not penetrate suciently over time to cause toxicity. In addition, molecular weight is not the sole determinant of penetration. For example, lipophilicity, polarity, chemical structure, volatility and drug concentration have all been identied as properties that can aect dermal16 and oral absorption.17 Given the need to be cautious when faced with the uncertainty of occupational exposure risks, we have followed the NIOSH approach and have resisted empirically creating dierent levels of hazards. Therefore, as noted earlier, we assign risk level based on the inherent toxicity and develop safe handling practice based on the likelihood of occupational exposure from specic dosage forms. Although our handling of intact, non-sterile forms of hazardous drugs is largely similar to that with non-hazardous drugs, our approach ensures the clear identication of drugs with inherent toxicity so any manipulation of their intact, non-sterile forms would readily lead to more stringent safe handling.

Evaluating a drug (Figure 1)

Assessment of the hazardous potential of a drug is a complex issue. Although the NIOSH alert provides several general considerations when evaluating a drug, the NIOSH decisions often require consultation with expert peer reviewers and extensive public consultation.58 In fact, it is clear from the NIOSH changes proposed in 20065,6,9 and 20118 that fullling one or more of the criteria set out by NIOSH (see below) would not necessarily make a drug hazardous. Therefore, whenever possible, we relied on the decisions derived from the NIOSH review rather than evaluating a drug ourselves (Figure 1). We would only review a drug if: 1. it was not available in the US, 2. it was available in the US after 2004 but not included or mentioned in any of the NIOSH documents (see above), or 3. new information on its hazardous risk became available through Health Canada alerts, US Food and Drug Administration warnings, etc.

Drugs were evaluated using a standardized data collection form (see last page of Supplementary material, Appendix 1). The product monograph for each drug was reviewed, based on the NIOSH criteria, for information regarding2: 1. 2. 3. 4. 5. 6. Carcinogenicity Teratogenicity or other developmental toxicity Reproductive toxicity Organ toxicity at low doses Genotoxicity Structural similarity to drugs already evaluated as hazardous.

By the NIOSH denition, a hazardous drug is a drug which exhibits one or more of these six characteristics in animals or humans. In addition, we would consider a drug to be hazardous if it is used primarily as an antineoplastic agent and information about these characteristics is not available. Drugs that were found to meet the above criteria for a hazardous drug were then added to our BC Cancer Agency hazardous drug list (Supplementary material, Appendix 3).

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4 Recently, based on the NIOSH 2012 List,3 we have created one new hazard category for drugs classied as biohazardous (e.g. Bacillus Calmette-Guerin) which carry dierent inherent risks. This will be incorporated into the next revisions of our directives.

Journal of Oncology Pharmacy Practice 0(0)

6. National Institute for Occupational Safety and Health (NIOSH). New FDA drugs and warnings not fitting NIOSH criteria for hazardous drugs 2006. Cincinnati, OH: NIOSH Publications Dissemination, 2006, pp.15. 7. National Institute for Occupational Safety and Health (NIOSH). NIOSH response to peer review comments from draft proposed additions and deletions to appendix A of NIOSH alert on hazardous drugs (6 April 2009). Cincinnati, OH: NIOSH Publications Dissemination, April 2009, pp.18. 8. National Institute for Occupational Safety and Health (NIOSH). NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2012: proposed additions and deletions to the NIOSH hazardous drug list. Cincinnati, OH: NIOSH Publications Dissemination, July 2011. 9. National Institute for Occupational Safety and Health (NIOSH). NIOSH draft proposed additions and deletions to appendix A of NIOSH alert on hazardous drugs (6 April 2009). Cincinnati, OH: NIOSH Publications Dissemination, 6 April 2009, pp.12. 10. Chaffee BW, Armitstead JA, Benjamin BE, et al. Guidelines for the safe handling of hazardous drugs: consensus recommendations. Am J Health-Syst Pharm 2010; 67: 15451546. 11. University HealthSystem Consortium. UHC consensus statement: model hazardous drug safety plan for institutions. Oak Brook, IL: University HealthSystem Consortium, 2009, pp.122. 12. Center for Disease Control and Prevention. NIOSH Docket 105: Submission to the docket from Reilly/ Coffey (American Society of Health-System Pharmacists) 20 September 2007. http://www.cdc.gov/ niosh/docket/archive/docket105.html (6 July 2010, accessed 6 March 2013). 13. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J HealthSyst Pharm 2006; 63: 11721193. 14. Center for Disease Control and Prevention. NIOSH Docket 105A: Submission to NIOSH Docket from Sara Radcliffe (BIotechnology Industry Organization) 30 June 2009. October 12, http://www.cdc.gov/niosh/docket/ archive/docket105A.html (2010, accessed 6 March 2013). 15. Bos JD and Meinardi MMHM. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol 2000; 9: 165169. 16. Hoang KT, ed. Dermal exposure assessment: principles and applications. Washington, DC: US Environmental Protection Agency, Office of Health and Environmental Assessment, EPA/600/8-91/011B, 1992. 17. Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997; 34: 325.

Conclusion
The NIOSH list and evaluation criteria have provided an important foundation to help facilities, institutions and health authorities identify and create a list of hazardous formulary drugs. However, we found that we needed to provide further guiding principles to make the adoption feasible. First, we developed separate directives for determining the inherent hazardous toxicity of a drug and the requirements for safe handling based on dosage forms (exposure risks) of the hazardous drugs. Secondly, we created a systematic approach in determining the scope of the drugs reviewed by NIOSH. Thirdly, we streamlined our review process by dening which drugs needed to be evaluated by the BC Cancer Agency. Finally, we took into consideration the pros and cons of creating a tiered system for classifying hazardous drugs that goes beyond those recommended by NIOSH. Funding
This research received no specic grant from any funding agency in the public, commercial, or not-for-prot sectors.

References
1. National Institute for Occupational Safety and Health (NIOSH). Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. Cincinnati, OH: NIOSH Publications Dissemination, September 2004, pp.3140. 2. National Institute for Occupational Safety and Health (NIOSH). NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2010. Cincinnati, OH: NIOSH Publications Dissemination, September 2010, pp.111. 3. National Institute for Occupational Safety and Health (NIOSH). NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2012. Cincinnati, OH: NIOSH Publications Dissemination, June 2012, pp.114. 4. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990; 47: 10331049. 5. National Institute for Occupational Safety and Health (NIOSH). New FDA drugs and warnings fitting NIOSH criteria for hazardous drugs 2006. Cincinnati, OH: NIOSH Publications Dissemination, 2006, pp.13.

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