August 2014 FAQs

What are the proposals of the new USP <800> chapter, “Hazardous Drugs – Handling in Healthcare Settings?”

Introduction

The United States Pharmacopeial Convention (USP) is developing a chapter for the National Formulary (USP-NF) that will establish safety standards for handling hazardous drugs (HDs).1 Although guidelines on hazardous drug handling are available from other organizations, USP has yet to include a specific chapter on this in the USP-NF.2-7 The current USP <797> (Pharmaceutical compounding – sterile preparations) and <795> (Pharmaceutical compounding – nonsterile preparations) chapters include brief sections on HDs, but the proposed <800> chapter provides more detail on hazardous drug storage, transportation, and handling, as well as compounding, administration, and disposal.1,8,9 The proposed <800> chapter emphasizes HD containment in order to protect personnel and the environment when handling both sterile and nonsterile HDs. This chapter will be a resource for healthcare practitioners and staff, occupational health and safety specialists, and human resources. The current language in the proposed chapter includes the word “shall,” meaning required, and “should,” meaning strongly recommended. The chapter will be useful in addressing the following in relation to HDs:

• Design of clean rooms
• Logistics of transportation
• Prevention of worker and environmental exposure
• Clean-up and disposal
• Unpacking
• Storage
• Compounding
• Dispensing
• Administration
• Use of personal protective equipment

Hazardous drug definition and risks

A HD is defined as any chemical that is a health hazard, including those considered to be carcinogens, teratogens, reproductive toxins, genotoxins, irritants, corrosives, sensitizers, and/or agents that produce target organ effects.2,3 While the proposed <800> chapter does not contain a list of HDs, they refer to The National Institute for Occupational Safety and Health (NIOSH) list of HDs which is updated periodically.10 Drugs that are classified as chemotherapy, antivirals, hormones, and immunosuppressants are commonly considered hazardous. The proposed <800> chapter requires institutions to maintain their own list of HDs, including those on the NIOSH list and any others they determine to be hazardous. Institutions should review their list annually.

Hazardous drugs have been associated with spontaneous abortion and congenital malformations.11,12 In a 2012 retrospective study of nurses who had reported exposure to antineoplastic drugs (n=7482 women who each became pregnant), an associated 2-fold risk for spontaneous abortion was identified. 11 The risk was increased to 3.5-fold in nulliparous women. In an earlier study of both nurses and pharmacists who had been exposed to antineoplastic drugs (n=2976 women and a total of 7094 pregnancies), the risk of spontaneous abortion was increased by 1.5-fold. A 1.4-fold increase was identified for the combined risk of spontaneous abortion and stillbirth .12

Given these data and risk for immediate adverse effects with exposure to HDs, there is a clear need for preventing exposure of HDs to all involved in handling them.

Highlights of USP <800>

The proposed <800> chapter begins with discussion of fundamental practices and precautions, maintaining a list of HDs, types of exposure, and personnel responsibilities including appropriate training and designation of a compounding supervisor.1 The remainder of the chapter provides specific guidance on facility design and engineering controls, as well as personal protective equipment (PPE) and transportation of HDs.

Engineering controls, facility design, and compounding

A major focus of the <800> chapter is on primary and secondary containment engineering controls (C-PECs and C-SECs) as related to storage and compounding of HDs.1 The C-PECs are ventilated devices used to minimize worker and environmental exposure to HDs. Biological safety cabinets (BSCs), compounding aseptic containment isolators (CACIs) and containment ventilated enclosures (CVEs) constitute C-PECs. The C-SEC is the room in which the C-PECs are placed. These should be negative pressure separate rooms that are externally ventilated. Hazardous drugs that require refrigeration will need to be placed in a refrigerator in a negative pressure room. The rooms in which HDs are stored and compounded also require certain air changes per hour (ACPH). The ACPH for storage of HDs is 12. See the Table for required ACPH for compounding nonsterile and sterile HDs, as well as a detailed description of other engineering controls. In general, separate areas should be designated in the facility for unpacking of HDs, compounding of nonsterile HDs, and compounding of sterile HDs.

The <800> chapter is very detailed in its discussion of possible configurations for compounding, and Appendix E contains actual diagrams that institutions may refer to when considering the possibilities and limitations of their own space.1 Most of the information in <800> is in addition to the information found in <797> and <795>.1,8,9 However, there are a couple of recommendations that differ from <797>.1,8 These are outlined in Box 1 below. Perhaps the greatest impact will come from removal of the <797> exemption that allows for small volumes of HDs to be compounded in a positive pressure room. However, <800> mitigates removal of this exemption by allowing for low- and medium-risk HDs to be compounded in a containment segregated compounding area (C-SCA), which does not need to be a “clean room,” but does need to have negative air pressure. Chapter <797> currently does not allow for this.

C-SCAs=containment segregated compounding areas; CSTDs=closed system transfer devices.

Personal protective equipment and personnel training

The proposed chapter requires personal protective equipment (PPE) to be worn when handling HDs, and describes its use in detail.1 The appropriate use of gloves, gowns, and head, hair, and shoe covers, as well as eye and face protection is discussed in the proposed chapter. Appendix F of the chapter is a table that lists certain activities involving HDs (eg, receiving, stocking) and the PPE that is required.

The proposed chapter also requires each institution to develop a training program so anyone who works with HDs is knowledgeable on standard procedures for their storage, handling, and disposal.1 Competency should be assessed and documented annually. The compounding supervisor is responsible for developing the training and demonstrating procedures for personnel involved.

Dispensing and administration

If an HD is in a unit dose packaging, there are no further requirements for alteration prior to dispensing to the patient.1 If non-antineoplastic drugs need to be transferred from their packaging to a prescription bottle, they should be counted with equipment (spatula, tray) dedicated for use with these drugs.

Along with addressing storage and handling, USP <800> provides measures for protecting those administering HDs.1 When the dosage form allows, a closed-system transfer devices (CSTD) should be used to administer an HD. Nurses and anyone administering HDs should also be familiar with the Oncology Nursing Society Safe Handling of Hazardous Drugs.4

Conclusion

The proposed <800> chapter will be another resource and helpful addition that will complement USP <797> and <795>. The publication date is unknown, but it will become enforceable 6 months after publication.13 Once <800> is published, <797> will be revised to reflect the changes in <800>. The proposed <800> chapter can be accessed through a link on USP’s website: http://www.usp.org/usp-nf/notices/compounding-notice.

References

1. General Chapter <800> Hazardous Drugs—Handling in Healthcare Settings. US Pharmacopeial Convention website. http://www.usp.org/usp-nf/notices/compounding-notice. Accessed June 19, 2014.

2. ASHP Guidelines on Handling Hazardous Drugs. American Society of Health-System Pharmacists website. http://www.ashp.org/DocLibrary/BestPractices/PrepGdlHazDrugs.aspx. Accessed June 19, 2014.

3. NIOSH alert: preventing occupational exposure to anti-neoplastic and other hazardous drugs in health care settings. National Institute for Occupational Safety and Health website. www.cdc.gov/niosh/docs/2004-165/. Accessed June 23, 2014.

4. Polovich M. Safe Handling of Hazardous Drugs. 2nd Ed. Pittsburgh, PA: Oncology Nursing Society; 2011.

5. 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(18):1545-1546.

6. International Society of Oncology Pharmacy Practitioners Standards Committee. ISOPP standards of practice. Safe handling of cytotoxics. J Oncol Pharm Pract. 2007;13 Suppl:1-81.

7. 2014 U.S. Pharmacopeia National Formulary: USP 37 NF 32. Rockville, MD: The United States Pharmacopeial Convention; 2014. http://www.uspnf.com/uspnf/pub/index?usp=37&nf=32&s=0&officialOn=May%201,%202014 . Accessed June 20, 2014.

8. <797> Pharmaceutical compounding – sterile preparations. 2014 U.S. Pharmacopeia National Formulary: USP 37 NF 32. Rockville, MD: The United States Pharmacopeial Convention; 2014. http://www.uspnf.com/. Accessed June 23, 2014.

9. <795> Pharmaceutical compounding – nonsterile preparations. 2014 U.S. Pharmacopeia National Formulary: USP 37 NF 32. Rockville, MD: The United States Pharmacopeial Convention; 2014. http://www.uspnf.com/. Accessed June 23, 2014.

10. NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2012. Centers for Disease Control and Prevention website. http://www.cdc.gov/niosh/docs/2012-150/pdfs/2012-150.pdf. Accessed June 23, 2014.

11. Lawson CC, Rocheleau CM, Whelan EA, et al. Occupational exposures among nurses and risk of spontaneous abortion. Am J Obstet Gynecol. 2012;206(4):327.e1-327e8.

12. Valanis B1, Vollmer WM, Steele P. Occupational exposure to antineoplastic agents: self-reported miscarriages and stillbirths among nurses and pharmacists. J Occup Environ Med. 1999;41(8):632-638.

13. Kienle PC. New proposed USP <800>: Hazardous drug handling. PP&P. 2014;11(5):34-38.

August 2014

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How should beyond-use-dates for compounded preparations be determined?

Introduction

In light of drug shortages, concerns about outsourcing pharmacy services, and unique patient needs, Hospital Pharmacy Services is often required to compound pharmaceutical preparations. To ensure appropriate compounding practices and assignment of a beyond-use-date (BUD), appropriate resources should be consulted and multiple factors including stability, sterility, compatibility, and risk level should be considered.1-3 This article summarizes steps in determining the most appropriate BUD for a compounded sterile preparation (CSP) or a compounded nonsterile preparation based on United States Pharmacopeia (USP) guidance and best practices.

Compounded sterile preparations include injections, aqueous bronchial and nasal inhalations, baths and soaks for live organs and tissues, irrigations for wounds and body cavities, and ophthalmic drops and ointments.1 Other preparations can generally be classified as nonsterile.2 When compounding nonsterile preparations, stability and compatibility need to be considered. When compounding sterile preparations stability, sterility, compatibility, and risk level need to be considered.1 Compounding of sterile preparations is guided by USP <797>, whereas compounding of nonsterile preparations is guided by USP <795>.1,2 USP provides guidance on appropriate compounding practices and assignment of BUDs. Extended-dating or use of a preparation later than the USP recommended BUD should be supported by the literature or by sterility testing.

Steps to determine BUDs

When determining appropriate compounding practices and assignment of a BUD, the manufacturer(s) of the pharmaceutical ingredients should provide the most accurate information.1-3 In the absence of manufacturer information, published literature can be reviewed. However, if there are any deviations between the literature and the institution’s practices, then USP guidance should be used to assign a BUD. Deviations include differences in brands, concentrations, or formulations of products used; types of containers or devices; risk level; environmental variables; and storage conditions. Additionally, deviations may render the ingredients incompatible and these factors should be carefully considered before proceeding. For CSPs, the literature should address both stability and sterility of the final preparation.1,3 If the dates are different for stability and sterility, then the shorter of the 2 dates should be used to assign a BUD. If the literature addresses only one of these factors, then USP guidance should be followed when assigning a BUD. Critical interpretation of sources is necessary to determine a conservative and safe BUD.

USP guidance to assign BUDs

The BUD per USP guidance indicates the amount of time the preparation is expected to be stable (for sterile and nonsterile preparations) and sterile (for CSPs) from the start of preparation to the time of administration.1,2 USP <795> BUDs for nonsterile preparations are summarized in Table 1 below.2

API=active pharmaceutical ingredient.

When assigning BUDs for CSPs, multiple factors should be considered such as sterility of the products used, number and types of manipulations, time needed for preparation, equipment, and environment.1 These factors are used to determine the risk-level as detailed in Table 2. To achieve the lowest risk level, all criteria for that risk-level must be met. For example, if a nonsterile product is used to make the final CSP, then this must be classified as high-risk even if only a single simple transfer is performed. It is important to note that for all risk levels, quality assurance procedures such as routine disinfection, appropriate garbing, order review, and visual inspection of the CSP should be performed. Media-fill tests that duplicate the most challenging or stressful conditions encountered during compounding the given risk-level should be performed by all compounding personnel semi-annually for high-risk CSPs and annually for other risk levels.

Table 2. Factors in determining risk-level per USP <797>.1

BUD=beyond-use-dating; CPR=cardiopulmonary resuscitation; ISO=International Standards Organization; LAFW=laminar air flow hood; PEC=primary engineering controls; TPN=total parenteral nutrition.

These risk levels can then be used to determine appropriate BUDs as summarized in Table 3. For CSPs, the BUD indicates stability from the beginning of preparation to the start of administration.

BUD=beyond use-dating.

Single-dose and multiple-dose containers

Both USP <797> and the Centers for Disease Control and Prevention provide guidance on compounding using single-dose and multiple-dose containers. 1,4 Multiple-dose containers should be discarded after 28 days, unless otherwise specified by the manufacturer. When multiple-dose containers are used to make CSPs then the container should be inspected and disinfected with each use. Single-dose containers should be used within 1 hour if opened in worse than International Standards Organization (ISO) Class 5 air quality and within 6 hours if exposed to ISO Class 5 air quality or better. Leftover contents from single-dose containers should never be pooled or maintained for later use. However, unopened single-dose containers can be repackaged into multiple single-use vehicles (eg, syringes) under ISO Class 5 conditions and in compliance with manufacturer’s recommendations for safe storage of the medication outside of the original container.

Sterility testing

USP <797> addresses when sterility testing should be performed, whereas USP <71> details the methods to perform sterility testing. 1,5 Facilities that seek to store CSPs for periods longer than that specified in the literature or per USP guidance should perform sterility testing. Sterility testing should also be performed for certain high-risk CSPs including batches of 25 or more identical preparations (with the exception of ophthalmic and inhalation preparations), multiple-dose vials intended for administration to multiple patients, or preparations exposed to temperatures of 2 to 8oC for longer than 12 hours or to temperatures greater than 8oC for longer than 6 hours prior to terminal sterilization. Additionally, the American Society of Health-System Pharmacists recommends that facilities consider sterility testing of batches of fewer than 25 high-risk CSPs as part of a quality assurance plan.3 Sterility testing should be completed prior to dispensation or administration of the preparation.1,5 If results are not received prior to dispensation, then procedures for daily observation of sterility test specimens, immediate recall if needed, and notification of patients and physicians of any microbial growth must be in place. If a sterility test returns positive, then the root cause of contamination must be investigated.

Conclusion

Assignment of BUDs to compounded preparations requires critical evaluation and application of appropriate resources. When extrapolating data from the literature, it is crucial to ensure that the findings are valid and suitable for application based on each institution’s practices. Additionally, it is necessary to consider the implications of relevant factors including stability, sterility, and risk level. To minimize risk, a conservative approach to the assignment of BUDs should be employed.

References

1. General chapter <797> pharmaceutical compounding – sterile preparations. United States Pharmacopeia website. Available at: http://www.uspnf.com/uspnf/pub/index?usp=37&nf=32&s=0&officialOn=May%201,%202014 . Accessed June 10, 2014.

2. General chapter <795> pharmaceutical compounding – nonsterile preparations. United States Pharmacopeia website. Available at: http://www.usp.org/sites/default/files/usp_pdf/EN/gc795.pdf. Accessed June 10, 2014.

3. ASHP guideline on compounding sterile preparations. American Society of Health-System Pharmacists website. Available at: http://www.ashp.org/DocLibrary/BestPractices/PrepGdlQualAssurSterile.aspx . Published June 3, 2013. Accessed June 10, 2014.

4. Protect patients against preventable harm from improper use of single-dose/single-use vials. Centers for Disease Control and Prevention website. Available at: http://www.cdc.gov/injectionsafety/cdcposition-singleusevial.html. Updated August 30, 2012. Accessed June 10, 2014.

5. General chapter <71> sterility testing. United States Pharmacopeia website. Available at: http://www.uspnf.com/uspnf/pub/index?usp=37&nf=32&s=0&officialOn=May%201,%202014 Accessed June 10, 2014.

Prepared by:

Aparna Reddy, PharmD

PGY2 Drug Information

University of Illinois at Chicago

June 2014

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Is intravenous ketamine useful for the treatment of major depressive disorder?

The National Institute of Mental Health estimates that every year 6.7% of adult Americans experience major depressive disorder (MDD).1 Women are more likely to have MDD than men, and the disease is most prevalent in people age 40 to 59 years.2 In fact, between 2005 and 2008 antidepressants were the most common prescription drug class taken by adults age 18 to 44 years.3 Despite the numerous antidepressants currently available, approximately 50% of patients with MDD fail to respond to their first treatment, and 35% do not achieve response with 2 treatment courses. 4

According to the American Psychiatric Association 2010 guidelines for major depressive disorder, the choice of initial antidepressant is usually based on the adverse effect profile because the effectiveness of the agents is similar.5 They suggest that for most patients a selective serotonin reuptake inhibitor (SSRI), a serotonin/norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion are appropriate. Pharmacologic options for patients who fail to respond to an appropriate dose of the first antidepressant include changing to an alternative antidepressant, augmenting therapy with nontraditional antidepressants (e.g., lithium, buspirone, anticonvulsants), or combining antidepressants.

Currently available antidepressants take several weeks to improve symptoms and are clearly not effective for all patients.6,7 A desire to overcome these limitations has researchers looking for treatment options that avoid the usual inhibition of serotonin, norepinephrine, or dopamine neurotransmitters. Glutamate, an excitatory neurotransmitter, is one potential target.8 Ketamine, an analgesic and anesthetic that has been available in the United States for over 40 years, regulates glutamate as an N-methyl-D-aspartate (NMDA) receptor antagonist. There has been increasing interest in using ketamine for patients with MDD.

Literature review—ketamine efficacy

The first trial demonstrating the efficacy of intravenous (IV) ketamine for MDD was published in 2000 and included only 8 patients.9 Since that time many other small trials have been published. Key controlled trials are summarized in the Table. The studies generally demonstrated efficacy with a rapid onset of effect. Zarate et al observed antidepressant effects within 2 hours of the infusion, and the antidepressant effect was maintained for approximately 7 days.10 In the study conducted by Murrough and colleagues, 64% of patients responded within 24 hours of the ketamine infusion, but the percentage of responders declined to 45% by day 7.11

Table. Intravenous ketamine controlled trials in patients with MDD.9-11

In addition to the controlled studies summarized above, a number of open-label studies and case series have evaluated the efficacy of ketamine for MDD. Most of these studies have also used the 0.5 mg/kg dose given over 40 minutes, but one trial extended the infusion time to 100 minutes and proposed that this may improve tolerability.12,13 No controlled studies have evaluated the efficacy of multiple doses, but small, open-label trials have found efficacy with repeated doses.13,14 Murrough reported data for 24 patients who completed up to 6 ketamine infusions given Monday, Wednesday, and Friday for up to 12 days.14 At the end of the 12-day study period 17 (70.8%) patients responded (≥50% improvement in depressive symptoms by the Montgomery-Asberg Depression Rating Scale [MADRS]) to ketamine. Patients who responded to ketamine had a median time to relapse of 18 days after the final infusion.

Ketamine has also been studied for use in acutely suicidal patients, for use in conjunction with electroconvulsive therapy (ECT), and in patients with bipolar depression with positive results.6 Thirty-three patients with suicidal ideation who were administered IV ketamine 0.5 mg/kg had significant improvement on all suicide scales with minimal adverse effects; however, the patients were only followed for 4 hours after the infusion. 15 A smaller study administered a 0.2 mg/kg dose but found improvements in suicide scales for 10 days.16 Ketamine has been used for many years as an anesthetic during ECT, but its potential adjunct antidepressant effects with ECT have only more recently been realized.6 At this time, further study on the dose and combination of medications used in this setting is warranted. Studies in patients with bipolar depression mimic those in patients with MDD with a rapid but transient response found with ketamine.17

Ketamine safety

Dizziness and drowsiness are common side effects of ketamine.13 Other adverse events common in controlled trials include euphoria, headache, blurred vision, nausea or vomiting, dry mouth, impaired coordination or concentration, confusion, and elevated libido.10,11 Hemodynamic changes (increases or decreases in blood pressure and heart rate) are generally mild but have resulted in ketamine discontinuation.11 As expected, ketamine can cause dissociative symptoms including euphoria, derealization, or depersonalization, but this dissipates within 2 hours of the infusion. 6 Another concern with ketamine is its potential for abuse. Ketamine, or “Special K”, is sometimes abused recreationally because of its dissociative effects, inducing a state of relaxation or well-being. Because there are no long-term studies of ketamine, its full safety profile remains unknown.

Conclusion

Despite the number of reports describing the efficacy of ketamine for treatment-resistant depression, the total number of patients studied remains low, and there are no long-term data supporting the safety and efficacy of this treatment option. In addition, the IV route of administration used in these studies is not practical for many patients. At this time it appears there is a minimal role for ketamine in the treatment of depression. However, further studies of long-term treatment or for the induction of remission in acutely suicidal patients are warranted.

References

1. Depression. National Institute of Mental Health. http://www.nimh.nih.gov/health/topics/depression/index.shtml?utm_source=BrainLine.orgutm_medium=Twitter . Accessed June 17, 2014.

2. Quick Stats: Prevalence of Current Depression Among Persons Aged ≥ 12 years, by Age Group and Sex – United States, National Health and nutrition Examination Survey, 2007-2010. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6051a7.htm?s_cid=mm6051a7_w . Published January 6, 2012. Accessed June 16, 2014.

3. Antidepressant Use in persons Ages 12 and Over: United States, 2005-2008. NCHS Data Brief. http://www.cdc.gov/nchs/data/databriefs/db76.htm. Published October 2011. Accessed June 17, 2014.

4. Nemeroff CB. Prevalence and management of treatment-resistant depression. J Clin Psychiatry. 2007;68(Suppl 8):17-25.

5. Practice guideline for the treatment of patients with major depressive disorder, third edition. American Psychiatric Association Practice Guidelines. http://psychiatryonline.org/content.aspx?bookid=28&sectionid=1667485 . Published October 2010. Accessed June 17, 2014.

6. Naughton M, Clarke G, O’Leary OF, Cryan JF, Dinan TG. A review of ketamine in affective disorders: current evidence of clinical efficacy, limitation of use and pre-clinical evidence on proposed mechanisms of action. J Affect Disord. 2014;156:24-35.

7. Covvey JR, Crawford AN, Lowe DK. Intravenous ketamine for treatment-resistant major depressive disorder. Ann Pharmacother. 2012;46(1):117-123.

8. Jun C, Choi Y, Lim SM. Disturbance of the glutamatergic system in mood disorders. Exp Neurobiol. 2014;23(1):28-35.

9. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354.

10. Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864.

11. Murrough JW, Iosifescu CV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-1142.

12. aan het Rot M, Zarate CA Jr, Charney DS, Mathew SJ. Ketamine for depression: where do we go from here? Biol Psychiatry. 2012;72(7):537-547.

13. Rasmussen KG, Lineberry TW, Galardy CW, et al. Serial infusion of low-dose ketamine for major depression. J Psychopharmacol. 2013;27(5):444-450.

14. Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250-256.

15. DiazGranados N, Ibrahim LA, Brutsche NE, et al. Rapid resolution of suicidal ideation after a single infusion of an NMDA antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010;71(12):1605-1611.

16. Larkin GL, Beautrais AL. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int J Neuropsychopharmacol. 2011;14(8):1127-1131.

17. Sienaert P, Lambrichts L, Dols A, De Fruyt J. Evidence-based treatment strategies for treatment-resistant bipolar depression: a systematic review. Bipolar Disord. 2014;15(1):61-69.

August 2014

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