This activity is supported by educational grants from Pharmacyclics LLC. An Abvie Company; Jannsen Biotech, Inc; and Cure Media Group 

Associate Professor of Clinical Education

UNC Eshelman School of Pharmacy Oncology Clinical Pharmacist

SECU Mission Cancer Center Asheville, North Carolina

At the completion of this activity, the participant will be able to:

Explain the recommendations of the place in therapy for new and emerging CLL treatment options

Illustrate the management of relapsed and refractory CLL

Examine the management of adverse events and complications of novel therapies

Demonstrate how to implement strategies that improve communication, patient engagement, education, and decision making with patients with CLL and their health care providers

TARGET AUDIENCE: Clinical and specialty pharmacists 

ESTIMATED TIME TO COMPLETE ACTIVITY: 2.0 hours

FEE: This lesson is offered for free at www.pharmacytimes.org.

Articles

Continuing Education

Recent Advances in the Care of Patients with Chronic Lymphocytic Leukemia (CLL)

This activity is supported by an education grant from Sun Pharmaceutical Industries, Inc. 

Evaluating Effective Protective Measures for Minimizing the Risk of Exposure to Hazardous Drugs

Center for Integrated Global Biomedical Sciences

Empire State Patient Safety Assurance Network

School of Pharmacy and Pharmaceutical Sciences University at Buffalo

State University of New York Buffalo, New York

Rachel L. Brown, PharmD, MPHAbingdon, Virginia

Describe how exposure and contamination can lead to health risks to pharmacists and nurses who compound and administer hazardous drugs (HDs), such as chemotherapeutic agents

Review the new USP chapter and be able to employ these measures to reduce or prevent unintentional exposure to HDs

Discuss effective as well as protective and educational measures to minimize risks for those health care professionals who compound and administer HDs

: Health-system pharmacists ACTIVITY TYPE: Knowledge

: This lesson is offered for free at www.pharmacytimes.org.

Opioid use, abuse, and associated deaths have skyrocketed in the United States over the past decade. Since 1999, the number of opioid-related deaths has quadrupled. In 2015, the CDC reported 33,091 deaths from opioids, which included prescription pain medications and heroin.

About 12.5 million people misused prescription opioids in 2015, and 2 million received a diagnosis of opioid-use disorder.

The severity of this epidemic has become a public health crisis and spurred a federal response, including an initiative by the secretary of Health and Human Services and other government entities. Collaborative efforts emphasize evidence-based methods to improve prescribing practices, the deployment of naloxone to reverse overdoses, and improved access to medication-assisted treatment for opioid-use disorders.

The FDA is also expanding the use of its advisory committees, working with drug manufacturers to develop better safety labeling, updating risk evaluation and management strategies, and strengthening post-marketing requirements.

The public health consequences of the opioid epidemic include deaths from drug overdose, legal problems, higher crime rates, newborn withdrawal syndrome, contribution to accidents, and the spread of infectious diseases such as hepatitis C and HIV.

Diagnostic and Statistical Manual of Mental Disorders,

, the psychiatric diagnoses of opioid abuse and opioid dependence have been replaced by opioid-use disorder. Opioid-use disorder is defined as a problematic pattern of opioid use that leads to clinically significant distress or impairment.

The diagnosis centers on the repeated occurrence of 2 of the 11 criteria, including taking larger amounts of the drug or for a longer period than prescribed, the presence of craving and/or tolerance, and continued use, despite interpersonal or social problems over a 12-month period.

Risk factors for misuse include a prior history of substance abuse, increasingly severe pain, co-occurring mental disorders, and certain demographic factors. For example, females are more likely to use prescription painkillers, but males are more likely to abuse them. Studies have shown that illicit use often first begins in late adolescence to early adulthood. Other risk factors can be individual, family, peer, social, and environmental. For instance, impulsivity and novelty-seeking behaviors are related to a person’s temperament but may be genetically determined.

Opioids are prescribed for the management of severe acute and chronic pain. An opioid is a natural or synthetic substance that acts on one of the main opioid receptor systems (mu, kappa, delta) in the central nervous system (CNS) and to a lesser extent in the periphery.

Activation of mu endogenous opioid receptors results in many of the prototypical effects we associate with opioids: reward, withdrawal, and analgesia. Mu receptor activation in the CNS is also responsible for respiratory depression, euphoria, and miosis.

Tolerance to opioids happens in response to long-term exposure to exogenous opioids. Increased opioid levels and increased opioid potency are needed to generate the same effect. 

Opioid intoxication usually presents as symptoms of apathy, attention impairment, dysphoria, euphoria, miosis, motor retardation, sedation, and/or slurred speech. Overdose symptoms include respiratory depression, a depressed level of consciousness, coma, and miosis.

Overdose can be treated with an opioid antagonist that inhibits opioid action at the receptor site, such as naloxone. Naloxone is available as an injectable solution, an intramuscular (IM)/subcutaneous autoinjector, and a nasal spray. In overdose, an initial dose of 0.4 mg to 2.0 mg IM/intravenous should be given, and a response should occur within 1 to 2 minutes.

The dose can be repeated every 2 to 3 minutes up to 10 mg. If the nasal spray is used, 1 spray should be administered intranasally into 1 nostril. If repeat doses of the nasal spray are needed, alternating nostrils is recommended. The effects of naloxone wear off after 2 to 3 hours, so individuals must seek emergency treatment and continue to be monitored for up to 72 hours, especially if the overdose is the result of using longer-acting drugs, such as methadone.

As part of the public health response, naloxone (Narcan) nasal spray has been made available as an OTC drug in pharmacies in many states. Emergency first responders are also carrying naloxone. 

Guidelines for opioid addiction set by the American Psychiatric Association recommend combining pharmacological treatment with psychosocial treatment, such as cognitive-behavioral therapy, psychodynamic therapy, and group and family therapy.

Pharmacological treatment strategies for the management of opioid dependence and withdrawal include:

Opioid substitution with methadone or buprenorphine, followed by a gradual taper

Abrupt opioid cessation, with the use of clonidine

Symptoms of withdrawal are generally the opposite of the acute effects of the drug and include 3 of the following over the course of minutes to several days (depending on the drug consumed): dysphoric mood, nausea or vomiting, muscle aches, lacrimation or rhinorrhea, pupillary dilation, piloerection, sweating, diarrhea, yawning, fever, insomnia, and a mild elevation in body temperature, respiratory rate, and blood pressure.

Methadone is a long-acting synthetic opioid agonist that has been the maintenance treatment gold standard for years. Methadone can be dosed once daily and replaces the need for multiple daily heroin injections. Methadone maintenance therapy (MMT) must be administered in a specialty program under the supervision of a physician with special training.

The opioid partial agonist buprenorphine and an opioid partial agonist/antagonist buprenorphine/naloxone are also good choices for maintenance therapy. Because buprenorphine can only partially activate the mu receptor, the user does not generally feel the intense rush or high that they would with other opioids. The mechanism of action of buprenorphine also prevents craving and withdrawal symptoms. Because it tightly binds to the mu receptor, users are not able to get high from other drugs when taking buprenorphine.

In 2016, the FDA approved the buprenorphine implant Probuphine for opioid dependence. Probuphine provides a constant, low-level dose for 6 months.

Historically, l-alpha-acetylmethadol has been used for opioid dependence. However, it is associated with a prolonged QT interval and, in severe cases, cardiac arrhythmias and death and is therefore rarely used anymore.

Although there is a need for larger multicenter, randomized trials, several Cochrane Reviews have been conducted to look at maintenance treatments. Results from the reviews have shown that patients who took methadone were 4 times more likely to stay in treatment compared with placebo, patients who took buprenorphine significantly decreased their number of opioid-positive drug tests, and positive outcomes significantly increased when maintenance therapy was combined with counseling.

The reviewsalso found that high-dose MMT was more effective than low-dose MMT, low-dose MMT was less effective than buprenorphine, and high-dose MMT was more effective than buprenorphine maintenance treatment.

Pharmacists can play a key role in the dissipation of the opioid epidemic. Whether they are screening in clinics, assisting in the treatment of intoxication or withdrawal in emergency departments, or dispensing naloxone, they are instrumental in the education of both patients and providers. Many states also use online prescription drug monitoring programs that allow pharmacists to proactively work with providers when prescribing and dispensing opioids.  Opioid abuse and overdose remain big problems in the United States. However, drug manufacturers, government agencies, and health care providers are working together to find solutions to the crisis.

Joanna Lewis, PharmD, MBA, is clinical pharmacist who is passionate about medication safety, clinical quality, leadership development, and regulatory affairs. She received her pharmacy degree from the Medical University of South Carolina and is an active member of the American Society of Health-System Pharmacists. She has worked in a variety of practice settings, most recently as a coordinator at Duke University Hospital in Durham, North Carolina.

1.CDC. Opioid overdose-understanding the epidemic. 

. Updated August 30, 2017. Accessed December 2, 2017. 

2. Rudd RA, Seth P, David F, Scholl L. Increases in drug and opioid-involved overdose deaths - United States, 2010-2015. 

. 2016;65(5051):1445-1452. doi: 10.15585/mmwr.mm655051e1.

3. National Institute on Drug Abuse. Opioid overdose crisis. 

drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis

. Updated June 2017. Accessed December 4, 2017. 

4. FDA. FDA opioid action plan. fda.gov/drugs/drugsafety/informationbydrugclass/ucm484714.htm. Updated July 11, 2017. Accessed December 4, 2017.

Diagnostic and Statistical Manual of Mental Disorders. 

5th ed.Washington, DC: American Psychiatric Association; 2013:541-546.

Medscape. emedicine.medscape.com/article/287790-overview#a1

. Updated November 15, 2017. Accessed December 4, 2017.

7. American Psychiatric Association. Practice guideline for the treatment of substance use disorders.In: 

American Psychiatric Association Practice Guidelines for Psychiatric Disorders: Compendium 2006.

2nd ed. Arlington, VA: American Psychiatric Association, 2006:291-563.

8.  Schuckit MA. Treatment of opioid-use disorders.

. 2016;375(4):357-68. doi: 10.1056/NEJMra1604339.

9. Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. 

2009;8;(3):CD002209. doi: 10.1002/14651858.CD002209.pub2.

Chronic Care Focus

Opioid use, abuse, and associated deaths have skyrocketed in the United States over the past decade. Since 1999, the number of opioid-related deaths has quadrupled

Opioid Addiction and Overdose 

As drug prices continue to increase, affecting all areas of patient care in which medications are administered or dispensed, identifying avenues for reducing costs has become even more paramount. Entities covered by 340B, the federal drug discount program that serve a disproportionate share of underinsured and uninsured patients shoulder even more of this financial burden, which escalates the necessity to control drug expenses. The costs of medications paid by these entities, along with the potential costs associated with drug preparation, administration, and/or dispensing of the medications, often exceed reimbursement. Many 340B hospitals have worked to control their drug expenses through optimization of procurement practices, including examining purchases on wholesale acquisition cost (WAC) accounts to identify unnecessary spending. Although some WAC account purchases are necessary to maintain 340B program compliance, other purchases may end up on this account because of program maintenance issues, such as infrequent split billing maintenance, lost charges, and policies that do not clearly articulate products that fall outside the 340B program (ie, noncovered outpatient drugs).

340B hospitals subject to the group purchasing organization (GPO) prohibition typically have 3 separate accounts on which to purchase medications: 340B, GPO, and WAC. When using WAC as the comparator, 340B-priced drugs are typically discounted about 25% to 50% (

), and GPO-priced drugs are typically discounted about 15% to 20%. In many cases, the difference between the WAC price and the other price points is minimized by Apexus Prime Vendor Program (PVP) sub-WAC contracts. For this reason, a good strategy for a covered entity to use to review the impact of WAC purchasing may be to focus on the items with no PVP contract or on those in which there are unfavorable pricing differences between what is loaded to their GPO and their WAC accounts. This calculation (WAC account price minus GPO account price) is often referred to as the WAC premium. If operational considerations (mentioned below) are addressed, hospitals may begin to see their total WAC premiums decrease from baseline.

Covered entities using a virtual inventory or replenishment model are required to make their first purchases at WAC pricing to establish a neutral inventory before replenishment using non-WAC pricing can take place. These WAC-priced purchases are then dispensed to patients who are determined to be either 340B- or GPO-eligible. Once eligibility is determined, that dispensation is accumulated to a split billing software that will allow future replenishment purchases. Because of this requirement, a certain level of WAC exposure is expected to ensure compliance. However, a lack of proper management regarding this accumulation process can result in unnecessary WAC spending that would have otherwise resulted in 340B or GPO purchases.

A comprehensive approach to addressing and minimizing WAC exposure is through establishing a regularly convening WAC minimization work group. This group can include stakeholders from contracting, information technology, pharmacy, procurement, and the organization’s split billing vendor. The next step should be to determine which metrics to use for tracking progress. Although minimizing the WAC percentage is often mistakenly chosen as the defining measurement, it is even more valuable to focus on minimizing exposure to the WAC premium and its related missed 340B or GPO savings opportunity. Once the items with the greatest opportunities are identified, this work group will then focus on the operational causes of the WAC account spending.

Common causes of unnecessary WAC spending can include deficiencies in technology that support the virtual inventory model; lost charges; and unclear policies and procedures. Nearly all these causes are complicated and could require involvement from multiple departments to resolve. The 

illustrates examples of causes that could be identified and the departments that may be involved in implementing a resolution. For example, if a covered entity only accumulates what is administered to its patients, any drug waste will subsequently result in WAC exposure. Rectifying this issue could mean collaboration between nursing and pharmacy to implement initiatives to reduce drug waste. At 340Bpvp.com, Apexus offers a free tool that hospitals can use as a template to minimize WAC exposure.

A focused effort on minimizing WAC exposure while maintaining 340B program compliance is a strategic approach to mitigating the impact of increasing drug costs in this environment of decreasing reimbursements.

Grayson K. Peek, PharmD, MS, BCPS, is the manager of business development and integrity at Duke University Hospital Department of Pharmacy in Durham, NC. 

Halena Leah Marcelin, PharmD, MS, BCPS, is the 340B program manager for Memorial Healthcare System in Hollywood, FL. 

Viewpoints

Minimizing WAC Exposure to Decrease Drug Expense in the Virtual Inventory Setting

The US Pharmacopeia (USP) Convention’s General Chapter <800> draft guidelines have already raised the bar for hazardous drug (HD) management and imposed costs for compliance.

The impact of these changes will be significant. Prior to the publication of USP <800>, many clinicians used a biosafety cabinet (BSC) and personal protective equipment for handling HDs. Although these offered some protection, formal education about HD management was all but nonexistent, and the lack of detailed policy and procedures made enforcement and optimal use of HD equipment a significant challenge. USP <800> brought this issue to the forefront by providing a clear explanation of the spectrum of safeguards needed to protect employees.

Readiness for enforcement of USP <800> varies from full compliance (rare) to no compliance decision having been made (also rare). Although not all are in conformance, most clinicians intend to comply.

USP <800> was intended to be enforceable starting on July 1, 2018. However, the final document release has been postponed to coordinate with the scheduled December 1, 2019, publication of the USP <797> revision. These guidelines cover pharmaceutical compounding and sterile preparations. The intent is to provide a unified approach to compounding practices that is safe for both patients and employees. USP <797> describes responsibilities of drug compounding personnel, training, facilities, environmental monitoring, and storage and testing of finished preparations. USP <800> describes requirements for HDs; facility and engineering controls; procedures for deactivating, decontaminating and cleaning; spill control; and documentation.

Many clinicians have been preparing for USP <800> for a long time and are well on their way to compliance. However, for those just getting started, the following steps may make the process more manageable:

Although USP <800> clearly states that it is the responsibility of all employees who handle HDs to understand the chapter’s requirements, for ideal stewardship, each practice should designate a person to oversee implementation of USP <800> procedures and compliance.

Identify the HDs handled to ensure proper management in the future. Closely read the National Institute for Occupational Safety and Health’s 2016 list of HDs to see which are classified as hazardous.

Obviously, it is important to thoroughly understand USP <800> requirements. Once comfortable with these requirements, focus on how HDs move through, from the point of receipt to inventory, storage, compounding, administration, and, finally, disposal. This will identify trouble spots where compliance is lacking.

USP <800> is specific about design and engineering controls, so evaluate the compounding area and BSC ventilation.

Prior to the date that USP <800> becomes enforceable, a drug compounding hood that vents to room air is acceptable. After December 1, 2019, USP <800> requires that all BSC hoods be vented to the outside environment.

Next, examine the compounding room design, as there are minimum requirements that must be met. In addition to the requirement for BSC hoods that vent to the outside, all quantities of HDs must now be compounded in a segregated, negative-pressure room that is properly ventilated.

One of the standards for this room is that it must be constructed of a specific type of material. This represents the greatest challenge to general compliance because many do not yet conform to this requirement.

If facility and engineering changes are needed, it is important to understand these may require 12 to 18 months to complete. If possible, it may be helpful to delay this aspect of compliance until the publication of the second-draft revision (late 2018) of USP <797>. Although unfinished, this draft should provide greater clarity about facility requirements.

Evaluate processes for personal protective equipment (PPE), and determine the level of compliance.

Understanding the degree to which staff members embrace PPE is critical and necessary to developing improvement initiatives. Once management has a good understanding of the staff’s compliance level, it can identify improvements and begin drafting policies and procedures. Many templated products are available that make this job a bit easier. Training processes that include competency exams should be established, and strategies should be developed to ensure that the consistent use of PPE becomes part of the practice culture.

PPE compliance often requires a change in culture. Establishing this culture can be challenging. Management must stress the need for safe handling of HDs at every opportunity and take responsibility for developing practice improvement policies that educate, establish accountability, and drive compliance.

USP <800> compliance requires policies and procedures that outline staff training, validation of skills, and documentation of staff knowledge of HD safe handling. Policy development is the low-cost piece of this challenge and, as such, should be done first.

Each USP <800> solution is unique. Until the final versions of USP <797> and <800> are released, it will be difficult to determine the cost of meeting requirements. However, estimates can be made. Costs for PPE are minimal. It could mean about an additional $5000 annually for PPE. In most cases, facility improvements should be achievable with an investment of $50,000 or less. A new expense resulting from USP <800> arises from the required use of closed-system transfer devices (CSTDs). CSTDs are required for administration of all HDs. Expect an additional annual expense in the range of $40,000 to $50,000 for these items. Those incorporating CSTDs into the compounding process in the BSC, which is recommended but not required by USP <800>, could incur an additional annual expense of $50,000 to $60,000.

Those electing to do medium- to high-risk compounding (category 2, under a reclassification anticipated in the updated USP <797>) beyond 12-hour-use dating will require a fully engineered clean room, which can be extremely expensive. This can cost as much as $200,000 or more. For this reason, it is important to have a thorough understanding of what is required from its admixture/compounding program.

Uncertainies Over Enforcement and Noncompliance 

As with USP <797>, uncertainties exist regarding USP <800> enforcement. Compliance enforcement will vary state by state, depending on medicine and pharmacy board rules and regulations. It is possible that a state’s public health department may be charged with the task. However, in most states, there is no designated agency to enforce compliance. Because employee safety is involved, it is reasonable to anticipate the state office of the Occupational Safety and Health Administration eventually will be responsible. 

According to a joint statement in 2015 by the American Society of Clinical Oncology, the Hematology/Oncology Pharmacy Association, and the Oncology Nursing Society, over the past 2 decades, at least 100 studies have provided evidence of HD contamination in the work environment.

Although the deadline for compliance has been delayed, early implementation of USP <800> requirements is strongly recommended. 

This article originally appeared in sister publication 

Brian Larson, BS Pharm, RPh, is director of clinical specialists at McKesson Specialty Health in Chicago.

US Pharmacopeial Convention. USP general chapter <800>: hazardous drugs—handling in healthcare settings. USP website. usp.org/sites/default/ files/usp/document/our-work/healthcare-quality-safety/general-chapter-800.pdf. Published December 1, 2017. Accessed January 10, 2018

Tomkins J. Ensuring healthcare worker safety when handling hazardous drugs: the joint position statement from the Oncology Nursing Society, the American Society of Clinical Oncology, and the Hematology/Oncology Pharmacy Association.

2015;11(4):278-279. ascopubs.org/ doi/full/10.1200/jop.2015.004978. Accessed November 22, 2017.

Safe Handling

Ready for New Rules on Hazardous Drug Management? 

According to the American Cancer Society, bladder cancer is responsible for about 5% of all new cancers in the United States.

Additionally, it is the sixth most common cancer in the United States.

Bladder cancer occurs when cells in the urinary bladder begin to grow uncontrollably. Fortunately, the rates of new bladder cancer cases have decreased. Men are about 3 to 4 times more likely to experience bladder cancer than are women.

About half of all bladder cancers are first diagnosed while the cancer is still confined to the inner layer of the bladder wall, which is known as noninvasive or in situ cancer.

The most common risk factor for bladder cancer in the United States is cigarette smoking.

In fact, about half of all bladder cancers are caused by cigarette smoking.

Evidence suggests that smoking cessation counseling may prevent bladder cancer.

Additional risk factors for developing bladder cancer include family historygenetic mutations; occupational exposures to chemicals in processed paint, dye, metal, and petroleum products; treatment with cyclophosphamide, ifosfamide, or pelvic radiation for other malignancies; Chinese herbs; arsenic exposure; 

urinary tract infections; and neurogenic bladder and associated indwelling catheters.

Stage 0 bladder cancer is noninvasive and does not involve lymph nodes or any distant metastasis.

This is an early stage of cancer that has not invaded the bladder wall beyond the inner layer. Treatment usually involves transurethral resection of bladder tumor (TURBT) with close follow-up and no further treatment or intravesical (administered directly into the bladder) chemotherapy to prevent recurrence. The TURBT procedure involves surgery, using an instrument placed up the urethra to remove abnormal tissues and tumors for analysis.  Immunotherapy with bacillus Calmette-Guérin (BCG) has been shown to be more effective than chemotherapy at preventing cancer recurrence.

However, BCG has more adverse effects than does chemotherapy. Treatment with BCG consists of an attenuated live strain of 

(related to the bacteria that causes tuberculosis) that is placed directly into the bladder through a catheter. Treatment is usually started a few weeks after TURBT and is given once a week for 6 weeks. Long-term maintenance therapy with BCG may be required. Common adverse effects may include bladder irritation, malaise, and fever.

Severe complications are rare and may include prostatitis, pneumonia, and nephritis.

Stage I bladder cancer has spread to the connective tissue layer of the bladder but has not reached the muscle layer.

Treatment usually involves TURBT as first-line therapy to determine the extent of the cancer. Generally, a second TURBT is necessary several weeks later. Once the cancer has been removed, intravesical BCG or mitomycin is usually given (

). For cancer not removed by TURBT, treatment options include intravesical BCG or cystectomy, which is a partial or full bladder removal. Patients with contraindications to a cystectomy can receive radiation therapy, along with chemotherapy.

Table 1. Stage 1 Bladder Cancer Treatment

Stage II bladder cancer has spread to the bladder wall muscle layer.

Treatment initially involves TURBT to determine the extent of the cancer. Radical cystectomy, which involves removing the entire bladder and nearby lymph nodes, is usually necessary. Chemotherapy is usually given before or after surgery to prevent cancer recurrence. Evidence suggests that patients receiving chemotherapy prior to cystectomy may have better survival rates.

Neoadjuvant chemotherapy given prior to surgery can shrink the cancer, allowing for easier surgical removal.

The first-line chemotherapy regimen generally includes cisplatin, methotrexate, vinblastine, and doxorubicin (

The cycle should be repeated every 28 days for a total of 3 cycles.

Atezolizumab (Tecentriq) can also be used as a first-line treatment for locally advanced or metastatic urothelial carcinoma in patients who are not eligible for cisplatin-containing chemotherapy.

Table 2. Stage II Bladder Cancer Treatment

Stage III cancer has reached the outside of the bladder and possibly has spread to nearby tissues or organs. Initial treatment generally involves TURBT to determine the extent of the cancer. Radical cystectomy is usually considered the standard treatment protocol. Neoadjuvant chemotherapy with cisplatin, methotrexate, vinblastine, and doxorubicin can be given prior to the cystectomy.

Stage IV cancer has reached the abdominal or pelvic wall or has spread to nearby lymph nodes or organs and is known as metastatic bladder cancer. Radical cystectomy may not remove all the cancer, so the treatment goal is to slow the growth and improve the quality of life. Chemotherapy, with or without radiation, is usually the first-line treatment for cancers that are nonmetastatic. Patients unable to tolerate chemotherapy may be treated with radiation therapy or an immunotherapy drug such as atezolizumab.

Educate patients to quit smoking, as this can reduce the risk of developing bladder cancer.

Evidence also suggests that drinking plenty of water can reduce the risk of bladder cancer. Individuals should limit their exposure to certain chemicals in the workplace, such as aromatic amines and 4,4'-methylenebis(2-chloroaniline). These chemicals can be found in the products of the chemical, dye, and rubber industries, as well as hair dyes, paints, fungicides, plastics, cigarette smoke, metals, and motor vehicle exhaust.

Pharmacists can play an important role in smoking cessation counseling, as cigarette smoking is the most common risk factor for bladder cancer. Treatment depends on the bladder cancer stage and may involve TURBT, BCG, chemotherapy, radiation, or cystectomy. Encourage the use of neoadjuvant chemotherapy prior to cystectomy for stages II and III bladder cancer for better treatment outcomes. 

Jennifer Gershman, PharmD, CPh, is a medical writer and a Pharmacy Timescontributor residing in South Florida.

American Cancer Society. Key statistics for bladder cancer. https://www.cancer.org/cancer/bladder-cancer/about/key-statistics.html.  Updated January 5, 2017. Accessed October 21, 2017.

Soria F, Marra G, Capoun O, Soukop V, Gontero P. Prevention of bladder cancer incidence and recurrence: tobacco use. 

. 2017. doi: 10.1097/MOU.0000 000000000453. 

National Cancer Institute. Bladder cancer treatment (PDQ)—health professional version. cancer.gov/types/bladder/hp/bladder-treatment-pdq. Updated June 5, 2017. Accessed October 24, 2017.

Morales A. BCG: A throwback from the stone age of vaccines opened the path for bladder cancer immunotherapy.  

Decaestecker K, Oosterlinck W. Managing the adverse events of intravesical bacillus Calmette-Guerin therapy. 

. 2015;7:157-63. doi: 10.2147/RRU.S63448.

BCG Live [prescribing information].  Roseland, NJ: Organon Teknika Corp LLC; 2009. fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM163039.pdf. Accessed November 21, 2017.

American Urological Association. Intravesical administration of therapeutic medication.auanet.org/guidelines/intravesical-administration-of-therapeutic-medication. Accessed October 28, 2017.

Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. 

Cisplatin [prescribing information]. Paramus, NJ: WG Critical Care, LLC; 2015. accessdata.fda.gov/drugsatfda_docs/label/2015/018057s083lbl.pdf. Accessed November 21, 2017.

Methotrexate [prescribing information]. Lake Forest, IL: Hospira; 2011. accessdata.fda.gov/drugsatfda_docs/label/2011/011719s117lbl.pdf. Accessed November 21, 2017.

Vinblastine [prescribing information]. Lake Zurich, IL: Fresenius; 2016. accessdata.fda.gov/drugsatfda_docs/label/2016/206197Orig1s000lbl.pdf. Accessed November 21, 2017.

Doxorubicin [prescribing information]. New York, NY: Pfizer; 2013. labeling.pfizer.com/ShowLabeling.aspx?id=530. Accessed November 21, 20

17.Tecentriq [prescribing information]. South San Francisco, CA: Genentech Inc; 2017. gene.com/download/pdf/tecentriq_prescribing.pdf

Letasiova S, Medvedova A. Bladder cancer, a review of environmental risk factors.  

. 2012;11(Suppl 1): S11. doi: 10.1186/1476-069X-11-S1-S11.

Oncology Focus

Bladder Cancer Treatment and Prevention

Despite 35 years of prevention and health education efforts, increased access to health care, and improvements in HIV medication efficacy and tolerability, the disease continues to spread across both developed and developing countries. In 2017, almost 40,000 cases of HIV were diagnosed in the United States. The main route of transmission is sexual contact, predominantly in men who have sex with men (MSM).

 It is well documented that if a person living with HIV/AIDS (PLWH) is undetectable (HIV viral load <200 copies/mL), the risk of viral transmission to others is virtually zero. 

However, in the United States, just 61% of PLWH are consistently undetectable,

and 91.5% of new HIV infections are transmitted by people who have either not received a diagnosis or not engaged in care.

This continued transmission of HIV illustrates the need for additional tools for prevention. 

In July 2012, the FDA approved tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) 200 mg/300 mg taken once daily as pre-exposure prophylaxis (PrEP) for individuals at a higher risk of HIV infection. The approval was based on the results of various studies showing PrEP to be highly effective at preventing HIV transmission when used daily.

The CDC recommends PrEP for heterosexual men and women who report inconsistent condom use and in a high-prevalence area or network, injection drug users who share equipment, individuals with a sexual partner who is HIV positive, MSM with a recent sexually transmitted infection (STI) diagnosis or who report inconsistent condom use, and those who participate in transactional sex.

TDF/FTC is the first and only FDA-approved nonbarrier method of HIV prevention. Because of the novelty of using a medication to prevent HIV, lack of long-term data and the potential for increased resistance or increase in STI transmission have led to providers using caution with PrEP. However, more recent data continue to support the safety and efficacy of daily TDF/FTC. An analysis of real-world demonstration projects in 16 countries combining more than 8000 individuals showed a <1% HIV acquisition rate and few adverse events.

Populations included in the analysis included heterosexual women, injection drug users, MSM, serodiscordant couples, and transgender women. In the first 5 years of PrEP, about 100,000 individuals have started and about 60,000 individuals are currently taking it.

This number is less than the 10% of the individuals who the CDC estimates fit the criteria for being at a higher risk of HIV infection. Although the data show that PrEP implementation is expanding, few of the individuals are people of color or younger than 25—2 populations that are at higher risk of HIV acquisition.

Results from retrospective studies on real-world use have shown that early patients on daily PrEP have high adherence and motivation for continuing PrEP.

However, a concern of practitioners is that inconsistent PrEP adherence will decrease efficacy and lead to HIV resistance and increased transmission. Pharmacologic modeling analyses predict 96% to 99% protection in rectal tissue after just 4 tablets of TDF/FTC and continued protection with adherence of 4 to 6 tablets per week.

In addition, the inferred risk reduction remained ≥90% for 7 days after discontinuation of a 30-day regimen of daily TDF/FTC.

However, PrEP is not 100% effective, even with perfect adherence. Results of published case reports show HIV acquisition, despite evidence of high adherence. No method of HIV prevention is 100% effective. Therefore, individuals need to be aware of the risks and benefits of each method to make an informed decision. 

An important aspect of PrEP use and prescribing is the management of STIs. PrEP effectively reduces HIV transmission but is inactive against other STIs. It is recommended that individuals continue to receive education in safer sex practices, be given access to condoms, and get screened at least every 6 months for STIs, with some data suggesting every 3 months in the MSM population.

Will daily PrEP lead to a decrease in condom use and an increase in STI transmission? Data on real-world PrEP have shown similar STI rates pre- and post-PrEP initiation and suggest that PrEP may not replace other types of safer sex practices.

More long-term data are needed to better understand how certain populations view PrEP and safer sex options and how its use affects sexual behaviors. 

Clinicians and prescribers are concerned about the short- and long-term safety risks of PrEP. TDF can reduce renal function and bone mineral density (BMD) in those living with HIV. Is PrEP potentially harmful? A recent meta-analysis of randomized, placebo-controlled PrEP studies demonstrated that the risk of any adverse event or grade 3/4 adverse events was not statistically significantly different in tenofovir-based PrEP compared with placebo.

However, results from a BMD substudy in the iPrEx cohort comprising 498 patients showed a small decrease in hip and spine BMD in the TDF/FTC group at 24 weeks.

Fortunately, this did not lead to a difference in bone fracture rates, and BMD recovered within 6 months of the patients discontinuing PrEP.

Additionally, PrEP is meant to prevent transmission during a period of high risk. Risk continues to change throughout an individual’s life, and PrEP is not anticipated to be lifelong therapy for many individuals. 

Although results from studies have shown that PrEP is safe and effective in many different patient populations, the majority of data are in MSM. Different populations have different routes of transmission for HIV: female genital tissue for heterosexual women, intravenously in injection drug users, and penile and rectal tissues for MSM. Pharmacologic analyses have shown that FTC and TFV have different tissue distribution patterns, with FTC favoring female genital tissue and TFV favoring colorectal tissue.

Additionally, competing nucleotides are lower in colorectal than female genital tissue, suggesting that higher adherence is required to achieve sufficient drug concentrations in vaginal than in rectal tissue. More data are needed to fully understand this issue. 

Daily TDF/FTC is the only FDA-approved regimen for PrEP. However, innovative formulations and routes of administration of PrEP that do not rely on daily adherencewould offer further options for HIV protection.On-demand, or event-driven, PrEP is the practice of dosing medication(s) around a risk for transmission such as a sexual encounter. Results from the IPERGAY study and open-label extension showed an 86% to 97% risk reduction when MSM used TDF/FTC around a sexual encounter.

Although more data are needed before this can be recommended in practice, this is a potential option for individuals with infrequent episodes of risk.Various delivery methods such as intravaginal rings and long-acting injectable antiretroviral agents are under investigation and showing promise.

Subdermal implants have been designed but not tested in clinical trials yet.

Additionally, there is a lot of interest in rectal and vaginal microbicides, though trials have been disappointing. Ideally, individuals would have a variety of HIV and STI prevention products—both barrier and nonbarrier forms&mdash;that are safe, effective, and available when needed. 

Jacob A. Langness, PharmD, BCPS, is a clinical pharmacist specializing in infectious disease and internal medicine at Abbott Northwestern Hospital in Minneapolis, Minnesota. He completed his doctorate of pharmacy at the University of Minnesota and his PGY1 residency at University of Colorado Hospital. 

CDC. HIV surveillance report. cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2016-vol-28.pdf. Published November 2017. Accessed March 27, 2018.

Singh S, Mitsch A, Wu B. HIV care outcomes among men who have sex with men with diagnosed HIV infection - United States, 2015. 

. 2017;66(37):969-974. doi: 10.15585/mmwr.mm6637a2.

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