Written by Clinicians, for Clinicians

Fall 2009 Edition It is Neither Immoral Nor Unethical to Think About the Cost of Therapy
M. Mihalyo, B.S., Pharm.D

Black Box Warnings and Hospice Medications

Z. Elerick, Pharm.D. Candidate 2010, Duquesne University M. Mihalyo, B.S., Pharm.D.

Adverse drug reactions (ADRs) are a leading cause of death in the United States3. Pre-market clinical trials cannot always detect long term effects of medications, thus the majority of adverse drug effects are detected after a larger portion of patients have been exposed to a medication.2 Post-marketing adverse events are reported by physicians, pharmacists, nurses and patients to the FDA primarily through the use of MEDWATCH, which can be found by visiting www.fda.gov/Safety/MedWatch/default.htm.* After careful review of patient reports, an FDA committee is responsible for adding a Black Box Warning (BBW) to a package insert. BBWs are the most severe FDA mandated warnings. They signify a significant patient safety risk or risk of a life-threatening adverse event.5 These warnings, listed in the package insert, on the FDA website at www.FDA.gov, and on pharmaceutical manufacturer websites, provide a summary of information important to every medical professional prior to its administration.5 Unfortunately, less than 10% of adverse drug reactions are reported to the FDA1 and providers have been shown to be generally unaware of the monitoring needed for medications with black box warnings. In a retrospective analysis of health records of nearly 1 million patients in 10 health plans, Wagner et al. reported that approximately 40% of patients received at least one relevant BBW medication in their 30 day study period.4 Prescribers were observed to be careless in terms of laboratory monitoring (i.e., 50% of patients did not receive baseline labs prior to receiving BBW medications that required laboratory studies to be completed).4,5 Black box warnings have particular applicability to the hospice patient population. In an observational study by Lasser et al. of over 300,000 patients, the number of patients who received clinically relevant BBW medications was 7 in 1000 outpatients3. Lasser notes that most BBW medications distributed to patients in violation of the FDA warnings were among geriatric patients greater than 75 years of age and female3.
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Regardless of the type of health care setting a professional practice is in, it is neither immoral nor unethical to think about the cost of a particular therapy. In fact, thinking about the cost of therapy may be one of the most moral things we do as health care professionals. Cost of therapy consideration allows us to extend our therapeutic reach. When prescribing a new medication, it is important to recognize the economic impact the new medication may have on the payor, which may or may not be the patient. Whether or not a medication is formulary has economic ramifications for the payor. Formulary status also influences the time to first dose, meaning that non-formulary medications may result in a prolonged acquisition and prescription dispensing process. Consultation between the prescriber and the patients' primary pharmacist that take stock of personal and organizational economics when the prescription is written, promotes medication compliance and therefore improves quality of life. This kind of planning and consultation preserves health care resources. In the very near future, the American Society of Clinical Oncology will release guidelines to oncologists regarding the cost of therapy. These guidelines will prompt conversations between oncologists and their patients that are

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The results of both studies agree that there is further progress to be made in decreasing the incidence and increasing awareness of black box warnings in appropriate patient populations. Below is a focused list of medications with black box warnings commonly used in the geriatric patient population. *NOTE: Confidential Adverse Drug Reaction (ADR) reporting is now available online for ProCare HospiceCare clients. Please visit www.procarerx.com, and login with your user ID and password to utilize this resource today! For more information on how to use this valuable clinical tool, contact your ProCare HospiceCare account manager at 1-866-457-6337 or 866-699-3542.

Analgesics
NSAIDS Monitor CBC at baseline and thereafter. Monitor for signs of GI bleed, thrombotic events, MI, or stroke. Do not administer for treatment of perioperative pain in the setting of CABG. Celecoxib, Diclofenac, Cardiovascular Risk: NSAIDs may cause an increased risk of Etodolac, Flurbiprofen, serious cardiovascular thrombotic events, myocardial infarction, Ibuprofen, Indomethacin, and stroke, which can be fatal. This risk may increase with Ketoprofen, Ketorolac, duration of use. Patients with cardiovascular disease or risk Mefenamic Acid, Meloxicam factors for cardiovascular disease may be at greater risk. NSAIDs are contraindicated for the treatment of peri-operative Nabumetone, Naproxen, pain in the setting of coronary artery bypass graft (CABG) Piroxicam, Salsalate, Sulindac, surgery Tolmetin Gastrointestinal Risk: NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. DIPHENYLHEPTANES Methadone Consideration: Conversion from other opioids only if benefit outweighs risk. Propoxyphene Consideration: Avoid use. Cardiovascular Risk: Prolongation of the QT interval; Respiratory depression; death have occurred during initiation or transition from another opioid. Psychiatric Risk: Not for use in patients who are suicidal or addiction prone. CNS depression, caution with tranquilizers, antidepressants, or excess alcohol. Increased risk of fatal overdose

PHENANTHRENES Healthcare provider should be alert to problems of abuse, misuse, and diversion. Morphine (Sustained-Release), Abuse and Overdose Risk. Oxycodone (ControlledControlled release/extended release morphine are to be used in opioid Release), Oxymorphine, tolerant patients only (may cause respiratory depression in non-opioid Hydromorphone (tablets, tolerant patients). Tablets are to be swallowed whole and are not to be liquid, injection) broken, chewed, dissolved, or crushed; taking broken, chewed, dissolved, or crushed tablets leads to rapid release and absorption of a potentially fatal dose of morphine.

PHENYLPIPERIDINES For use in opioid tolerant patients; Monitor RR routinely. Monitor medication interactions and adjust dose if warranted. Monitor for signs of abuse of misuse. Fentanyl (Transdermal) Fentanyl can be abused and is subject to criminal diversion. Use in nonopioid tolerant patients may lead to life threatening hypoventilation. Cutting patch or applying heat can cause rapid release and absorption of fatal dose.

Antibiotics
FLUOROQUINOLONES Ciprofloxacin, Gemifloxacin, Levofloxacin, Moxifloxacin, Ofloxacin Carbemazepine Associated with increased risk of tendonitis and tendon rupture, especially in patients older than 60, in kidney, heart, and lung transplant patients, and with use of concomitant steroid therapy.

Anticonvulsants
Hematological and Dermatologic Risk: Aplastic anemia, agranulocytosis. Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS), have been reported during treatment with carbamazepine. Complete pre-treatment hematological testing should be done as baseline. Monitor patient closely if WBC decreases. Discontinuation of medication should be considered if any evidence of significant bone marrow depression develops Serious Dermatological Reactions Risk: Almost all life-threatening rashes have occurred within 2 to 8 weeks of lamotrigine therapy but have also occurred after prolonged treatment Hepatoxicity, Pancreatitis Risk: LFTs should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months.

Lamotrigine

Valproic Acid

Anticoagulants
Warfarin Severe Bleeding Risk: Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR). Risk factors for bleeding include high intensity of anticoagulation (INR greater than 4), age 65 or older, highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs.

Antidepressants
Selective Serotonin Reuptake Inhibitors (SSRIs) Citalopram, Escitalopram,Fluoxetine,, Fluvoxamine, Paroxetine, Sertraline Psychosis Risk: These medications are not FDA approved for the treatment of bipolar depression and may worsen psychosis in these patients.

Antipsychotics
All antipsychotics are associated with increased mortality when used in elderly patients with dementia related psychosis for psychotic symptom control. ATYPICAL (NEW) Aripiprizole, Clozapine, Olanzapine, Paliperidone, Questiapine, Risperidone, Ziprasidone TYPICAL (OLD) Fluphenazine, Haloperidol, Perphenazine, Thioridazine, Thiothixene, and Trifluoperazine Although there is QT-prolongation risk with some other typical antipsychotics, thioridazine has a BBW for dose-related QT prolongation.

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Diabetes Medications
Pioglitazone, Rosiglitazone Can cause or exacerbate CHF and MI; Use of these drugs in patients with established NYHA Class III or IV heart failure is contraindicated. Observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). Lactic Acidosis Risk: Should not be given to elderly >80 years of age unless adequate renal fnc; Avoid excess alcohol intake while on this medication. Also may exacerbate CHF. Avoid in patients with hepatic dysfunction; D/C with hypoxemia, sepsis, dehydration, radiocontrast, or surgery

Metformin

Individual Drugs
Long Acting Beta 2 Agonist Salmeterol Long acting beta2 adrenergic agonists, such as salmeterol, may increase the risk of asthma related death. Therefore, when treating patients with asthma, this drug should only be used as additional therapy for patients not adequately controlled on other asthma controller medications (e.g., low-to-medium dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies, including this drug.

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Generali, Joyce. Black Box Warnings: Formulary Productions. Kansas University. Available at http://www.formularyproductions.com/master/showpage.php?dir=blackbox&whichpage=215. Accessed July 11, 2009. Lasser E, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA. 2002:287(17). P2215-20. Lasser K, et al. Adherence to black box warnings for prescription medications in outpatients. Arch Intern Med. 2006:166. p338-44. Wagner, et al. FDA drug prescribing warnings: is the black box half empty or half full? Pharmacoepidemiology and Drug Safety. 2006:15. p369-86. Zarowitz B. Black box warnings- implications in practice. Geriatric Nursing. 2008:29(6). p402-09.

It is Neither Immoral Nor Unethical to Think About the Cost of Therapy (continued from page 1) necessary for care that addresses patients' health care needs in the best possible ways. Conversations about treatment options should include the cost of therapy and the guidelines surrounding new treatment. Including cost in this discussion is simple; it is a potential 'side effect' related to this patient's therapy. For the hospice industry with their eyes on open access, the new guidelines mentioned above are good news. They will promote a conversation about the cost of therapy beginning with the prescriber and patient, rather than with the payor and patient. Equally efficacious medication options will be compared from the side effect perspective that includes the cost of therapy. Hospice organizations can embrace medication use guidelines that further assist in promoting the oftendifficult conversation revolving around the continued use of medication interventions, which may no longer be effective.

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Copyright 2009, ProCare Rx Editor: Dr. Mary Mihalyo

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