Medicolegal Issues

Increased Attention


 

According to the American Diabetes Association, a normal fasting plasma glucose (FPG) level is less than 100 mg/dl; impaired fasting glucose (IFG) is defined as an FPG from 100 to 125 mg/dl; and any patient with an FPG greater than or equal to 126 mg/dL carries a provisional diagnosis of diabetes.1 When the oral glucose tolerance test is used for evaluation, similar definitions exist. Patients with IFG or impaired glucose tolerance (IGT) have “pre-diabetes,” and are at a high risk for developing diabetes. Elevated blood glucose levels can have major consequences, particularly in high-risk populations.2

Market watch

New Generics

  • Granisetron tablets (generic Kytril)11
  • Tenofovir dipivoxil (generic Viread), tentatively approved12
  • Topiramate tablets (generic Topamax)13

New Drugs, Indications & Dosage Forms

  • Budesonide/formoterol fumarate dihydrate 160/4.5 mcg (Symbicort), previously approved by the FDA to treat asthma, has been FDA-approved to treat chronic obstructive pulmonary diseases, including chronic bronchitis and emphysema. It is dosed twice daily.14
  • Glatiramer acetate (Copaxone), already FDA-approved for treating relapsing-remitting multiple sclerosis (MS), has been approved by the FDA as a preventive treatment in patients that have had a first episode of MS and have magnetic resonance imaging (MRI) results consistent with MS, also known as having a clinically isolated syndrome (CIS) suggestive of MS.15
  • Tigecycline (Tygacil) has been FDA-approved to treat adults with community-acquired bacterial pneumonia by susceptible strains of indicated pathogens.16 An initial dose of 100 mg is recommended, followed by 50 mg every 12 hours intravenously over approximately 30 to 60 minutes for seven to 14 days.17

New Warnings

  • Wearing medicated transdermal patches while undergoing MRI scans can cause skin burns on the direct patch area.18 Many transdermal patches contain metallic backing or other layers, including aluminum, that can overheat during an MRI. Patches are used to treat many conditions, including antiemesis, attention deficit hyperactivity disorder, depression, and pain, and are also used in hormone replacement and smoking cessation. The FDA is reviewing the composition and labeling of all medicated patches to ensure those that contain metal provide a patient a warning of potential burns. Until then, healthcare providers are being told to warn patients to remove and dispose of them prior to an MRI. The patch can be replaced after the scan. Patients should tell the MRI facility that they are using a patch when they call to schedule their appointment.19
  • Metoclopramide has been used for many years in the management of gastrointestinal disorders. Healthcare providers also have known, and it is listed in the product label, that this agent can cause tardive dyskinesia. However, the FDA now feels that it is necessary to warn healthcare providers and patients of this risk, which is mostly associated with long-term, high-dose use. Patients with the highest risk include the elderly (especially older women), and those who have been on the drug for a long time. In February, the FDA instituted a boxed warning and risk mitigation strategy for metoclopramide-containing drugs. This ensures that patients are provided with a medication guide that warns them of the risk.20
  • Through a clinical data review, the FDA has determined that zonisamide (Zonegran), an anti-epileptic drug (AED) utilized to treat adults with partial epilepsy, can sometimes cause metabolic acidosis in some patients. Therefore, the product labeling for zonisamide has been updated. Healthcare professionals treating patients with zonisamide should measure serum bicarbonate at baseline before starting treatment and periodically throughout treatment, even if the patient is asymptomatic. Symptoms include fatigue, anorexia, hyperventilation, stupor, and cardiac arrhythmia. Predisposed individuals include those with renal impairment, diarrhea, those on a ketogenic diet, surgery, and severe respiratory disorders. If metabolic acidosis develops and persists, consider reducing the dose or discontinuing the treatment. The patient’s antiepileptic treatment should be modified as needed. If the decision is made to continue metabolic acidosis patients on zonisamide, then alkali treatment should be considered. More information and management tips can be found at www.fda.gov.21

Macrovascular and microvascular complications, impaired wound healing, and a compromised immune system can occur in the setting of sustained, elevated blood glucose concentrations. Aside from patients with diabetes who have elevated blood glucose levels, schizophrenic patients might be predisposed to glucose intolerance and diabetes independent of treatment.3

It is not known whether IGT seen in schizophrenics is due to lifestyle risk factors (e.g., smoking, poor diet, being overweight, lack of exercise) or some genetic or biological component of the disease. However, this is complicated by the fact that many of these patients are treated with second-generation antipsychotics (SGAs), which might increase the risk of developing diabetes.4 Because of this, a warning regarding the risk of developing hyperglycemia and diabetes was mandated by the Food and Drug Administration (FDA) for SGA manufacturers.5

Hyperglycemia symptoms include polyuria, polydipsia, weight loss (sometimes with polyphagia), and blurred vision. Impairment of growth and susceptibility to certain infections might occur with chronic hyperglycemia. Hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome are acute, life-threatening consequences of uncontrolled diabetes. It is important for hospitalists and other healthcare professionals to be aware of drugs that can cause hyperglycemia or impair glucose tolerance. In some cases, the drug can be continued; in other cases, an alternate agent should be provided if necessary for patient management.

Certain drugs and drug classes known to cause hyperglycemia include: thiazide diuretics, glucocorticoids, oral contraceptives and sex hormones (e.g., testosterone), protease inhibitors, SGAs, thyroid hormone, phenytoin, niacin/nicotinic acid, diazoxide, and alfa-interferon.1-3,6

Limited evidence exists for some other agents/classes, including: asparaginase, beta-agonists, beta-blockers, calcium channel blockers, clonidine, cyclosporine, levodopa, lithium, minoxidil, phenothiazines, and others.7 The Seventh Report of the Joint National Committee (JNC 7) recommends thiazide diuretics as a first-line treatment for most patients with Stage 1 hypertension, alone or in combination for patients with diabetes.8 These thiazide doses tend to be smaller and, therefore, tend to have minimal effects on blood glucose levels.

In 2004, a consensus guideline was developed on antipsychotic drugs, obesity, and diabetes.9 It describes baseline and followup monitoring of patients treated with SGAs. The baseline includes personal/family history, weight/body mass index, waist circumference, blood pressure, FPG, and a fasting lipid profile. Monitoring of these parameters is then designated at specified times throughout treatment (e.g., weeks four, eight, 12, etc.). Haupt et al recently compared monitoring of lipids and glucose in a population of insured patients receiving SGAs in a retrospective cohort of patients pre- and post-guideline.10 Baseline lipid and glucose testing rates increased minimally post-guideline versus pre-guideline.

The results of this study demonstrate that even though monitoring guidelines to prevent potentially adverse outcomes in a patient population at high risk for developing adverse outcomes are available, clinicians do not always follow them. In order to improve patient outcomes, identified at-risk populations (e.g., patients receiving SGAs) need to be more closely evaluated and monitored throughout therapy to prevent IGT and/or diabetes. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a freelance medical writer based in New York City.

References

  1. American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2009;32:S62-S67.
  2. Luna B, Feinglos MN. Drug-induced hyperglycemia. JAMA. 2001;286:1945-1948.
  3. Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry. 2007;68(Suppl 1):20-27.
  4. Tahir R. Metabolic effects of atypical antipsychotics. US Pharm. 2007;32:HS3-HS14.
  5. Warning about hyperglycemia and atypical antipsychotic drugs. U.S. Food & Drug Administration Web site. Available at: www.accessdata.fda.gov/scripts/cdrh/cfdocs/psn/printer.cfm?id=229. Accessed March 31, 2009.
  6. Kaufman MB, Simionatto C. A review of protease inhibitor-induced hyperglycemia. Pharmacotherapy. 1999;19:114-117.
  7. Pandit MK, Burke J, Gustafson AB, Minocha A, Peiris AN. Drug-induced disorders of glucose tolerance. Ann Intern Med. 1993;118:529-539.
  8. Chobanian AV, Bakris GL, Clack HR, et al. The seventh report of the joint national committee on prevention, detection, evaluations, and treatment of high blood pressure. JAMA. 2003;289:2560-2572.
  9. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27:596-601.
  10. Haupt DW, Rosenblatt LC, Kim E, Baker RA, Whitehead R, Newcomer JW. Prevalence and predictors of lipid and glucose monitoring in commercially insured patients treated with second-generation antipsychotic agents. Am J Psychiatry. 2009;166:345-353.
  11. FDA approves generic treatment for emesis. Drug Store News Web site. Available at: www.drugstorenews.com/story.aspx?id=96143. Accessed March 6, 2009.
  12. Aurobindo Pharma gets tentative approval from US FDA for tenofovir disoproxil fumarate tabs. RTT News Web site. Available at: www.rttnews.com/ArticleView.aspx?id=860423. Accessed March 4, 2009.
  13. Teva announces approval and launch of generic Topamax tablets.Teva Web site. Available at: www.tevapharm.com/pr/2009/pr_835.asp. Accessed March 30, 2009.
  14. FDA approves Symbicort for chronic obstructive pulmonary disease (COPD). AstraZeneca Web site. Available at: www.astrazeneca-us.com/about-astrazenecaus/newsroom/all/4939997?itemId=4939997. Accessed June 5, 2009.
  15. Copaxone approved by the FDA for patients with a first clinical event suggestive of multiple sclerosis. Teva Web site. Available at: www.tevapharm.com/pr/2009/ pr_826.asp? Accessed June 5, 2009.
  16. Todoruk M. FDA approves new use for Wyeth’s Tygacil antibiotic. Available at: www.firstwordplus.com/Fws.do?articleid=CF71DE6056CE4120A295243AE2D6EC00. Accessed March 25, 2009.
  17. FDA Web site. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2009/021821s013s017s018lbl.pdf. Accessed June 5, 2009.
  18. Transdermal drug patches with metallic backings. FDA Web site. Available at: www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm111493.htm. Accessed June 5, 2009.
  19. FDA warns about risk of wearing medicated patches during MRIs. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149537.htm. Accessed March 6, 2009.
  20. FDA requires boxed warning and risk mitigation strategy for metoclopramide-containing drugs. FDA Web site. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149533.htm. Accessed March 4, 2009.
  21. Zonisamide (marketed as Zonegran, and generics). FDA Web site. Available at: www.fda.gov/ForConsumers/ConsumerUpdates/ucm095251.htm. Accessed March 4, 2009.

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