Medicolegal Issues

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There has been a lot of talk recently about pharmacogenomics and personalized medicine. Pharmaco-genomics—the way an individual responds to a medication—includes both positive and negative reactions, and how individual genetic differences affect drug response. It also examines the inherited variations in genes that dictate drug response and explores how these variations can be used to predict what type of response a patient will have to a particular drug, whether that is a good response, a bad response, or no response at all.1

In the race to catalog all the different gene variations, variations known as single nucleotide polymorphisms (SNPs, or “snips”) are used diagnostically to predict a patient’s response to a drug. In the future, pharmaceutical companies could use pharmacogenomics to predict which patients will have a negative response to a particular drug in clinical trials and, therefore, not study the medication in those patients.2 In essence, it would be a way to “streamline” therapy to those in most need of it or for those who likely will have a positive response with minimal adverse events.

Market watch

New Generics

  • Levetiracetam tablets (Keppra)9

New Drugs, Indications & Dosage Forms

Amiodarone hydrochloride injections (Nexterone) have been approved by the FDA as a novel, co-solvent-free formulation of amiodarone intravenous (IV).10 It is indicated for treating and prophylaxing frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients that are refractory to other therapy. It was developed to overcome limitations (e.g., fatal gasping syndrome) associated with the use of the co-solvents polysorbate 80 and benzyl alcohol while preserving its beneficial antiarrhythmic effects. It will be available in ready-to-use pre-mixed bags and pre-filled syringes.

Nicardipine hydrochloride IV (Cardene IV) is available in a double concentration (40 mg or 0.2-mg/mL) in ready-to-use 200 mL bags of 5% dextrose or 0.83% sodium chloride.11

Prasugrel (Effient, Eli Lilly/Daiichi Sankyo) was reviewed for FDA approval on Feb. 3 by the Cardiovascular and Renal Drugs Advisory Committee (CDRAC).12 The committee voted unanimously in favor of prasugrel as a treatment for acute coronary syndrome that is managed with percutaneous coronary intervention. CDRAC members advised against using prasugrel in patients with a history of stroke and for patients undergoing open-heart surgery. The CDRAC did not advise limiting its use in patients younger than 75. The committee did express caution regarding prasugrel use in patients weighing less than 130 pounds (59 kilograms) because these patients might be at a higher risk of bleeding. The CDRAC also noted higher cancer rates among prasugrel users compared with clopidogrel users, and stated the drug may have to carry warnings about this risk. The FDA has not set a date for its final decision.13

Ropinirole XL (Requip XL) is available in a new, 12-mg tablet for once-daily dosing. Other available tablet strengths include 2, 4, and 8 mg.14

Venlafaxine extended-release tablets (Osmotica Pharma) have been approved by the FDA as a “new drug,” though they are bioequivalent to Effexor XR capsules. However, they are not therapeutically interchangeable, due to the different dosage forms of these products (tablet versus capsule).15 In states with a therapeutic substitution law, pharmacists cannot automatically substitute venlafaxine extended-release tablets for Effexor XR without a prescriber’s authorization. It is important to note and tell patients that venlafaxine extended-release tablets travel through the gastrointestinal tract and are eliminated in the feces as a “ghost tablet” (i.e., a core tablet with no drug), so if they see a tablet in their stool, they shouldn’t worry that they didn’t absorb the medication.

By pre-screening patients, clinical trials could be smaller, faster, and less costly. The capability to pre-assess whether a patient will benefit from a particular medication before it is prescribed is a major advantage when it comes to medication use. It also might increase a prescriber’s confidence before starting a patient on a medication, and it might improve a patient’s confidence in taking the medication, which could increase medication adherence and lead to better patient outcomes.

Researchers have found that when patients with certain SNP variants of cytochrome P450 (CYP) take warfarin, metabolism and patient sensitivity are affected. Once this was discovered, the Food and Drug Administration (FDA) subsequently approved prescribing label changes for warfarin that incorporated pharmacogenomics information.3 This change included information on increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles.4

More recently, Eckman et al published a cost-effectiveness analysis evaluating pharmacogenetic information related to warfarin dosing in patients with nonvalvular atrial fibrillation.5 In the study, the authors concluded that currently limited data exist utilizing pharmacogenomics for dosing of warfarin and its effects on major bleeding. They did note, however, that genotyping may be beneficial and cost-effective in patients who are at high risk of hemorrhage.

Additionally, there has been recent media coverage of the genetic variations of CYP2C19 affecting clopidogrel metabolism and efficacy.6,7 Both Mega et al and Collet et al noted that patients carrying at least one genetic variation of CYP2C19 had diminished platelet inhibition. Published earlier this year, both studies noted that patients carrying the genetic variation of CYP2C19 exhibited a higher rate of major cardiovascular events—including death, stent thrombosis, myocardial infarction, or stroke—than did noncarriers.

The FDA warned healthcare providers in November 2008 about using phenytoin or fosphenytoin in patients with the HLA-B*1502 allele due to a potentially increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis. A similar warning exists for carbamazepine in the same patient population. This is another example of pharmacogenomics information at work.8

Patient-specific variables have been identified that can help determine how an individual will respond to certain medications. Ultimately, this could decrease healthcare costs. It is a slow process and might be the wave of the future, but we are not there yet. TH

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


  1. Just the facts: a basic introduction to the science underlying NCBI resources. National Center for Biotechnology Information Web site. Available at: Accessed Jan. 31, 2009.
  2. Gulseth MP, Grice GR, Dager WE. Pharmacogenomics of warfarin: uncovering a piece of the warfarin mystery. Am J Health Syst Pharm. 2009;66:123-133.
  3. FDA letter on approval of pharmacogenomics information for Coumadin label. Food and Drug Administration Web site. Available at: Accessed Feb. 4, 2009.
  4. Coumadin label updated. Food and Drug Administration Web site. Available at: Accessed Feb. 4, 2009.
  5. Eckman MH, Rosand J, Greenberg SM, Gage BF. Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med. 2009;150:73-83.
  6. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354-362.
  7. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450) 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009;373:309-317.
  8. Phenytoin and fosphenytoin information. Food and Drug Administration Web site. Available at: Accessed Feb. 4, 2009.
  9. Mylan receives final approval for first-to-file generic version of antiepileptic Keppra and launches immediately. Mylan Web site. Available at: Accessed Feb. 4, 2009.
  10. Prism pharmaceuticals receives FDA approval of Nexterone for life-threatening ventricular fibrillation and ventricular tachycardia. Prism Pharmaceuticals Web site. Available at: Accessed Feb. 4, 2009.
  11. Now in double concentration. E-Pharm/alert Web site. Available at: Accessed Feb. 4, 2009.
  12. Meeting of the Cardiovascular and Renal Drugs Advisory Committee. Food and Drug Administration Web site. Available at: Accessed Feb. 4, 2009.
  13. Bratulic, A. FDA panel recommends Eli Lilly’s, Daiichi Sankyo’s Effient. FirstWord Web site. Available at: Accessed Feb. 4, 2009.
  14. Now available 12-mg tablets. E-Pharm/alert Web site. Available at: Accessed Feb. 4, 2009.
  15. Tom WC. New venlafaxine extended-release formulation. Pharmacist’s Letter/Prescriber’s Letter. 2009;25(1)250108.

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