No. 99

Drug Safety - Whose Issue Is It?

Charles Lee, PhD


There are two sides of the drug safety issue. On one side are the pharmaceutical manufacturer and the regulatory agency, collectively the "maker". On the other side are the prescriber, the dispenser and the patient, collectively the "user". Undoubtedly, drug makers wish to produce the safest drug possible. Logistically however, clinical trials could not possibly proceed until every potential side effect is detected. This is why the FDA mandates post-marketing surveillance so that drug safety can be continuously monitored throughout the life cycle of the product. As well, pharmaceutical companies continue to search for new ways to tackle drug safety issues proactively.


Recent advance in pharmacometrics, the pharmacokinetic modeling and statistical analysis of ADME data, touts a more tailored, predictive approach to drug safety and efficacy. The PK/PD modeling and simulation using in vitro data from human and animal models is widely employed as a powerful tool to scout the auspicious leads for preclinical and clinical development. The practice will most certainly improve the overall safety profile of the marketed products in the future. The vast majority of healthcare professionals are well trained to prescribe or dispense medications competently. Medication errors typically do not represent errors of commission but errors of omission-a failure on the part of the physician, the pharmacist or the patient to detect certain signs that point to the error. Many of the errors can be avoided by communicating openly and concisely among all stakeholders. Lastly, the importance of educating the end user, the patient cannot be over-emphasized.

Drug Safety Concerns

Since the passage of PDUFA (Prescription Drug User Fee Act) in 1992, the pharmaceutical industry has been largely satisfied with the way FDA helped expedite the drug review process. However, consumer advocates have linked faster approval to more safety problems, and asserted that the system has fallen short of protecting patient safety and minimizing risks. In the near past, high profile drug recalls, notably the withdrawals of the painkiller Vioxx and diabetes drug Avanta, have shed light once again on drug safety.

A recent drug safety concern was raised by the Institute for Safe Medication Practices (ISMP) over several side effects associated with Pfizer's Chantix anti-smoking tablet, among which depression and suicidal ideation. The active ingredient of Chantix, varenicline is novel in that it both stimulates and blocks specific nicotinic receptors in the brain. It is thought that the stimulation of these receptors mimics the effects of nicotine and reduces cravings. As it also partially blocks the receptor from nicotine binding, it makes smoking less pleasurable and thus less tempting. Clinical trials of the drug demonstrated a cessation rate of 44%, which compared favorably with placebo and another major anti-smoking drug, bupropion. There have been 50 reports of depression to the Medicines and Healthcare products Regulatory Agency (MHRA) in Britain, along with another 16 reports of suicidal feelings. These have been mainly in patients with a previous psychiatric history, and no association of Chantix use and the neuropsychiatric side effects is evident. The FDA has asked Pfizer for any additional cases of adverse event for review; meanwhile, the agency advises prescribers to closely monitor patients for behavior and mood changes.

The second case in point is Actavis' Digitek heart pill, which was recalled in April 2008 due to the probable existence of double strength tablets. The excessive dose poses a risk of digitalis toxicity in patients with renal failure, including nausea, vomiting, dizziness, low blood pressure, cardiac instability and bradycardia. The recall prompted a broad review of adverse event reports that linked to 630 patient deaths. This GMP related problem was resolved at least for the time being by closing of the manufacturing facility.

Merck's Singulair asthma medication was tagged in an FDA communication over psychiatric side effect in March 2008, thereafter a substantial increase of adverse event reports were generated. The FDA issued an updated safety review report asserting that available data do not suggest an association with suicide or suicidal thoughts. However, the report also contended that the Singulair trials were not designed to inquest neuropsychiatric events.

Adverse Events

Published findings in 1999 by the Institute of Medicine (IOM) concluded that as many as 7000 Americans die from medication errors each year. Seven years later in 2006, the IOM stated that the frequency of medication errors and related injuries was still a serious concern. According to the Medication Errors Reporting Program (MERP) of ISMP, the top 10 medications implicated in adverse events that necessitate emergency treatment in a hospital are: (1) Insulin (8%); (2) Anticoagulants (6.2%); (3) Amoxicillin (4.3%); (4) Aspirin (2.5%); (5) Trimethoprim-Sulfamethoxazole (2.2%); (6) Hydrocodone & Acetaminophen (2.2%); (7) Ibuprofen (2.1%), (8) Acetaminophen (1.8%); (9) Cephalexin (1.6%); (10) Penicillin (1.3%).

Drug Overdose

Unintentional overdose made up 40% of the emergency room visit, followed by side effects and allergic reactions. Of the above 10 medications, the analgesics and the antibiotics belong to high volume prescription classes. Arthritis therapies exemplify the commonly misused medication with analgesics and non-steroidal anti-inflammatory drugs, prescription or over the counter (OTC). Misuse or unnecessary use of these drugs increases side effects such as dyspepsia, peptic ulcer and GI bleeding, resulting in hospitalization or death. Inappropriate prescribing of antibiotics for colds, bronchitis and upper respiratory infections amounts to wastefulness and further exacerbates the dreadful resistance problem. The sheer volume of prescriptions for hydrocodone and amoxicillin is a major factor for medication error.

Elderly Population

To further complicate the issue is the elderly who accounted for 34% of all prescriptions. Non-compliance issues frequently led to adverse events, including wrong dose, wrong administration time, missing dose or premature termination of medication. The average number of prescriptions for the elderly population was 28.5 per year in 2000 and is projected to reach 38.5 in 2010. Almost a quarter million seniors are hospitalized yearly due to drug interaction problems stemming from the concomitant use of prescription and/or OTC medications.


Based on the information from the United States Pharmacopoeia (USP), the top 10 medications that are most commonly misused or mismanaged by the healthcare professionals are: (1) Insulin (4%); (2) Morphine (2.3%); (3) Potassium Chloride (2.2%); (4) Albuterol (1.8%); (5) Heparin (1.7%); (6) Vancomycin (1.6%); (7) Cefazolin (1.6%); (8) Acetaminophen (1.6%); (9) Warfarin (1.4%); (10) Furosemide (1.4%).

It is worth noting that the most error prone medication is insulin. A 1998 ISMP study found that 11% of all serious medication errors involve insulin misadministration, which improved over the years but still occurring at an alarming rate of 4% in 2005. Errors include mixing products with similar packaging and confusing names (e.g., Humalog and Humulin). Confusing generic listings on the computer database and dose unit abbreviations also contributed to the error. The second drug on the list is morphine, which includes all opioids. Look-alike names often cause confusion, such as Avinza vs Evista, Morphine vs Hydromorphone, Oxycontin vs MS Contin, Hydrocodone vs Oxycodone, and Oxycodone vs Codeine. Morphine oral solutions cause many problems because of the multiple concentrations available. Confusion between “mL” and “mg” and between “qid” and “qd” has been reported to result in overdosing or underdosing the patient. Acetaminophen is another drug on the error list, because it is available in different dosage strengths, dispensed with various measuring vessels and is found in many combination products, prescription and OTC. A recent study showed that acetaminophen induced liver toxicity accounts for more than 40% US cases of acute liver failure. As with the opioids, the liquid dose concentration of antibiotics increases the incident of dispensing errors. Reconstitution of antibiotics can also be problematic.


When a medication error occurs, it is tempting to blame individuals. The pharmacist often becomes the first subject of suspicion. There is no doubt that individual effort and performance are keys to the prevention of medication error, but to err is also human. Improvement on system elements can favorably influence medication use, including patient information, drug information, communication network and environmental factors. Healthcare professionals and pharmacists in particular, are advised to stay current with safety alert or medication error update by regularly consulting web publications such as:





美國佛羅里達州西棕櫚灘,棕櫚灘大西洋大學藥學院教授 李慶三

Charles Lee, PhD

Professor of Pharmaceutical Sciences

Lloyd L. Gregory School of Pharmacy,

Palm Beach Atlantic University,

West Palm Beach, FL 33401