Principles and Practice of Pharmaceutical Medicine

39.6 Labeling

Product labeling describes currently known rele-
vant information about a drug and is intended to aid
in evaluating the risk versus benefit of a drug when
a prescriber is confronted by an individual patient.
The labeling is often in the form of a package insert
or compendium of information, such as theRote
List,Drug Sheet Compendium or Physicians’Desk
Reference.As the safety profile of a drug changes
over time, the product labeling is modified in order
to convey up to date information.

39.7 (Sub)populations

Different subpopulations may react differently to
drugs, due to a variety of reasons affecting meta-
bolism. Factors that could influence patient sus-
ceptibility include multiple drug therapies,
multiple disorders and severity of disease, types
of drugs prescribed, altered pharmacokinetics,
pharmacogenetics, altered pharmacodynamics
and the age of the population treated (Nolan and
O’Malley, 1988).
Differences in metabolism among patients can
lead to differences in susceptibility to adverse
events. Classic examples are patients with

abnormal pseudocholinesterase levels have pro-
longed apnea after receiving succinylcholine;

low activity ofN-acetyl transferase (‘slow acet-
ylators’) are more likely to develop lupus-like
reactions to procainamide, hydralazine and iso-
niazid; and

variants of the cytochrome P-450 family of
enzymes can lead to altered metabolism of a
variety of drugs, including antidepressants, anti-
arrhythmic agents, codeine, metoprolol terfena-
dine, cyclosporine, calcium channel blockers
and others (Pecket al., 1993).

The pharmacological action of drugs in children
may differ from adults, and may invoke a different
pattern of adverse events (Gustafson, 1969; Collins

et al., 1974). However, there is little systematic

pediatric pharmacoepidemiological data (Bruppa-

cher and Gelzer, 1991). Post-marketing safety sur-

veillance may be the only way new signals can be

detected in this population.

There may also be ethnic differences in suscept-

ibility to adverse event frequency and reporting.

Corzoet al.(1995) identified an association of

alleles of the HLA-B and DR loci with increased

risk of clozapine-induced agranulocytosis. Patients

with abnormal pscudocholinesterase levels have

prolonged apnea after receiving succinylcholine.

Patients with low activity onN-acetyl transferase

are more likely to develop lupus-like reactions to

procainamide, hydralazine and isoniazid (Pecket

al., 1993). In some countries, the reporting of

adverseevents is reducedbecause ofcultural biases

against upsetting the prescriber.

39.8 Pregnancy

Fetal injury and death can result from the use of

certain drugs by the mother, and decisions regard-

ing risk versus benefit must be made when no

alternative treatment is available. Certain drugs

are specifically contraindicated during pregnancy,

for example angiotensin converting enzyme (ACE)

inhibitors, used by a mother during the second and

third trimesters of pregnancy to treat hypertension

or congestive heart failure, can lead to fetal injury

and death (FDA, 1992). Thalidomide was found in

the early 1960s to cause fetal limb abnormalities

(phocomelia) in the children of mothers who took

thalidomide as an antiemetic or sedative during

pregnancy.

39.9 Post-marketing

surveillances studies

Duringclinical trials,investigatorsare instructedto

collect all adverse events reported by patients

enrolled in the study, which are tabulated. During

final study reports or product marketing applica-

tions, adverse event data are analyzed and com-

pared among treatment arms. Overall analyses of

39.9 POST-MARKETING SURVEILLANCES STUDIES 541