Drug safety monitoring is important in children.
Young age, polypharmacy, prolonged hospitaliza-tion, being
critically ill and use of unlicensed and off-label drugs have been
identified as risk factors which predispose a child to experience an
adverse drug reaction. In our country, the HIV/AIDS epidemic,
setting up of intensive care units, increasing availability of
imaging studies, and the introduction of several new drugs and
vaccines have accentuated the need for improving drug safety
monitoring in children. To achieve this aim, establishing
in-hospital computerized event monitoring program in major hospitals
and an effective national post- marketing drug surveillance network
are the need of the hour.
An adverse drug reaction (ADR) has been defined as
any noxious, unintended and undesired effect of a drug which occurs at
a dose used in humans for prophylaxis, diagnosis, therapy or
modification of physio-logical functions(1). Children constitute a
vulnerable group, since a new drug gets released to the market without
the benefit of even limited experience in them(2). Drug safety
monitoring, i.e., early detection of possible adverse effects
of a drug, especially a newly introduced one is, therefore, crucial in
children.
In this article we have reviewed recent data, which
highlights the importance of drug safety monitoring in children. We
have also discussed the newer situations and insights related to drug
safety in Indian children, the safety profiles of certain new drugs
being used in Indian children and the steps necessary to improve drug
safety in our pediatric population.
Importance of Drug Safety Monitoring in Children
In our country comprehensive information on the
safety of drugs used in the pediatric population is meager(2). A
recent meta-analysis of 17 prospective studies has shown that ADRs in
children are a significant public health issue all over the world(3).
The overall rate of pediatric hospital admissions due to ADRs was
2.09% and 39.3% of the ADRs causing hospital admissions were
life-threatening reactions. In hospitalized children, the overall
incidence of ADRs was 9.53%, with severe (fatal or potentially life
threatening) reactions accounting for 12.29% of the total. For
outpatient children the overall incidence of ADRs was 1.46%(3).
ADR data in adults cannot be relied upon to predict
ADRs in children(2). Recent examples of ADRs detected exclusively in
the pediatric age group include: greenish discoloration of teeth
following ciprofloxacin use in neonates(4); gastric outlet obstruction
due to prostaglandin infusion in neonates(5); fatal hepatotoxicity
following valproic acid use in developmentally-delayed children below
2 years of age(6); benign intracranial hypertension due to recombinant
growth hormone therapy in children with short stature(7); and
development of depression following isotretinoin use in
adolescents(8).
Risk Factors for Developing ADRs in Children
Recent studies have identified risk factors which
may predispose a child to develop an ADR:
(a) Young age: Neonates and infants
are more likely to suffer an ADR due to their physiological
immaturity(9).
(b) Polypharmacy: A consistent
relationship has been noted between the number of drugs administered
concomitantly and the incidence of ADRs in hospitalized
children(10,11).
(c) Length of hospital stay: Longer
the duration of hospital stay, more are the chances of a child
experiencing an ADR(10).
(d) Being critically ill: Neonates
and children in intensive care units are more likely to suffer an
ADR, as being critically ill affects drug metabolism(9,11). They
also get exposed to a far higher number of drugs that have a narrow
therapeutic index, for example, inotropes, vaso-dilators, and
anti-hypertensives(11).
(e) Use of unlicensed and off-label
drugs: By off-label prescribing is meant using a licensed drug
outside the terms of its product license. A recent study from an
U.K. hospital has reported that almost 25% drugs used in its
pediatric ward, 40% in its pediatric intensive care unit (PICU) and
55% in its neonatal intensive care unit (NICU) were either
unlicensed or being used in an off-label manner(11). ADRs were
associated with 95(6%) of the 1574 unlicensed or off-label drug
prescriptions, as compared to 112(3.9%) of the 2881 licensed drug
prescriptions(11).
Need to Improve Drug Safety Monitoring in Indian
Children
Children in India comprise a large number (400
million) and a variety of ethnic groups. It is of utmost importance
that we have our own comprehensive safety data(2). Also in the last
decade or so, pediatric practice in India has undergone changes, which
"mandates" that we improve our drug safety monitoring. The HIV/AIDS
epidemic, setting up of many intensive care units, increasing
availability of imaging studies, increasing awareness of pediatric
psychiatric conditions, introduction of newer drugs and vaccines have
accentuated the need for improving drug safety monitoring in Indian
children. We now review drug safety data in the pediatric population
for these newer developments:
HIV/AIDS Epidemic
This epidemic has led to
trimethoprim-sulphamethoxazole (TMP/SMZ) being frequently prescribed
in HIV-infected children for the treatment and prophylaxis of
Pneumocystis carinii pneumonia. Both life-threatening and
treatment-limiting adverse events due to suspected delayed
hyper-sensitivity are known to occur after 7 to 21 days of starting
TMP-SMZ(12). These include cardiorespiratory arrest, seizures, toxic
epi-dermal necrolysis, hypotension, respiratory distress, liver
function abnormalities, azo-temia, and gastrointestinal
disturbances(12). Also, anti-retroviral drugs have several adverse
effects. Currently, they are not available at affordable rates. In the
near future they may become available at concessional rates and
HIV-infected children in our country will have to be monitored for
their adverse effects.
Intensive Care Units
Drug safety monitoring is necessary and feasible in
intensive care units(11,13). A recent study from U.K. has reported
that the drugs most commonly used in a PICU, such as midazolam, are
also most likely to cause an ADR(13). Midazolam is being used as a
sedative in mechanically ventilated neonates and children. The plasma
clearance of midazolam is impaired in children below 3 years of age,
who are therefore at increased susceptibility to its toxicity(14). It
should be administered cautiously in very low birth weight (VLBW)
babies because it can cause hypotension and adverse neurological
events such as grade III-IV intra-ventricular hemorrhage(14).
Midazolam has also been reported to cause delayed time to become fully
alert /abnormal behavior on withdrawal in critically ill children(15).
Imaging Studies
CT, MRI, 2-D ECHO/Color Doppler, and
ultrasonography facilities are now increasingly available in our
country. A doctor, nurse or technician who is not well versed in
sedating children may administer the sedative drug before the imaging
study. A recent study from USA has highlighted that children are
vulnerable to adverse events from premedication(16). Nearly 80% of the
adverse events presented initially as respiratory compromise. Even
chloral hydrate, which is believed to be a very safe drug, was no
exception. Adverse sedation events viz., death or permanent
neurological injury was associated when 3 or more drugs were used,
despite the fact that each was administered within the recommended
dosing limits. This study has recommended that only experienced
medical personnel should administer sedatives to children and they
should be discharged only after they have recovered fully from the
sedation(16).
Pediatric Psychiatry
A recommended drug, methylphenidate (MPH), is being
increasingly used to treat ADHD in Indian children. Its side effects
increase linearly with dose, and these include appetite suppression,
insomnia, tachycardia, nervousness and headache(17). A small minority
of ADHD children on MPH therapy is also at risk for serious growth
decrement(18). Pediatricians should therefore closely monitor
dose-related side-effects and aim for the lowest effective dose.
(a) Inhaled Corticosteroid (ICS)
ICS are now the first-line therapy for persistent
asthma in children. The use of high doses of ICS (more than 400
micrograms per day) has been shown to cause a significant reduction in
growth rate(19). Its dose should therefore be minimized to the lowest
effective dose and growth velocity monitored(19). In our country the
use of ICS can have another risk. A report from Mumbai has documented
that 8 (1.4%) out of 548 patients asthmatics, including adults,
developed active tuber-culosis following the use of ICS(20).
(b) Nimesulide
Nimesulide has become popular as a routine
antipyretic and anti-inflammatory drug in Indian children. Randomized
controlled clinical trials have documented that its antipyretic
activity is greater and more rapid than paracetamol(21,22). However,
for any drug, it is not just its efficacy that is important, but also
its safety. It is believed that nimesulide is associated with rare
(0.1 per 100,000 patients treated), but serious and unpredictable
hepatotoxicity viz., increases in serum aminotransferases,
hepatocellular necrosis and intrahepatic cholestasis(23).
(c) Cisapride
Gastro-esophageal reflux (GOR) is an extremely
common and usually self-limiting condition in infants. Cisapride, a
pro-kinetic agent, is being commonly prescribed for the symptomatic
management of GOR in infants and to reduce feed intolerance in
premature neonates in India. Adverse cardiac events (serious
ventricular arrhythmias, QTc interval prolongation and sudden death)
have been reported in adult patients treated with cisapride,
especially with the concomitant ingestion of anti-fungal drugs (fluconazole,
miconazole) and macrolides (clarithro-mycin)(24). A study from USA has
suggested that documenting a prolongation of the QTc interval, 3 days
following cisapride initiation, would identify infants at risk for
adverse cardiac events(25).
(d) Newer Anti-epileptic Drugs (AEDs)
Newer AEDs (lamotrigine, oxcarbaze-pine, and
topiramate) are being marketed for pediatric use in India. All over
the world there is a lack of systematic pharmacoepidemio-logical
studies investigating ADRs to the newer AEDs, making it difficult to
assess accurately their incidence of ADRs(26). The ADRs identified
include: hypersensitivity reactions ranging from simple morbilliform
rashes to multi-organ failure, psychiatric ADRs and deterioration of
seizure control to lamotrigine; hyponatremia and skin rash to
oxcarbazepine; cognitive deficits, word-finding difficulties, renal
calculi and weight loss to topiramate; and, aphasia, encephalo-pathy,
motor disturbances and late-onset visual field constriction to
vigabatrin (26).
(e) Newer Vaccines
In India many newer vaccines have been recently
marketed viz., Measles Mumps Rubella (MMR) vaccine, Hepatitis B
(HB) vaccine, Hepatitis A (HA) vaccine, Hemophilus influenzae b
(Hib) conjugate vaccine and varicella-zoster (VZ) vaccine. These newer
vaccines are not yet on the UIP schedule due to financial constraints.
No official post-marketing data is available on the safety of these
newer vaccines in Indian children, as pediatricians in the private
sector, who usually prescribe these newer vaccines, are not duty-bound
to report the adverse events occurring to them.
In the developed world many perceived risks of
undergoing immunization have been debated. However current scientific
evidence, based on detailed epidemiological studies, does not support
a causal association between any vaccine and type 1 diabetes,
pertussis or measles vaccines and asthma, HB vaccine and demyelinating
autoimmune diseases, and MMR vaccine and autism(27). To fill the gaps
in current scientific knowledge of rare vaccine adverse events, the
Vaccine Safety Datalink (VSD) project has been started in the USA(28).
Computerized immunization registry data has been linked with the
computerized medical use data of millions of children who receive
vaccines. Currently, studies to determine causal associations, if any,
between vaccines and 34 medical outcomes (e.g., autism,
autoimmune diseases, asthma, etc.) are underway(28).
Newer Insights
There have been newer insights into drugs being
used in children for many decades which highlight the fact that drug
safety monitoring is a continuous process.
(a) Use of antipyretics: It is well
documented that both paracetamol and ibuprofen are safe drugs, when
used individually, in children. There is presently no scientific
evidence that an alternating regimen of paracetamol and ibuprofen is
safe, or that it achieves faster antipyresis than either drug used
alone(29). However, there is evidence that such a regimen may cause
harm. A 14-month-old girl, who was moderately dehydrated, received
this regimen for control of fever and developed acute renal failure,
which was attributed to the additive and synergistic renal
toxicities of paracetamol and ibuprofen(30).
(b) Cefaclor-induced serum
sickness-like reaction (SSLR): Cefaclor, an oral
second-generation cephalosporin, is used to treat respiratory and
skin infections. Recently this unique ADR, wherein the child
develops urticaria, arthralgia and facial edema on receiving a
second or third course of cefaclor, has been identified. It occurs
in 0.055% of children and its tendency to develop is probably
genetically inherited(31).
(c) Multiple antibiotic sensitivity
syndrome: This rare but distinct ADR manifests as urticaria,
serum sickness-like re- action, anaphylaxis, or Stevens-Johnson
syndrome to antibiotics of multiple classes viz., penicillin,
cephalosporins, sulfona-mides and macrolides. Although its incidence
in children is not known it is believed to occur after repeated use
of these antibiotics(32).
(d) Antiepileptic drug hypersensitivity
syndrome (AHS): This rare idiosyncratic reaction can occur to
aromatic AEDs (phenobarbital, phenytoin, carbamaze-pine, lamotrigine)
within three months of starting therapy. A classic triad of fever,
skin rash and hepatic dysfunction should serve as a presumptive
diagnosis of AHS and the offending AED should be promptly omitted.
Since there is a high rate of cross-sensitivity between the aromatic
AEDs, the child should henceforth receive benzodiazepines, valproic
acid, or topiramate for future seizure control(33).
How to Improve Drug Safety in Pediatric Practice?
Various efforts are being taken in the USA and in
Europe to improve drug safety in children. We now describe these
efforts and discuss their feasibility in our country:
(a) By conducting clinical drug trials:
The well-intentioned protectionist belief that children should
not be exposed to potentially harmful side effects of a medicine
until more is known about its effects in adults, has ironically led
to pediatric drug evaluation getting neglected(34,35).
In recent times in the USA and in Europe, there
has been an increasing demand by pediatricians and clinical
pharmaco-logists for conducting well designed drug trials in
children. Guidelines to conduct drug trials in children, without
compromising on the ethical issues, have already been
published(34,36). Since 1994, the Federal Drug Administration (FDA)
in the USA has introduced new regulations, which "require" the drug
manufacturer to re-examine existing information on marketed drugs,
in order to determine whether the labeling of the drug can be
modified for permitting its licensed use in children. All
information relevant to children, on the basis of adult studies and
available pediatric data, needs to be re-examined. If any such
information is available then the drug manufacturer will be
"required" to submit an application to the FDA for supplemental
pediatric labeling within two years of marketing the new drug(35).
Legislation passed in 1997 offers the drug manufacturer a major
financial incentive, in the form of a 6-month extension to patent
exclusivity, on the condition that a drug trial to determine its
efficacy and safety in children will be completed within that
period(37). This legislation has led to a dramatic increase in the
number of pediatric clinical trials being conducted in the USA(37).
It is hoped that such trials will result in children, like adults,
having access to safe and effective medicines. As yet in our
country, clinical drug trials are not permitted in the pediatric age
group, except for newer vaccines. Unless there is a change in this
policy by our drug regulatory authorities, this method of improving
drug safety in Indian children is not feasible.
(b) By using computerized pre-recorded
data to assess causality of adverse events: In many developed
countries all patient data (clinical history, symptoms and signs,
laboratory and radiological investigations done and treatment being
given) is recorded using computers. With the advent of
computerization, identifying "adverse events" occurring during
hospitalization has become relatively easy(38). Another advantage is
its ability to assess the causality of each "adverse event" within a
reasonable time frame(38). In some tertiary care hospitals in our
country where computers are already being used to record data of
patients, such intensive surveillance studies are feasible.
(c) By implementing pro-active measures
to improve spontaneous ADR reporting: The spontaneous reporting
system is the most productive and cost-effective method to detect
ADRs in children(2). Questionnaire-based postal surveys have been
conducted to gather information on ADRs occurring to ciprofloxacin
in Indian children(2). However this method has still not been well
established in India(2).
Two recent studies have shown the way to achieve an
active ADR reporting system(39, 40). In Italy a network of family
pediatricians was developed by properly presenting the project to them
and then training them in ADR reporting(39). Each week, for a year,
the participating pediatricians sent, by e-mail, a detailed report of
each observed ADR to the central authority. Although ADR reporting was
mandatory in Italy, till then, only 4 ADRs per 100 000 children were
being reported annually. After this project was started, 15 ADRs per
1000 children have been recorded annually(39). In U.K., a similar
pro-active project involving doctors working in tertiary centers and
smaller district general hospitals has proved successful(40). In the
U.K project, in addition, a monthly reminder letter was sent to each
participating doctor to stimulate ADR reporting for newer drugs.
Examples of ADRs mentioned in the reminder letter included: skin
reactions to lamotrigine, arrhythmias to cisapride, visual field
defects to vigabatrin and systemic adverse reactions to inhaled or
nasal corticosteroids(40). This has resulted in obtaining substantial
data on specific ADRs occurring to newly introduced drugs. In both
studies, the motivation of the participating doctors was maintained by
giving them prompt feedback and acknowledging their valuable
support(39,40). Such pro-active measures to improve spontaneous ADR
reporting are feasible in major cities, towns and districts
headquarters in our country, as internet services are now easily
available.
Contributors: SK was responsible for concept
and design, review of data and drafting the article; NJG for
discussing core ideas and critical review of the article; NAK for
concept, critical review, and final approval and will act as the
guarantor for the article.
Funding: None.
Competing interests: None stated.
