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Indian Pediatr 2017;54: 931-934 |
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Drug
Utilization in Neonatal Intensive Care Unit of a Tertiary-care
Hospital in Mumbai, India
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Shailesh Atmaram Chauthankar, Padmaja Anil Marathe,
Anirudha Vyankatesh Potey and
*Ruchi Nimish Nanavati
From Departments of Pharmacology and Therapeutics and
*Neonatology, Seth GS Medical College and KEM Hospital, Mumbai,
Maharashtra, India.
Correspondence to: Dr Padmaja Anil Marathe,
Department of Pharmacology and Therapeutics, Seth GS Medical College and
KEM Hospital, Mumbai, Maharashtra 400 012, India.
Email: [email protected]
Received: September 22, 2016;
Initial Review: April 07, 2017;
Accepted: July 24, 2017.
Published online:
August 24, 2017.
PII:S097475591600084
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Objective: To study the
prescription pattern (using applicable WHO indicators), cost analysis
and off-label use of drugs in neonatal intensive care unit (NICU) of a
tertiary-care hospital. Methods: The prescriptions of 460
neonates admitted to a NICU during July 2014-March 2015 were studied
prospectively. Results: Of 460 neonates, 54.8% were preterm and
73% were low birth weight (LBW). The mean (SD) prescription items per
neonate were 5.7 (3.6). Overall off-label use was 12.3%, while 38%
neonates received at least one off-label drug. Of 326 off-label drugs,
antibiotics (69.6%) followed by non-steroid anti-inflammatory drugs (7%)
were commonly used. Premature and LBW babies required more drugs with
higher cost and longer stay, compared to full term and normal weight
babies (P<0.01), while the pattern of off-label use was similar
across both these categories (P>0.05). Conclusion:
Off-label antibiotics use was common, and prescribing practices were
uniform in NICU.
Keywords: Audit, Antibiotic, Cost analysis,
Prescriptions.
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E
vidence of safety and efficacy of drugs in adults
is often extrapolated to neonates without evidence of systematic studies
in neonates [1,2]. Such practices often result in ineffective drug
therapy, increased use of off-label drugs, wastage of resources,
increased mortality and morbidity, adverse events and cost of the
treatment. We studied prescription pattern, cost and off-label use in
neonatal intensive care unit (NICU) of a tertiary-care hospital.
Methods
This descriptive study was conducted in a NICU of a
tertiary-care hospital, Mumbai, India over a period of 9 months (July
2014 to March 2015). Institutional Ethics Committee approval was
obtained. Neonates admitted to NICU and receiving at least one drug were
recruited after written informed consent from a parent/guardian.
Neonates only under observation or not receiving any medications other
than blood and blood products, vitamin K prophylaxis, prophylactic
ophthalmic treatment, vaccines or intravenous fluids were excluded.
Demographic details were noted. Various drugs prescribed, total (direct
and indirect) cost, off-label use of drugs, availability of drugs on
hospital schedule, duration of hospital stay and outcome of treatment
(survived/dead) were noted at the time of discharge or death.
For purpose of prescription analysis, individual drug
prescribed to each neonate was considered as a ‘prescription item’
irrespective of total duration of its administration [3].
Off-label status of the drug was determined by
referring to British National Formulary for Children (2011-2012) and
Neofax (2011) whenever there was any deviation in prescribing drugs with
respect to indication, dose, dosage forms, frequency of administration,
and age [4,5]. Costs were calculated from patients’ perspective (in
Indian Rupees (INR), 1US Dollar = 62.4 INR as on 31st March 2015).
Expenses incurred due to investigations conducted outside the hospital
or drugs purchased from outside and cost of travel were included in the
direct cost. Loss of wages of attending parents/guardians during period
of neonatal hospitalization were considered as indirect costs [6,7].
Statistical analysis: Data were analyzed using
SPSS version 21. Non-parametric data between groups were compared using
Mann-Whitney U test. P value <0.05 was considered significant.
Results
Out of 1080 neonates screened, 460 were included in
the study, while 620 were excluded as they received no medications and
were managed by other supportive measures. Mean (SD) birth weight was 2
(0.7) kg (range 0.7 kg to 3.8 kg). Median (range) age at the time of
hospitalization and length of hospital stay were 1 (1, 27) day and 10
(2, 78) days, respectively. Among neonates, 59.3% were males, 54.8% were
preterm, 42.8% had low birth weight and 81.1% were from lower middle and
lower socioeconomic class [8]. Common clinical conditions were
respiratory distress, sepsis and pneumonia, followed by meconium
aspiration, neonatal seizures, and congenital heart diseases. A total of
392 (85.2%) neonates were admitted within first few hours after birth
while 421 (91.5%) were admitted during the first week of their life; 417
(90.7%) neonates survived and were discharged.
Prescription pattern analysis is described in
Table I. ‘Injection’ was the most commonly used dosage form
(61.9%) followed by drops (23.3%) and syrups (13.4%). Amikacin (35.8%),
meropenem (10.1%) and dobutamine (7.7%) were most commonly prescribed
generic drugs, while multivitamins (20.7%), ampicillin+sulbactam (19.9%)
and calcium with phosphorus (17%) were most commonly prescribed by brand
names. Drugs unavailable on hospital schedule and purchased from market
constituted 41.3%, of which multivitamins syrup (30.7%) was most
commonly prescribed followed by calcium with phosphorus (25.2%), iron
(17.9%) and caffeine (13.4%).
TABLE I Prescription Pattern Analysis (WHO/INRUD Indicators) of Drugs in Nicu
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WHO Indicators |
Results |
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Total number of prescription items |
2642 |
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Average number of drugs per neonate |
5.7 |
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Drugs prescribed by generic name (%) |
38.8 |
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Prescriptions with antibiotics (%) |
40.8 |
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Prescriptions with injections (%) |
61.9 |
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Drugs prescribed from hospital schedule (%) |
58.7 |
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Days per hospital admission (mean) |
13.5 |
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Drugs per inpatient-day (mean) |
0.4 |
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Antibiotics per inpatient-day (mean) |
0.2 |
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Injections per inpatient-day (mean) |
0.3 |
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Drug cost per inpatient-day (in INR) (mean) |
15 |
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WHO/INRUD- World health
organization / International network for rational use of drugs,
INR – Indian Rupees. |
Of 460 neonates, 374 (81.3%) received antibiotics.
Among them, 215 (57.5%) received ampicillin-sulbactam with amikacin as
first-line empirical therapy, as per departmental protocol. High-end
antibiotics like carbapenems, piperacillin-tazobactam, colistin,
linezolid, tigecycline were used in remaining cases (42.5%), while 18.7%
of neonates did not receive any antibiotic.
Out of 2642 drugs used, 326 (12.3%) drugs were used
off-label. About 175 (38%) neonates were prescribed at least one
off-label drug ranging from 0-9 off-label drugs in one neonate.
Most of the drugs were off-label for the ‘dose’ category (52%) followed
by categories - ‘age’ (21%) and ‘combined’ (15%). No drug was used
off-label for ‘dosage form’ and ‘route’. Magnesium sulphate,
administered for controlling seizures in neonates, was the only drug
used off-label for ‘indication’. Antibiotics were the most commonly
prescribed off-label class of drugs accounting for 69.6%, followed by
NSAIDs (7%) and steroids (3%). Among antibiotics, meropenem (31.7%) was
most commonly prescribed off-label drug followed by
piperacillin-tazobactam (19.8%) and ampicillin-sulbactam (14.5%). Among
NSAIDs, paracetamol, and ibuprofen and among steroids, hydrocortisone
were most commonly prescribed off-label drugs, respectively.
Meropenem (39%) followed by piperacillin-tazobactam (24%) were most
commonly prescribed off-label drugs in ‘dose’ category.
Ampicillin-sulbactam (18%) and colistin (43%) were most commonly used as
off-label as per ‘frequency’ of administration and ‘age’, respectively.
In ‘combined’ category, meropenem (98%) was most commonly used, which
was off-label for dose as well as for frequency.
The average cost of hospitalization per neonate was
7383 INR (median 4925 INR) of which direct cost was 2609 INR and
indirect cost was 4774 INR. Minimum and maximum total cost of
hospitalization were 60 INR and 60880 INR, respectively. Mean (SD)
medical cost per neonate was 1411 (1341) INR while the average total
cost of hospitalization per day was 545 INR.
Preterm (<37 weeks) and low birth weight (<2.5 kg)
neonates were exposed to significantly higher number of drugs, had
longer hospital stay with overall cost of treatment compared to full
term neonates (P <0.05), while number and pattern of off-label
drug use was similar across all neonates irrespective of gestational age
and birthweight (P<0.05) (Table II).
TABLE II Comparison of Various Variables Among Different Age- and Weight-Categories
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According to
gestational age on delivery |
According to
birth weight |
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Preterm |
Term |
P value |
Low birth
weight |
Normal birth
weight |
P value |
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Total drug use |
6.6
(3.8) |
4.7
(3) |
<0.01 |
6.1(3.7) |
4.8
(3.1) |
<0.01 |
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Off-label drug use |
0.7
(1.3) |
0.6
(1.1) |
0.311 |
0.7
(1.2) |
0.6
(0.9) |
0.877 |
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Hospital stay (in d) |
16.4 (13.7) |
10.1 (8) |
<0.01 |
14.9 (12.2) |
9.9
(9.1) |
<0.01 |
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Cost of the treatment (INR) |
9069 (9294) |
5341(4752) |
<0.01 |
7979(8363) |
5770(5751) |
0.002 |
Values in mean (SD); INR- Indian Rupees.
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Discussion
In the present study, injections and antibiotics were
the most common dosage form and class of drug used in neonates,
respectively. Use of one or more off-label drugs was seen in 38% of
neonates, and ‘antibiotics’ was the most common class for off-label use.
The number of drugs, duration of hospital stay and cost was higher in
preterm and low birth weight neonates.
The study results should be interpreted in the light
of following limitations. Direct costs excluded drugs and investigations
which were free of cost from hospital under government funded scheme –
Janani Shishu Suraksha Karyakram [9]. Parents had to bear minimum cost.
Indirect costs did not include capital costs (buildings, medical
equipment, beds) and recurrent cost (staff salary, telephone electricity
and laundry bills etc), but considered costs incurred only by parents.
Prevalence of off-label use in neonates has been
reported in the range of 26-62% [10-13]. In NICUs of Germany [10],
Australia [11], Derby, UK [12], Portugal [13] and Ireland [14], at least
one off-label drug was received by 70%, 80%, 90%, 69.7% and 76%, of
neonates, respectively; and regulatory labels or summary of product
characteristic were followed for determining off-label use.
Category-wise, Carvalho, et al. [3] reported ampicillin as most
commonly prescribed off-label drug in ‘dose’ and ‘frequency’ category
while paracetamol as off-label for ‘age’. In a study by Jain, et al.
[1] antibiotics, and anti-epileptics were off-label in ‘age’ and ‘dose’
categories. Differences in off-label drug use reported in different
studies can be attributed to differences in neonatal conditions,
duration of hospitalization, availability of drugs and different
resource materials (formularies/ labels) referred to determine off-label
status.
Prescribing drugs by generic names and from hospital
schedule is recommended to reduce the cost of treatment and thereby to
promote rational use of drugs. It is usual practice to initiate
antibiotic therapy empirically considering the seriousness of illness.
Differences across NICUs regarding antibiotic use, are affected by
experience of the neonatologist with respective antibiotics, local
microorganism susceptibility pattern and local availability of
antibiotics. Good prescribing practices were observed in our study (over
50 % neonates on supportive therapy alone, one-fifth without
antibiotics, and use of lower-end antibiotics) with survival rate of 91
%.
Considering dearth of controlled clinical trials due
to lack of interest by pharmaceutical companies and ethical issues
related to neonatal recruitment, neonatologists are compelled to use
drugs in an off-label manner to provide maximum benefit from available
drug therapies [15]. Often
prescription of off-label drugs is based on data from medical literature
like case reports and series, recommendations from experts or
neonatology societies [2,16].
Hence, this practice may be considered acceptable and
even necessary in absence of a suitable alternative or guidelines [17].
Clinical studies are required to validate off-label use of drugs used in
neonatal practice.
Acknowledgments: Dr Amit Birajdar and Dr Sarita
Dabba for their generous help.
Contributors: SAC and PAM:
conceptualisation, data collection, data analysis, manuscript writing;
AVP: data analysis and interpretation, data collection, article writing;
RNN: protocol designing, providing expertise and significant
contributions in the conduct of study and in the drafting of the
article, interpretation of data analysis.
Funding: None; Competing interest: None
stated.
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What This Study Adds?
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Off-label drug use is common in
NICU, and needs validation. Higher drug use is involved in
treating preterm and low birth weight neonates.
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References
1. Jain S, Saini SS, Chawla D, Kumar P, Dhir S.
Off-label use of drugs in neonatal intensive care units. Indian Pediatr.
2014;51:644-6.
2. Zheng Z, Yang M, Wu J. Ethical off-label drug use:
Need for a rethink? Indian Pediatr. 2017;54:447-50
3. Carvalho CG, Ribeiro MR, Bonilha MM, Fernandes Jr
M, Procianoy RS, Silveira RC. Use of off-label and unlicensed drugs in
the neonatal intensive care unit and its association with severity
scores. J Pediatr (Rio J). 2012;88:465-70.
4. BMJ Publishing Group, London. The British National
Formulary for Children 2011-2012. Available from:
http://www.sbp.com.br/pdfs/British_National_ Formulary_ for_
Children_2011-2012.pdf. Accessed October 18, 2014.
5. Thomson R. Neofax, 24th ed. Inc Montvale, NJ.
Thomson Reuters/Physicians’ Desk Reference; 2011.
6. McIntyre D, Thiede M, Dahlgren G, Whitehead M.
What are the economic consequences for households of illness and of
paying for health care in low- and middle-income country contexts? Soc
Sci Med. 2006;62:858-65.
7. Leardini G, Salaffi F, Caporali R, Canesi B,
Rovati L, Montanelli R. Italian group for study of the costs of
arthritis- direct and indirect costs of osteoarthritis of the knee. Clin
Exp Rheumatol. 2004;22:699-706.
8. Ravi Kumar BP, Dudala SR, Rao SR. Kuppuswamy’s
Socio-Economic Status Scale - a revision of economic parameter for 2012.
Int J Res Dev Health. 2013;1:2-4.
9. Neogi SB, Malhotra S, Zodpey S, Mohan P.
Assessment of special care newborn units in India. J Health Popul Nutr.
2011;29:500-9.
10. Neubert A, Lukas K, Lies T, Dormann H, Brune K,
Rascher W. Drug utilisation on a preterm and neonatal intensive care
unit in Germany: a prospective, cohort-based analysis. Eur J Clin
Pharmacol. 2010;66:87-95.
11. O’Donnell CP, Stone RJ, Morley CJ. Unlicensed and
off-label drug use in an Australian neonatal intensive care unit.
Pediatrics. 2002;110:e52.
12. Conroy S, McIntyre J, Choonara I. Unlicensed and
off label drug use in neonates. Arch Dis Child Fetal Neonatal Ed.
1999;80:F142-5.
13. Kumar P, Walker JK, Hurt KM, Bennett KM,
Grosshans N, Fotis MA. Medication use in the neonatal intensive care
unit: current patterns and off-label use of parenteral medications. J
Pediatr. 2008;152:412-5.
14. Kieran EA, O’Callaghan N, O’Donnell CP.
Unlicensed and off-label drug use in an Irish neonatal intensive care
unit: a prospective cohort study. Acta Paediatrica. 2013:e139- e142.
15. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey
DL, Leeder LS, Kauffman RE. Developmental pharmacology: Drug
disposition, action, and therapy in infants and children. N Engl J Med.
2003;349:1157-67.
16. Jain SS, Bavdekar SB, Gogtay NJ, Sadawarte PA.
Off-label drug use in children. Indian J Pediatr. 2008;75: 1133-6.
17. Hill P. Off-licence and off-label prescribing in
children: Litigation fears for physicians. Arch Dis Child.
2005;90:i17-8.
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