International Journal of Risk & Safety in Medicine 27 (2015) 45–53 DOI 10.3233/JRS-150642 IOS Press
45
Is off-label use a risk factor for adverse drug reactions in pediatric patients? A prospective study in an Indian tertiary care hospital Mohd Masnoon Saiyeda,∗ , Tarachand Lalwania and Devang Ranab a
Department of Pharmacology and Clinical Pharmacy, K.B Institute of Pharmaceutical Education and Research, Gandhinagar, Gujarat, India b Department of Pharmacology, Smt. N.H.L Municipal Medical College, Seth V.S General Hospital, Ellisbridge, Ahmedabad, Gujarat, India Received 17 August 2014 Accepted 20 January 2015 Abstract. BACKGROUND: The lack of specific medicines and labeling recommendations for the pediatric population is a long-standing problem. Using data from an observational study of adverse drug reactions (ADRs) among pediatric inpatients, we aimed to test the hypothesis that off-label status is a risk factor for ADRs. METHODS: A prospective intensive surveillance was conducted at a pediatric ward of a public teaching hospital. Adverse events to labeled and off-label use were assessed for incidence, severity and predictors. A multivariate Cox proportional hazards regression model used to assess off-label use is a risk factor for ADR occurring. RESULTS: Off-label and labeled use were responsible for 34 (67%) and 17 (33%) ADRs respectively. Medicines which lacked complete pediatric labeling had the greatest odds for ADRs (9.21% of medicines in this category were implicated, OR 2.84 (95% CI 1.37–7.09). Number of off-label medicines given to patient significantly increased the hazard of an ADR (hazard ratio (HR) 1.28, 95% CI 0.43–3.78, P = 0.002). Number of medicines given also significantly increased the hazard (HR 1.2, 95% CI 0.80–1.71, P < 0.001). CONCLUSIONS: Use of off-label medicines were more likely to be implicated in an ADR than labeled medicines. This off-label use would be acceptable if evidence of potential benefits outweighs ADRs risk. Keywords: Adverse drug reactions, pediatrics, prescribing, off-label
1. Background Learning lessons from the numerous pediatric pharmacology disasters such as phocomelia following prenatal exposure to thalidomide and gray baby syndrome in infants secondary to chloramphenicol, the drug approval process was introduced in the UK and USA in the 1960s. The abovementioned pharmacological tragedies make it clear that safe and rational pediatric prescribing requires controlled studies of drugs in children. Despite many regulatory amendments in pediatric drug development, numbers of pediatric clinical trials are still very less compared to adult [1, 2]. In the absence of clinical trials, standard information and labeling is not available for pediatric prescribing [3]. As a result, clinicians use medicines ∗
Address for correspondence: Mohd Masnoon Saiyed, Department of Pharmacology and Clinical Pharmacy, K.B Institute of Pharmaceutical Education and Research, Gh-6, Sector 23, Gandhinagar-382024, Gujarat, India. Tel.: +91 9662202921; E-mail: [email protected]. 0924-6479/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved
46
M.M. Saiyed et al. / Is off-label use a risk factor for adverse drug reactions?
in off-label manner which is inconsistent with its approved product license. Off-label use in children has been reported in several studies in Pediatric Wards, Neonatal Intensive Care Units and Community settings. In general off-label prescribing in pediatric ward has been around 18 to 60% and widespread across several therapeutic areas [4]. The rationalization for off-label prescribing is that it should provide the best available treatment and individual patient welfare should direct such use based on risk-benefit ratio [5]. Most studies had focused on magnitude of off-label prescribing rather than associated risks. There is accumulating evidence that off-label medicines use is an independent risk factor for adverse drug reactions (ADRs) in pediatric patients [6]. Most recently in a study of 1388 patients, Bellis et al. found that off-label medicines are more likely to be implicated for ADRs compared to authorized use [7]. Currently, there is distinct lack of research to evaluate off-label medicines associated ADRs in developing countries like India. Using the data generated by our study evaluating the incidence of ADRs in pediatric inpatients, we have employed prospective study design to assess the impact of number off-label medicines on ADR risk in pediatric inpatients. 2. Methods 2.1. Data collection We conducted a prospective non-interventional study at a public teaching hospital in Ahmedabad (India) for the period of six months. Pediatric patients aged between 0 to 12 years receiving at least one medication and admitted in pediatric ward were included in the study. Pediatric surgery patients were excluded. Patient’s details, clinical characteristics and medication uses were obtained from the medical records using predefined paper case record forms. As reference, we utilized National Formulary of India (NFI, 4th edition, 2011) which is an official publication of Indian Pharmacopoeia Commission, Table 1 Off-label medicine use categories Category Off-Label Use – With Pediatric Labeling in NFI
Off-Label Use – Without Pediatric Labeling in NFI
NFI: National Formulary of India, 2011.
Sr. no 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Definition Dose greater or lower than labeled Not labeled in child of this age Not labeled in child of this age and at this dose Not labeled for this indication Not labeled by this route and in a child of this age Not labeled by this route Not labeled by this route and at this dose Not labeled for this indication and at this age Not labeled for this indication and at this dose Not labeled for this indication and this route or this age Not labeled for use in children Not labeled for use in children and in adults by this route Not labeled for use in children and in adults for this indication Not labeled for use in children and in adults for this indication or in adults by this route
M.M. Saiyed et al. / Is off-label use a risk factor for adverse drug reactions?
47
Ministry of Health and Family Welfare, Government of India [8]. Medicine use could be off-label for more than one reason, hence we distributed off-label use in 14 possible different categories (Table 1). Categories for off-label use were allocated for each medicine according to the reason(s) why their use was deemed off-label when compared to the terms of the product labeling for that medicine. Off-label use was defined into two main groups: with pediatric labeling (e.g. levocetrizine) and without pediatric labeling (e.g. nifedipine). In these two main categories a drug could be used for more than one off-label reason, hence sub-categories were also classified. The suspected adverse drug reactions were assessed with WHO-UMC causality assessment tool and severity was graded with Common Terminology Criteria for Adverse Events (CTCEA), version 4.0 [9, 10]. According to CTCEA, severity grade 1 refers to mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated and grade 2 means moderate symptoms; minimal, local or noninvasive intervention indicated; limiting ageappropriate instrumental activities of daily living. The detected ADRs were coded as per International Conference on Harmonization – Medical Dictionary for Regulatory Activities; lowest level terms (ICHMedDRA) by personnel at Cognizant, a pharmacovigilance consulting organization (Mumbai, India). 2.2. Statistical analysis The unit of analysis comprised of medication, adverse drug reaction (ADR) and off-label medicine status. Variables such as age and number of off-label medications were regarded as continuous, and expressed as mean with standard deviation (SD). Categorical variables are presented as numbers with percentages (%). Risk factors for ADRs were analyzed with Cox proportional hazards regression model The Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated for each off-label category implicated in a probable or possible ADR in comparison to labeled medicines. A probability value of less than 0.05 was considered statistically significant for all analyses. The data were analyzed using Statistical Package for the Social Sciences (SPSS Inc., IBM). 2.3. Ethics statement The study received ethical approval from Ethics Committee (Protocol No. 39), K.B Institute of Pharmaceutical Education and Research, India. 2.4. Research reporting This study was reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [11]. 3. Results 3.1. Study participants and medicines utilization A total of 320 patients admitted in pediatric general ward of the public teaching hospital over a period of six months were included in the study. Among the patients, 138 (43%) were infants (1 m to 1 yr), 63 (20%) were toddlers (1–3 yrs), 74 (23%) were preschoolers (3–6 yrs) and 45 (14%) were school-age children (6–12 yrs). There were 206 (64%) male and 114 (36%) female patients and the mean age was 2.73 years (Range = 0.1 to 12 years and standard deviation: 3.09).
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M.M. Saiyed et al. / Is off-label use a risk factor for adverse drug reactions?
During the study cohort total 1645 medications were administered. A total of 1152 (70%) medicines were prescribed in off-label manner when its usage was assessed with NFI for 14 possible different off-label categories. Patients received on average 3.66 (SD = 2.13) off-label medicines and within a range of one to 10. The most common cause of off-label prescribing 641 (55.64%) was due to higher/lower dose use (category 1) than stated for particular pediatric patients. Off-label medicines use for category of dose-age (category 3) and indication (category 4) was found to be 225 (19.53 %) and 116 (10.06%) respectively. The use of off-label medicine use in where no pediatric labeling (category 11) is given and uses beyond certain age limits (category 2) was 76 (6.6%) and 40 (3.5%) respectively. The off-label use for all remaining categories was collectively 54 (4.67%). Table 2 Distribution of ADR and causative medicines MedDRA coded adverse drug reactions
No. (%)
CTCEA severity grades
Angioedema Anorexia Ataxia
1 1 5
2 1 2
Chills
6
2
Conjuctivitis Constipation Diarrhea Drowsiness Dry mouth Ear pruritus Pyrexia
1 1 2 2 1 1 4
2 1 2 2 2 1 1
Hypoglycemia Hypokalemia Lethargy Nausea Papilloedema Macupapular rash
1 1 1 1 1 9
2 1 1 1 2 2
SGPT increased Tachycardia Tachypnea Thrombocytopenia
1 3 1 1
2 2 2 2
Vomitting
5
1,2
Yellow skin
1
1
WHO UMC causality category
Drugs Implicated (O/L)
Possible Probable Possible OR Probable Probable
Phenytoin (O) Sodium Valproate (O) Pantoprazole(O) and Phenytoin (O)
Probable Probable Probable Probable Probable Probable Possible OR Probable Probable Probable Probable Probable Probable Possible OR Probable Probable Probable Probable Possible OR Probable Probable Probable
Acyclovir (L). Amikacin (O), Clindamycin (L), Vancomycin (O) and Levetiracetam (O) Ipratopium (O) Azithromycin (L) Amoxycillin (L) and Ampicillin(O) Lorazepam (L) and Dexmethasone (L) Atropine (O) Ondansetron (O) Ondansetron (O), Mannitol (L), Levetiracetam (O) and Vancomycin (O) Aspirin (O) Insulin (L) Salbutamol (O) Clobazam (L) Vancomycin (O) Ceftriaxone (O), Chloroquine (L), Dexmethasone (L), Ofloxacin (O), Phenytoin (L) Vancomycin (O) Ceftriaxone (O) Salbutamol (O), Ipratopium (O) and Dopamine (O) Ipratopium (O) Ceftriaxone (O) Ceftriaxone (O), Prednisolone (L),Clobazam (L), Cefotaxime (L) and Azitromycin (L) Ceftazidime (L)
MedDRA = Medical Dictionary for Regulatory Activities, O = off-label and L = label, WHO-UMC-World Health Organization Uppsala Monitoring Centre and SGPT-Serum Glutamate Pyruvic Transaminase.
M.M. Saiyed et al. / Is off-label use a risk factor for adverse drug reactions?
49
3.2. Characteristics of adverse drug reactions Of the total 320 patients studied, 51 adverse drug reactions occurred in 47 patients, hence incidence rate was 10.85%. Patients aged 0 to 2 years experienced 28 (55%) ADRs, > 2 to 6 years had 13 (25%) and >6 to 12 years suffered 10 (20%) ADRs. Total 28 different medicines were implicated for different adverse drug reactions as shown in the Table 2. Of the total ADRs, 28 (55%) were probable and 13 (45%) deemed possible. The ADRs mostly belonged to CTCEA severity grade 2 (70%) or 1 (30%). All the detected ADRs were reported to regional pharmacovigilance centre in spontaneous ADR reporting forms. Most common ADRs were macupapular rash, chills, ataxia and pyrexia. Among the medications prescribed, vancomycin (25%), phenytoin (18%) and ceftriaxone (14%) were frequently found responsible for ADRs. 3.3. Off-label use and adverse drug reactions Off-label and labeled medicine use were responsible for 34 (67%) and 17 (33%) of ADRs respectively. The ADRs were also distributed according to causative medicine’s label and off-label uses. A total 10 off-label categories were utilized in this evaluation as shown in Table 3. Category 1: dose greater/lower than labeled had 15 medicine uses (3.4%, OR 0.64, CI 0.33–1.24) implicated for ADRs. Category 2: Not labeled in child of this age had 3 medicine uses (7.5%, OR 2.27, CI 0.64–8.10) responsible for ADRs and association was significant. Category 3: not labeled for child of this age or at this dose had 9 medicines uses (5%, OR 1.35 CI 0.60–3.05) associated with ADRs. Category 11: not labeled for use in children had 7 medicines uses (9.21%, OR 2.84, CI 1.37–7.09) accountable for ADRs and risk was noteworthy. Among the frequently prescribed drug class, the risk of adverse drug reaction was not considerable for off-label use in respiratory system (1.08%, OR 0.30, 0.11–0.83), anti-infectives for systemic use (2.82%, OR 0.81, CI 0.45–1.85) and nervous system (2.19%, OR 0.63, CI 0.27–1.42). Table 3 Total number of medicines in each labeled, off-label category and number implicated in at least one ADR (n = 1645) Type of medicine Labeled Use Off-label use category 1 2 3 4 5 6 7 8 9 11 Respiratory system Anti-infectives for systemic use Nervous system
Number of medicines
% of medicines for at least one ADR
Odd ratio of ADR versus labeled
95% CI
493 641 40 225 116 5 13 7 9 20 76 463 531 411
3.5% 3.4% 7.5% 5% 0 0 0 0 0 0 9.21% 1.08% 2.82% 2.19%
1.00 0.64 2.27 1.35 – – – – – – 2.84 0.30 0.81 0.63
– 0.33 –1.24 0.64 –8.10 0.60 –3.05 – – – – – – 1.37–7.09 0.11–0.83 0.45–1.85 0.27–1.42
ADR: adverse drug reaction; CI: confidence interval.
50
M.M. Saiyed et al. / Is off-label use a risk factor for adverse drug reactions? Table 4 ADR risk factors assessed by multivariate analysis (Cox Proportional Hazard Regression Model)
Covariate Age on admission (years) Gender Male Female Number of total medicines per patient Number of off-label medicines use per patient Number of labelled medicines use per patient
HR (95% CI)
P-value
1.07 (0.96–1.18)
0.205
1 0.64 (0.32–1.30) 1.17 (0.80– 1.71) 1.28 (0.43–3.78) 0.75 (0.51–1.09)
– 0.502
45
Is off-label use a risk factor for adverse drug reactions in pediatric patients? A prospective study in an Indian tertiary care hospital Mohd Masnoon Saiyeda,∗ , Tarachand Lalwania and Devang Ranab a
Department of Pharmacology and Clinical Pharmacy, K.B Institute of Pharmaceutical Education and Research, Gandhinagar, Gujarat, India b Department of Pharmacology, Smt. N.H.L Municipal Medical College, Seth V.S General Hospital, Ellisbridge, Ahmedabad, Gujarat, India Received 17 August 2014 Accepted 20 January 2015 Abstract. BACKGROUND: The lack of specific medicines and labeling recommendations for the pediatric population is a long-standing problem. Using data from an observational study of adverse drug reactions (ADRs) among pediatric inpatients, we aimed to test the hypothesis that off-label status is a risk factor for ADRs. METHODS: A prospective intensive surveillance was conducted at a pediatric ward of a public teaching hospital. Adverse events to labeled and off-label use were assessed for incidence, severity and predictors. A multivariate Cox proportional hazards regression model used to assess off-label use is a risk factor for ADR occurring. RESULTS: Off-label and labeled use were responsible for 34 (67%) and 17 (33%) ADRs respectively. Medicines which lacked complete pediatric labeling had the greatest odds for ADRs (9.21% of medicines in this category were implicated, OR 2.84 (95% CI 1.37–7.09). Number of off-label medicines given to patient significantly increased the hazard of an ADR (hazard ratio (HR) 1.28, 95% CI 0.43–3.78, P = 0.002). Number of medicines given also significantly increased the hazard (HR 1.2, 95% CI 0.80–1.71, P < 0.001). CONCLUSIONS: Use of off-label medicines were more likely to be implicated in an ADR than labeled medicines. This off-label use would be acceptable if evidence of potential benefits outweighs ADRs risk. Keywords: Adverse drug reactions, pediatrics, prescribing, off-label
1. Background Learning lessons from the numerous pediatric pharmacology disasters such as phocomelia following prenatal exposure to thalidomide and gray baby syndrome in infants secondary to chloramphenicol, the drug approval process was introduced in the UK and USA in the 1960s. The abovementioned pharmacological tragedies make it clear that safe and rational pediatric prescribing requires controlled studies of drugs in children. Despite many regulatory amendments in pediatric drug development, numbers of pediatric clinical trials are still very less compared to adult [1, 2]. In the absence of clinical trials, standard information and labeling is not available for pediatric prescribing [3]. As a result, clinicians use medicines ∗
Address for correspondence: Mohd Masnoon Saiyed, Department of Pharmacology and Clinical Pharmacy, K.B Institute of Pharmaceutical Education and Research, Gh-6, Sector 23, Gandhinagar-382024, Gujarat, India. Tel.: +91 9662202921; E-mail: [email protected]. 0924-6479/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved
46
M.M. Saiyed et al. / Is off-label use a risk factor for adverse drug reactions?
in off-label manner which is inconsistent with its approved product license. Off-label use in children has been reported in several studies in Pediatric Wards, Neonatal Intensive Care Units and Community settings. In general off-label prescribing in pediatric ward has been around 18 to 60% and widespread across several therapeutic areas [4]. The rationalization for off-label prescribing is that it should provide the best available treatment and individual patient welfare should direct such use based on risk-benefit ratio [5]. Most studies had focused on magnitude of off-label prescribing rather than associated risks. There is accumulating evidence that off-label medicines use is an independent risk factor for adverse drug reactions (ADRs) in pediatric patients [6]. Most recently in a study of 1388 patients, Bellis et al. found that off-label medicines are more likely to be implicated for ADRs compared to authorized use [7]. Currently, there is distinct lack of research to evaluate off-label medicines associated ADRs in developing countries like India. Using the data generated by our study evaluating the incidence of ADRs in pediatric inpatients, we have employed prospective study design to assess the impact of number off-label medicines on ADR risk in pediatric inpatients. 2. Methods 2.1. Data collection We conducted a prospective non-interventional study at a public teaching hospital in Ahmedabad (India) for the period of six months. Pediatric patients aged between 0 to 12 years receiving at least one medication and admitted in pediatric ward were included in the study. Pediatric surgery patients were excluded. Patient’s details, clinical characteristics and medication uses were obtained from the medical records using predefined paper case record forms. As reference, we utilized National Formulary of India (NFI, 4th edition, 2011) which is an official publication of Indian Pharmacopoeia Commission, Table 1 Off-label medicine use categories Category Off-Label Use – With Pediatric Labeling in NFI
Off-Label Use – Without Pediatric Labeling in NFI
NFI: National Formulary of India, 2011.
Sr. no 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Definition Dose greater or lower than labeled Not labeled in child of this age Not labeled in child of this age and at this dose Not labeled for this indication Not labeled by this route and in a child of this age Not labeled by this route Not labeled by this route and at this dose Not labeled for this indication and at this age Not labeled for this indication and at this dose Not labeled for this indication and this route or this age Not labeled for use in children Not labeled for use in children and in adults by this route Not labeled for use in children and in adults for this indication Not labeled for use in children and in adults for this indication or in adults by this route
M.M. Saiyed et al. / Is off-label use a risk factor for adverse drug reactions?
47
Ministry of Health and Family Welfare, Government of India [8]. Medicine use could be off-label for more than one reason, hence we distributed off-label use in 14 possible different categories (Table 1). Categories for off-label use were allocated for each medicine according to the reason(s) why their use was deemed off-label when compared to the terms of the product labeling for that medicine. Off-label use was defined into two main groups: with pediatric labeling (e.g. levocetrizine) and without pediatric labeling (e.g. nifedipine). In these two main categories a drug could be used for more than one off-label reason, hence sub-categories were also classified. The suspected adverse drug reactions were assessed with WHO-UMC causality assessment tool and severity was graded with Common Terminology Criteria for Adverse Events (CTCEA), version 4.0 [9, 10]. According to CTCEA, severity grade 1 refers to mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated and grade 2 means moderate symptoms; minimal, local or noninvasive intervention indicated; limiting ageappropriate instrumental activities of daily living. The detected ADRs were coded as per International Conference on Harmonization – Medical Dictionary for Regulatory Activities; lowest level terms (ICHMedDRA) by personnel at Cognizant, a pharmacovigilance consulting organization (Mumbai, India). 2.2. Statistical analysis The unit of analysis comprised of medication, adverse drug reaction (ADR) and off-label medicine status. Variables such as age and number of off-label medications were regarded as continuous, and expressed as mean with standard deviation (SD). Categorical variables are presented as numbers with percentages (%). Risk factors for ADRs were analyzed with Cox proportional hazards regression model The Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated for each off-label category implicated in a probable or possible ADR in comparison to labeled medicines. A probability value of less than 0.05 was considered statistically significant for all analyses. The data were analyzed using Statistical Package for the Social Sciences (SPSS Inc., IBM). 2.3. Ethics statement The study received ethical approval from Ethics Committee (Protocol No. 39), K.B Institute of Pharmaceutical Education and Research, India. 2.4. Research reporting This study was reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [11]. 3. Results 3.1. Study participants and medicines utilization A total of 320 patients admitted in pediatric general ward of the public teaching hospital over a period of six months were included in the study. Among the patients, 138 (43%) were infants (1 m to 1 yr), 63 (20%) were toddlers (1–3 yrs), 74 (23%) were preschoolers (3–6 yrs) and 45 (14%) were school-age children (6–12 yrs). There were 206 (64%) male and 114 (36%) female patients and the mean age was 2.73 years (Range = 0.1 to 12 years and standard deviation: 3.09).
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M.M. Saiyed et al. / Is off-label use a risk factor for adverse drug reactions?
During the study cohort total 1645 medications were administered. A total of 1152 (70%) medicines were prescribed in off-label manner when its usage was assessed with NFI for 14 possible different off-label categories. Patients received on average 3.66 (SD = 2.13) off-label medicines and within a range of one to 10. The most common cause of off-label prescribing 641 (55.64%) was due to higher/lower dose use (category 1) than stated for particular pediatric patients. Off-label medicines use for category of dose-age (category 3) and indication (category 4) was found to be 225 (19.53 %) and 116 (10.06%) respectively. The use of off-label medicine use in where no pediatric labeling (category 11) is given and uses beyond certain age limits (category 2) was 76 (6.6%) and 40 (3.5%) respectively. The off-label use for all remaining categories was collectively 54 (4.67%). Table 2 Distribution of ADR and causative medicines MedDRA coded adverse drug reactions
No. (%)
CTCEA severity grades
Angioedema Anorexia Ataxia
1 1 5
2 1 2
Chills
6
2
Conjuctivitis Constipation Diarrhea Drowsiness Dry mouth Ear pruritus Pyrexia
1 1 2 2 1 1 4
2 1 2 2 2 1 1
Hypoglycemia Hypokalemia Lethargy Nausea Papilloedema Macupapular rash
1 1 1 1 1 9
2 1 1 1 2 2
SGPT increased Tachycardia Tachypnea Thrombocytopenia
1 3 1 1
2 2 2 2
Vomitting
5
1,2
Yellow skin
1
1
WHO UMC causality category
Drugs Implicated (O/L)
Possible Probable Possible OR Probable Probable
Phenytoin (O) Sodium Valproate (O) Pantoprazole(O) and Phenytoin (O)
Probable Probable Probable Probable Probable Probable Possible OR Probable Probable Probable Probable Probable Probable Possible OR Probable Probable Probable Probable Possible OR Probable Probable Probable
Acyclovir (L). Amikacin (O), Clindamycin (L), Vancomycin (O) and Levetiracetam (O) Ipratopium (O) Azithromycin (L) Amoxycillin (L) and Ampicillin(O) Lorazepam (L) and Dexmethasone (L) Atropine (O) Ondansetron (O) Ondansetron (O), Mannitol (L), Levetiracetam (O) and Vancomycin (O) Aspirin (O) Insulin (L) Salbutamol (O) Clobazam (L) Vancomycin (O) Ceftriaxone (O), Chloroquine (L), Dexmethasone (L), Ofloxacin (O), Phenytoin (L) Vancomycin (O) Ceftriaxone (O) Salbutamol (O), Ipratopium (O) and Dopamine (O) Ipratopium (O) Ceftriaxone (O) Ceftriaxone (O), Prednisolone (L),Clobazam (L), Cefotaxime (L) and Azitromycin (L) Ceftazidime (L)
MedDRA = Medical Dictionary for Regulatory Activities, O = off-label and L = label, WHO-UMC-World Health Organization Uppsala Monitoring Centre and SGPT-Serum Glutamate Pyruvic Transaminase.
M.M. Saiyed et al. / Is off-label use a risk factor for adverse drug reactions?
49
3.2. Characteristics of adverse drug reactions Of the total 320 patients studied, 51 adverse drug reactions occurred in 47 patients, hence incidence rate was 10.85%. Patients aged 0 to 2 years experienced 28 (55%) ADRs, > 2 to 6 years had 13 (25%) and >6 to 12 years suffered 10 (20%) ADRs. Total 28 different medicines were implicated for different adverse drug reactions as shown in the Table 2. Of the total ADRs, 28 (55%) were probable and 13 (45%) deemed possible. The ADRs mostly belonged to CTCEA severity grade 2 (70%) or 1 (30%). All the detected ADRs were reported to regional pharmacovigilance centre in spontaneous ADR reporting forms. Most common ADRs were macupapular rash, chills, ataxia and pyrexia. Among the medications prescribed, vancomycin (25%), phenytoin (18%) and ceftriaxone (14%) were frequently found responsible for ADRs. 3.3. Off-label use and adverse drug reactions Off-label and labeled medicine use were responsible for 34 (67%) and 17 (33%) of ADRs respectively. The ADRs were also distributed according to causative medicine’s label and off-label uses. A total 10 off-label categories were utilized in this evaluation as shown in Table 3. Category 1: dose greater/lower than labeled had 15 medicine uses (3.4%, OR 0.64, CI 0.33–1.24) implicated for ADRs. Category 2: Not labeled in child of this age had 3 medicine uses (7.5%, OR 2.27, CI 0.64–8.10) responsible for ADRs and association was significant. Category 3: not labeled for child of this age or at this dose had 9 medicines uses (5%, OR 1.35 CI 0.60–3.05) associated with ADRs. Category 11: not labeled for use in children had 7 medicines uses (9.21%, OR 2.84, CI 1.37–7.09) accountable for ADRs and risk was noteworthy. Among the frequently prescribed drug class, the risk of adverse drug reaction was not considerable for off-label use in respiratory system (1.08%, OR 0.30, 0.11–0.83), anti-infectives for systemic use (2.82%, OR 0.81, CI 0.45–1.85) and nervous system (2.19%, OR 0.63, CI 0.27–1.42). Table 3 Total number of medicines in each labeled, off-label category and number implicated in at least one ADR (n = 1645) Type of medicine Labeled Use Off-label use category 1 2 3 4 5 6 7 8 9 11 Respiratory system Anti-infectives for systemic use Nervous system
Number of medicines
% of medicines for at least one ADR
Odd ratio of ADR versus labeled
95% CI
493 641 40 225 116 5 13 7 9 20 76 463 531 411
3.5% 3.4% 7.5% 5% 0 0 0 0 0 0 9.21% 1.08% 2.82% 2.19%
1.00 0.64 2.27 1.35 – – – – – – 2.84 0.30 0.81 0.63
– 0.33 –1.24 0.64 –8.10 0.60 –3.05 – – – – – – 1.37–7.09 0.11–0.83 0.45–1.85 0.27–1.42
ADR: adverse drug reaction; CI: confidence interval.
50
M.M. Saiyed et al. / Is off-label use a risk factor for adverse drug reactions? Table 4 ADR risk factors assessed by multivariate analysis (Cox Proportional Hazard Regression Model)
Covariate Age on admission (years) Gender Male Female Number of total medicines per patient Number of off-label medicines use per patient Number of labelled medicines use per patient
HR (95% CI)
P-value
1.07 (0.96–1.18)
0.205
1 0.64 (0.32–1.30) 1.17 (0.80– 1.71) 1.28 (0.43–3.78) 0.75 (0.51–1.09)
– 0.502
