Adverse drug reaction profile in Amravati region of India: A pharmacovigilance study.

BACKGROUND: This pharmacovigilance study was conducted in Amravati region of central India to identify the nature and prevalence of adverse drug reactions, which will be helpful for better drug prescription practice and management of diseases.
MATERIALS AND METHODS: Adverse drug reaction reporting forms from April 2016 to March 2019, were collected from the pharmacovigilance center, which include details of demographics, investigations, concomitant drug history, and details of present complaints including reaction details, onset, recovery, drug information, hospitalization, management, and assessment.
RESULTS: A total of 19 cases were reported. Approximately 47.4% male and 52.6% female experienced the reactions with age-group ranging from 15 to 75 years. The most common adverse drug reactions were caused by antimicrobial agents (47.6%) followed by other group of drugs (37%) and nonsteroidal anti-inflammatory drugs (15.9%). Polypharmacy was the most common cause (31.6%) with the most common route being intravenous (42.1%). Skin reactions were the most common (84.2%). Antitubercular drugs were more commonly responsible for exfoliative lesions, whereas paracetamol and unknown drugs were responsible for multiple ulcerative lesions. Reactions to antitubercular drugs were considered as possible (15.8%), whereas with other drugs (63.2%), it was probable.
CONCLUSION: It is a tip of the iceberg, which provides important demographic details in which adverse drug reactions were reported. Cutaneous reactions due to common drugs are responsible for hospitalization of the patients. There is an urgent need of training for health-care providers so that reporting can be improved and better picture can emerge.

INTRODUCTION

Whenever a new drug is launched in the market, it is assumed to be safe, as before launching, it goes through vigorous studies of quality, effectiveness, and safety parameters. Still adverse drug reactions (ADRs) are common. It is because regulatory authorities approve the drug depending on its efficacy at acceptable limit of safety.[1] Rarely serious ADRs can occur, which may not be predictable during the preapproval period of the drug; hence, the post-marketing surveillance of ADRs has a very important role for the establishment of safety of the drug.

The World Health Organization (WHO) has defined ADR as a response to a drug that is noxious and unintended, and occurs at doses normally used in human for the prophylaxis, diagnosis, and treatment of disease, or for the modification of physiological function.[2] ADR most commonly occurs due to Drug’s pharmacological action and is predictable and depends on the dose of the drug although unpredictable drug reaction can also occur.[3] There are a number of factors that affect or influence the susceptibility to ADRs, which include age, sex, number of drugs, and disease severity.[4] Moreover, as per the findings of Duijnhoven et al.,[5] the number of patients used in the studies to evaluate safety and long-term efficacy of drugs, which are intended to be used for the management of diseases on chronic basis, is insufficient. Hence, pharmacovigilance (PV) studies play important role in identifying such types of unpredictable drug reactions.

PV is “the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects, or any other possible drug-related problems.”[6] PV program is useful for the identification of uncommon ADRs, which are escaped during the animal studies and clinical trials of the drugs. WHO initiated PV program in 1968 with 10-member countries to promote ADR reporting.[7] But ADR reporting is not uniform in the world. Different countries use different types of spontaneous reporting forms for ADR reporting, such as in the United States (US), Form 3500 and US online reporting system are used, whereas in the United Kingdom (UK), it is Yellow card form and Yellow card online reporting system.[8] Bailey et al.[9] in their systemic review about adverse drug event (ADE) reporting identified 108 ADE reporting systems, of which 11 were used internationally and 97 at national level. A total of 22 systems of reporting were used in Africa, 16 in Asia, 3 in Australia, 28 in Europe, 13 in South America, and 15 in North America at national level.[9] In India, ADR reporting (Red) form and “VigiFlow” is used.[8]

Most of the drugs are developed and studied in developed countries but their safety profile cannot be compared with developing countries, which bear almost 90% of global disease burden.[10] In developing countries, disease pattern, accessibility to drugs, and disease management trend are different in comparison to developed countries; hence, profile of ADR may be different.[4] PV has low priority in developing countries as it is still a relatively new concept in those countries.[11] Hence, it is necessary that PV program should be implemented in such countries to identify the profile of ADRs.

PV is still not fully developed in African countries with low number of individual case safety reports reporting to VigiBase (WHO–Uppsala Monitoring Centre Software). More than one-third of the countries are not involved in PV program. The contribution to ADR reporting is around 0.88% in comparison to rest of the world till September 2015. Moreover, there are differences in the age-group and drugs involved in drug reactions in comparison to rest of the world.[712]

The Democratic Republic of Congo, which is one of the poorest countries in the world, developed the National PV Centre in 2009, and now it has PV centers in 115 of 518 health zones. It has developed one of the most active PV systems in Africa, although South Africa, Morocco, and Nigeria contribute more than 50% reporting of ADRs to VigiBase in Africa.[713]

In Arabian region, only 45% countries are involved in PV program. Among them, Morocco, Tunisia, Saudi Arabia, Egypt, and Jordan have developed good PV centers, whereas Libya, Yemen, and Palestine are in early stage of development of PV system, and Somalia, Djibouti, Mauritania, and Comoros Island have not developed the system.[14] In Pakistan, PV program was established in 2017, and it became full member of WHO monitoring center in 2018. The program is still in early stage in Pakistan.[15]

India started PV activity in 1986 with ADR monitoring system under drug controller general of India, but the formal National Pharmacovigilance Programme was launched in 2005 with unsuccessful attempt in 1998. It was renamed as Pharmacovigilance Programme of India (PvPI) in 2010. It is relatively successful in India as 250 PvPI centers are established all over the country.[16]

Amravati district is located in the central India, which is a part of Vidarbha region of Maharashtra state of India. This study was conducted in a tertiary care center of this district to identify the nature and prevalence of ADRs in this region, which will be helpful for better drug prescription practice and management of diseases and ADRs.

MATERIALS AND METHODS

It was a retrospective study, which was conducted at a tertiary care center of Amravati region of India. ADR monitoring forms from April 2016 to March 2019, were collected from the PV center of the tertiary care and analyzed for the study. All the ADR forms were of the patients irrespective of their age and sex. Forms of those patients who were mentally retarded, unconscious, or drug addict were not included in the study. We found that a total of 19 forms were submitted to the department of pharmacology during this period by various doctors and paramedical staff of the institute. A total of 19 ADRs were reported in 19 patients.

Identity of the patient was not revealed in the study. Institutional ethics committee permission (Reference No. PDMMC/SS/Ethical/8416/2019) was obtained for the study. All the ADRs were analyzed from the forms, which were designed by the National Pharmacovigilance Programme of India, which include demographic details such as name, age, sex, weight, and other details such as present history, investigations, concomitant drug history, and details of present complaints, including reaction details, onset, recovery, drug information, hospitalization, management, and assessment. Causality assessment was performed according to recommendations by the WHO Uppsala Monitoring Centre.[17] To observe statistical significance, chi-square test was applied.

RESULTS

A total of 19 ADRs were reported in 19 patients. As far as male to female distribution was concerned, the distribution was almost same, as 9 (47.4%) males and 10 (52.6%) females experienced ADRs. The age-group involved in the ADRs was between 15 and 75 years. The frequency of ADRs was maximum (5, 26.3%) in patients in fourth decade of life followed by second, third, and fifth decade of life with 4 (21.1%) in each, respectively. The difference was statistically significant [Table 1]. The number of ADRs was least in the sixth and seventh decade of life as only 1 (5.3%) case was reported in each decade of life in this age-group. When age-group and male to female cases with relation to ADRs was compared, no statistical significant difference was observed in the groups of younger than 35 years of age and older than 35 years of age [Table 2].

Table 1

Demographic details

Age-group	Male	%	Female	%	P value
Second decade	2	10.5	2	10.5	P = 0.03505 < 0.05 (df = 5) is significant
Third decade	0	0.0	4	21.1
Fourth decade	5	26.3	0	0.0
Fifth decade	1	5.3	3	15.8
Sixth decade	0	0.0	1	5.3
Seventh decade	1	5.3	0	0.0

Table 2

Correlation between adverse drug reaction with age and sex

Age-group (years)	Male	Female	P value
<35	3 (15.79%)	6 (31.58%)	P = 0.245084 >0.05 not significant (with df = 1, and confidence level = 95%)
>35	6 (31.58%)	4 (21.05%)

Most common ADRs were caused by antimicrobial agents (47.6%) [Table 3] followed by other group of drugs (37%) [Table 4], whereas nonsteroidal anti-inflammatory drugs (NSAIDs) comprised 15.9% [Table 5]. In 4 (21.1%) cases, the drugs that were involved in ADRs were not known, whereas in 3 (15.8%) cases, antitubercular regimens (Isoniazid, rifampicin, pyrazinamide, and ethambutol) were involved in ADRs. In rest of the cases, same drugs were not involved in the reactions. Polypharmacy was the most common cause of ADR as observed in 6 (31.6%) cases [Tables 3 and 4]. Most common route of drug administration involved in ADRs was intravenous (IV) route as observed in 8 (42.1%) cases, whereas the second most common route of drug administration was oral route (5, 26.3%), and in 2 (10.5%) cases, topical route was involved.

Table 3

Antimicrobial agents associated adverse drug reactions

Drugs	Cases	Percentage
Ceftriaxone	1	5.3
Gentamicin	1	5.3
INH, rifampicin, pyrazinamide, ethambutol	3	15.8
Metronidazole with dextrose 5%	1	5.3
Levofloxacin	1	5.3
Ofloxacin + ornidazole	1	5.3
Ranitidine, amoxicillin + clavulanic acid, amikacin	1	5.3
Total	9	47.6

Table 4

Other drugs associated adverse drug reactions

Drugs	Cases	Percentage
Divalproex sodium	1	5.3
Lignocaine	1	5.3
Zinc and chlorhexidine	1	5.3
Multiple unknown drugs	4	21.1
Total	7	37

Table 5

Nonsteroidal anti-inflammatory drug-associated adverse drug reactions

Drugs	Cases	Percentage
Diclofenac	1	5.3
Nimesulide	1	5.3
Paracetamol	1	5.3
Total	3	15.9

Skin reactions were the most commonly observed reactions, 16 (84.2%) patients complained about these. Antitubercular drugs were more commonly responsible for exfoliative lesions, whereas paracetamol and unknown drug were responsible for multiple ulcerative lesions over oral mucosa/lips and glans penis. Use of ranitidine, amoxicillin + clavulanic acid and amikacin in a patient was responsible for much severe reaction as the patient had initial tachycardia, hypotension followed by severe bradycardia, slurring of speech, and breathlessness. Difficulty in breathing was also observed with the use of zinc + chlorhexidine mouthwash and with one unknown drug. Corneal epithelial toxicity was observed with the use of topical lignocaine [Table 6].

Table 6

Types of adverse drug reactions

Reactions	Generic
Exfoliative lesions all over the body in generalized manner	INH, rifampicin, pyrazinamide, ethambutol
Rash all over the body and oral ulcers	INH, rifampicin, pyrazinamide, ethambutol
Diffuse exfoliation with few excoriation over bilateral hand	INH, rifampicin, pyrazinamide, ethambutol
Multiple ulcerative lesion over oral mucosa and glans penis	Paracetamol
Multiple erosive lesions present over the lips with suppurative lesions over the inner prepuce and glans penis	Not available
Erythematous plaques present over the abdomen and back, with erythematous macular lesions present on the forearm and thighs	Nimesulide
Palpitation, sweating, swelling of lips	Diclofenac
Erythematous rash all over the body	Ceftriaxone
Swelling on cheek and lower lip	Levofloxacin
Reddish pruritic macular rash all over the body	Divalproex sodium
Itching all over body, burning vision, and difficulty in breathing	Zinc and chlorhexidine
Chills with rigors	Gentamicin
Initial tachycardia, hypotension followed by severe bradycardia, slurring of speech, and breathlessness	Ranitidine, amoxicillin + clavulanic acid, amikacin
Macular rash over abdomen	Ofloxacin/ornidazole
Swelling of lips	Metronidazole with dextrose 5%
Corneal epithelial toxicity	Lignocaine
Exfoliative lesions present over the inner thighs, upper legs, and trunk. Oral mucosa shows ulcerative lesions with swelling and crusting of lips	Not available
Difficulty in breathing, pain over the arm injection site	Not available
Multiple erythematous hyperpigmented patches present over the upper limb and lower limb bilateral	Not available

In the probability scale, the reactions, which occurred due to use of antitubercular drugs, were considered as possible (3, 15.8%), whereas with other drugs (12, 63.2%), it was probable. In case of unknown drugs (4, 21.1%), probability scale was not applied. As far as severity is concerned, one ADR with the use of ranitidine, amoxicillin + clavulanic acid, amikacin was considered as life-threatening, in which hospitalization was required. Hospitalization was also required when ADRs were observed with the use of ceftriaxone, mouthwash, antitubercular drugs, paracetamol, nimesulide, ofloxacin/ornidazole, and reactions due to unknown drugs except in one unknown drug reaction. In remaining 9 (47.4%) cases, hospitalization was not required. All the drugs were withdrawn after observation of ADR except antitubercular drugs. All the patients were recovered after suitable management of the ADRs.

DISCUSSION

The aim of medicine teams in the WHO is to assure safety of medicine, for that purpose, WHO is promoting PV activity and exchanging information on drug safety issues throughout the world.[1] As the member country of WHO’s PV program, India is running National Pharmacovigilance Programme, which encourages doctors and paramedics to report ADR.[8] The PV center in the tertiary care center is also playing role in the PV program. Under this center, we have tried to see the scenario of ADR situation in the region. We found extremely low number of cases, which may not be the real picture. The cause may be due to improper implementation of National Pharmacovigilance Programme, low literacy rate or may be due to overburden of medical and paramedical staff.

In this study, common age-group involved in ADR was between second and fifth decade of life. Singhet al. found mean age for ADR as 35 years, whereas Yu et al. observed median age for ADR as 58 years, and the most common occurrence was reported in adult population followed by geriatric population.[1819] The studies including ours point out the involvement of adult population in ADRs more commonly. There might be different reasons behind this distribution, among them, one can be more accessibility of adult population to health-care system. Moreover, involvement of fourth decade of life in ADR significantly indicates vulnerability of this population.

We found almost equal distribution of ADR cases among male and females. Singh et al. observed predominance of female population as ADRs were more common among them. They attributed this difference to more weight and body mass index, hormonal changes, which are unique to females such as during puberty, menstrual cycles, and menopause, and the effect of these changes on drug metabolism. They also concluded that genomic constitutional differences can influence the levels of various enzymes involved in drug metabolism among the females.[1820,21] Vervloet and Durham also observed female predominance as far as ADRs are concerned.[22]Tranet al. found that ADRs are more common among females but they opined that further work is needed to elucidate the reason behind such differences.[20] Kunnooret al.[23] in their study, which was conducted on patients admitted to a coronary care unit found gender-related differences in the ADR patterns, although polypharmacy was more common in males but ADRs were 1.5- to 1.7-fold more common in females than males. Their explanation for these differences was different pharmacokinetic, pharmacodynamic, immunological, and hormonal factors in females as well as differences in the pattern of use of medications in them.[23] Gor and Desai found no influence of age and sex in the incidence of ADRs.[24] We also found no differences between both the sex in the occurrence of ADRs, but we cannot rule out the possibility of lower number of cases, which may be the reason behind the lack of differences.

In this study, the most common route of drug administration involved in ADRs was IV route followed by oral and topical route. Singhet al. and Sen M et al. also observed parental route as the most common route of drug administration involved in ADRs.[1825] Polypharmacy was the most common cause of ADR in this study. Polypharmacy is widely prevalent throughout the world. As the number of drugs increases in the prescription, the chances of ADR also increases; hence, the polypharmacy must be discouraged to avoid such reactions.[224,2627] But Mishraet al.[28] observed single drug as the most common drug involved in ADRs, followed by multiple drugs. They have not provided explanation for this variation in their study.[28]

In this study, we found role of multiple unknown drugs more commonly in ADRs, followed by antitubercular drugs. It is because of improper filling of the ADR monitoring form, which reflects the lack of literacy among the population to report the name of drugs to the medical and paramedical staff. It also may be due to poor population that turns up in such centers in India, which provide quality health-care facilities with minimum expenditure. As far as antitubercular drugs are concerned, we found second highest number of ADRs with it. Gor and Desai observed antimicrobials as the topmost group of drugs, among which chloroquine, amoxicillin, and antitubercular drugs topped the list.[24] Preetiet al. and Salvo et al. also had similar types of findings, in which antimicrobials were the main drugs leading to ADRs.[2629]

In this study, skin reactions were the most commonly observed reactions. Exfoliative lesions, rash all over the body, with oral ulcers were observed with antitubercular drugs. Practically, all the first-line antitubercular drugs can cause skin reactions. Documented common ADRs observed with INH are peripheral neuritis, hepatitis, lethargy, rashes, fever, acne, and arthralgia, with rifampicin are hepatitis, cutaneous syndrome (flushing, pruritus + rash, redness and watering of eyes), with pyrazinamide are hepatotoxicity, hyperuricemia, abdominal distress, arthralgia, flushing, rashes, fever, and loss of diabetes control, whereas with ethambutol, loss of visual acuity, nausea, rashes, fever, and rarely peripheral neuritis.[30] Michaelet al. found the most common ADRs with antitubercular drugs, which were neuropathy followed by skin rash, whereas Abhijeet et al. observed allergic skin reactions as the fourth most common type of ADRs with antitubercular drugs.[3132] In this study, we also found the skin reactions as the most common reaction with antitubercular drugs.

We found that most of the ADRs were due to antimicrobial agents (ceftriaxone, levofloxacin, ofloxacin/ornidazole, and metronidazole with dextrose 5%), which were cutaneous in nature. Antimicrobial agents were found to be causative agents in most of the allergic reactions including cutaneous reactions. They can cause both immediate and delayed type of hypersensitivity reactions in adult as well as in pediatric population. Among them beta-lactam antibiotics and quinolones are prominent.[33]

In one of the case, when amoxicillin + clavulanic acid were used along with ranitidine and amikacin, the patient had initial tachycardia, hypotension followed by severe bradycardia, slurring of speech, and breathlessness. Allergic reactions to amoxicillin are not uncommon, including anaphylaxis reaction.[34] Clavulanic acid, which is prescribed along with amoxicillin, is also found to have capacity to cause allergic reactions.[3536] Hence, Salaset al. recommended that if the patient is sensitive to amoxicillin, they should be evaluated with skin test regarding the sensitivity of the clavulanic acid.[37]

Other notable drugs that were responsible for allergic skin reactions were paracetamol, nimesulide, diclofenac, zinc, and chlorhexidine, Divalproex sodium, and unknown drugs. These drugs belong to NSAIDs and antimicrobial groups except mouthwash (zinc + chlorhexidine) and divalproex sodium. NSAID-induced ADRs were found in almost 1.6% of patients.[3839] NSAID-induced hypersensitivity reactions were observed in almost 20% of all ADRs to NSAIDs. These are unpredictable “bizarre” (type B) ADRs and are due to individual factors.[40] Type IV and type I allergic reactions can occur but these are the rare reactions.[38] Although the exact mechanism behind NSAID-induced hypersensitivity reactions is not fully understood, it is proposed that NSAID-induced Cyclooxygenase blockade results in excessive prostaglandin E2 production in the affected persons, which may be the reasons.[2841]

Side effect profile of paracetamol is related to other NSAIDs; hence, it can cause allergic reactions including skin reactions.[42] Sakeet al. reported generalized fixed-dose eruption in a 10-year-old male patient in Kadapa region of India and opined that it can occur but rarely.[43] Rajanet al. and Khawaja et al. also reported allergic reactions to paracetamol, specifically they found Steven–Johnson syndrome.[4445] In one of the study by Patelet al., 6.17% of cases of Steven–Johnson syndrome and toxic epidermal necrolysis were reported among the Indian population due to the ingestion of paracetamol during the period from 1995 to 2011.[46] These indicate paracetamol as potential allergic drug although reaction is rare with it.

Hypersensitivity reactions can occur with chlorhexidine.[47] In this study, zinc and chlorhexidine combination, which was used as mouthwash was responsible for itching all over body, burning vision, and difficulty in breathing. A variety of hypersensitivity reactions can occur due to chlorhexidine, which include allergic contact dermatitis, pruritus, vesicle formation, urticaria, dyspnea, and anaphylactic shock.[4748] These reactions may be due to contact of chlorhexidine with skin and mucous membrane.[47] Moghadamet al. reported chlorhexidine mouthwash-induced fixed drug eruption, and they were of the opinion that there is a possibility of systemic reaction if exposed to previously sensitized person.[49] We found reddish pruritic macular rash all over the body with the use of divalporex sodium (coordination compound of valproic acid with sodium valproate). Parket al.[50] investigated antiepileptic drug-induced severe cutaneous adverse reactions using a nationwide registry in Korea. They found valproic acid as the major causative agent in severe cutaneous adverse reaction, indicating its role in skin reactions.[50]

Lignocaine-induced corneal epithelial toxicity was observed when cataract extraction surgery was being performed by phacoemulsification technique under topical anesthesia (lignocaine) after instilling the drug. Judgeet al. observed statistically significant lidocaine-induced corneal thickening and opacification in experimental pigmented rabbits, and suggested that ophthalmic surgeon should be cautious about the potential of endothelial cell injury when the anesthetic agents enter the eye during cataract surgery.[51]

Majority (63.2%) of the cases were considered as probable in the Naranjo probability scale. The reasons are, drug reactions followed reasonable time after the use of that particular drug, the response was known to that drug, the reaction was confirmed after the withdrawal of drug but not by re-exposure of drug, the reaction could not be explained from condition of the patient. A total of 15.8% reactions that occurred due to the use of antitubercular drugs were considered as possible, as it was the sequential reaction after the drug, followed a recognized pattern, and could be explained by characteristics of the patient’s condition. In 21.1% reactions, probability scale was not applied because of nonavailability of information about the drugs.

In this study, in most of the cases, hospitalization was required. One of the conditions was life-threatening, in which ranitidine, amoxicillin + clavulanic acid, and amikacin was used. All the suspected drugs were discontinued except antitubercular drugs. In this study, all the patients recovered after suitable management of the ADRs.

CONCLUSION

This study provides important information regarding ADRs to the drugs in the region. It was a very short duration study of 3 years with very low number of ADR cases. In the region, these ADRs are just a tip of iceberg. But the present study still provides valuable information regarding prevalence of ADRs in relation to the demographics. It also indicates that cutaneous reactions due to common drugs are responsible for hospitalization of the patients. Hence, there is an urgent need of training of health-care providers such as doctors and paramedical staff so that reporting can be improved and better picture can emerge. Still we feel that a large-scale prospective PV study is needed, which will be useful for better understanding of ADRs to drugs commonly used in the region so that good health-care services can be provided.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.