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Orange Journal / Volumen 6 Número 11/Enero-junio 2024
DOI: https://doi.org/10.46502/issn.2710-995X/2024.11.03
Cómo citar:
Berenguer Rivas, C.A., Domínguez Fernández, I., Labañino Roldo, F.J., Molina Bertrán, S. del C., & Rodríguez Ferreiro, A.O.
(2024). Pharmacovigilance of carbamazepine in the treatment of Central Nervous System conditions. Orange Journal, 6(11), 33-42.
https://doi.org/10.46502/issn.2710-995X/2024.11.03
Pharmacovigilance of carbamazepine in the treatment of Central Nervous
System conditions
Farmacovigilancia de la carbamazepina en el tratamiento de afecciones del Sistema
Nervioso Central
Recibido: 15 de diciembre de 2023 Aceptado: 21 de abril de 2024
Escrito por:
Clara Azalea Berenguer Rivas1
https://orcid.org/0000-0002-1259-3910
Isabela Domínguez Fernández2
https://orcid.org/0009-0005-6832-1032
Félix Jesús Labañino Roldo3
https://orcid.org/0009-0003-6900-9863
Silvia del Carmén Molina Bertrán
4
https://orcid.org/0000-0003-1560-0191
Annarli Olivia Rodríguez Ferreiro
5
https://orcid.org/0000-0002-3483-2804
Abstract
Anticonvulsants are crucial for treating neurological diseases, necessitating close pharmacovigilance due to their
potential risks. For this reason, a prospective descriptive study was conducted to characterize drug-related
adverse reactions associated with the use of carbamazepine in the health area of the "Ramon Lopez Peña"
Polyclinic, covering the period from July to December 2022. The sample consisted of 35 patients, characterized
based on demographic, clinical, and pharmacotherapeutic variables. The detected drug-related adverse events
were classified according to causality, severity, and frequency of occurrence. The results showed that the age
group of 40-75 years (45.7%) predominated, along with female gender, mixed ethnicity, pre-university education
level, and 54.2% did not have any unhealthy habits. The most common diagnosis was epilepsy (68.4%) and
among the associated diseases, hypertension was prevalent. The most consumed medications were captopril,
hydrochlorothiazide, paracetamol, and metamizole (dipirona). Drug interactions were detected, and 73 adverse
reactions occurred, with the nervous system being the most affected at 56.0%. Possible adverse reactions
(42.5%), frequent (49.4%), and mild (58.9%) predominated. This study underscores the importance of continuous
and effective monitoring in pharmacovigilance to enhance patient safety under carbamazepine treatment, thereby
promoting a more rational use of this medication.
Keywords: carbamazepine, Adverse drug reaction, pharmavigilance.
1 Profesor Auxiliar. Doctora en Ciencias Farmacéuticas y en Ciencias de la Salud. Departamento de Farmacia. Universidad de Oriente,
Santiago de Cuba, Cuba.
2 Profesor Instructor. Departamento de Farmacia. Universidad de Oriente, Santiago de Cuba, Cuba.
3 Licenciado en Ciencias Farmacéuticas Empresa de farmacias y Óptica, Provincia Guantánamo, Cuba.
4
Profesor Asistente. Doctora en Ciencias Farmacéuticas y en Ciencias Biológicas. Departamento de Farmacia. Universidad de Oriente,
Santiago de Cuba, Cuba.
5
Profesor Auxiliar. Doctora en Ciencias Farmacéuticas y en Ciencias Biológicas. Departamento de Farmacia. Universidad de Oriente,
Santiago de Cuba, Cuba.
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Resumen
Los anticonvulsivantes son cruciales para el tratamiento de enfermedades neurológicas y requieren una estrecha
farmacovigilancia debido a sus riesgos potenciales. Por este motivo se realizó un estudio descriptivo prospectivo
con el objetivo de caracterizar las reacciones adversas medicamentosas asociadas al consumo de la
carbamazepina en el área de salud del Policlínico" Ramón López Peña”, en el período comprendido de julio a
diciembre del 2022. La muestra consistió en 35 pacientes, caracterizados según variables demográficas, clínicas
y farmacoterapéuticas. Las reacciones adversas medicamentosas detectadas se clasificaron según causalidad,
severidad y frecuencia de aparición. Los resultados mostraron que predominó el grupo de edad de 40-75 años
(45,7%), el sexo femenino, los mestizos, el nivel de escolaridad pre-universitario y el 54,2% no presentó ningún
hábito no saludable. El diagnóstico predominante fue epilepsia 68,4% y entre las enfermedades asociadas la
hipertensión arterial. Los medicamentos más consumidos fueron el captopril, hidroclorotiazida, paracetamol y
metamizol (dipirona). Se detectaron interacciones medicamentosas y 73 reacciones adversas siendo el sistema
nervioso el más afectado con un 56,0 %. Predominaron las RAM posibles 42,5 %, las frecuentes 49,4 % y las
leves 58,9 %. Este estudio destaca la importancia de una vigilancia continua y efectiva en farmacovigilancia para
mejorar la seguridad del paciente bajo tratamiento con carbamazepina, promoviendo así un uso más racional de
este medicamento.
Palabras Claves: Carbamazepina, Reacción adversa a medicamentos, farmacovigilancia.
Introduction
Pharmacovigilance, a multidisciplinary field inherently linked to epidemiological and pharmacological
studies, plays a crucial role in the continuous evaluation of the safety and effectiveness of medicines after
their post-marketing approval. This process is essential as it allows for the monitoring of medication safety
in real-use scenarios, thereby ensuring that the benefit-risk ratio remains favorable throughout the drug
lifecycle. This activity involves rigorous control of biomedical and pharmacological risks, which is vital
for public health protection (Bihan et al., 2020; Choudhury et al., 2023).
Anticonvulsants, such as carbamazepine (CBZ), are essential for treating epilepsy and other neurological
disorders. However, the use of these medications is not without risks, as they can cause serious adverse
reactions, some potentially fatal, such as Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis
(NET). Carbamazepine, initially synthesized with properties similar to tricyclic antidepressants like
Imipramine, has proven effective not only in convulsive disorders but also in managing bipolar affective
disorder and trigeminal neuralgia, providing relief in conditions of intense facial pain (Montastruc & de
Laportaliere, 2024)
Despite its efficacy, numerous adverse reactions associated with its use were reported, such as vertigo,
somnolence, ataxia, skin rashes, thrombocytopenia, and leukopenia, raising concerns in various studies
conducted in countries like Peru, Italy, and Malaysia (Balbuena Veliz, & Damian Ricaldi, 2018; Hariraj et
al., 2023; Guarnieri, et al., 2024). Additional research in Colombia and Cuba has highlighted the prevalence
of skin conditions and the importance of understanding adverse effects to optimize the clinical use of CBZ
(García Torres, & Aldana Becerra, 2016; Adrián,2022). Specifically, recent studies haveunderscored the
lack of effective strategies for patient-reported adverse effect notification, as well as the need to expand the
scientific evidence supporting policies for the prevention and management of adverse reactions in the region
(Barrero Viera, & Bestard Pavón, 2022; Trabanca Beltrán et al., 2018).
Given the increasing use of carbamazepine in Cuba and the insufficient documentation regarding its most
frequent adverse reactions, this study aims to characterize these reactions in the population served at the
"Ramón LópezPeña" Polyclinic in Caimanera, Guanánamo Province. This analysis seeks not only to fill a
knowledge gap but also to improve risk mitigation strategies and strengthen pharmacovigilance in the
context of Cuban community medicine.
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Theoretical Framework
Pharmacovigilance: is defined as the science and activities related to the detection, evaluation,
understanding, and prevention of adverse effects or any other medication-related problem (MRP) (World
Health Organization, 2002). The European Commission (EU) defines it as “the process and science of
monitoring the safety of medications and taking actions to reduce risks and enhance the benefits of
medications” (Narayanan, et al., 2020).
Medication-Related Problems: are defined as any undesirable event experienced by the patient, which
involves or is suspected to involve drug therapy, and that interferes or has the potential to interfere with
desired health outcomes (Cipolle et al., 2012; Calvo-Salazar et al., 2018).
Adverse Drug Reaction: is any harmful and unintended response to a medication. (Sychev et al., 2020)
Materials and Methods
A prospective descriptive study was conducted on patients using carbamazepine to detect adverse reactions
associated with this medication in the healthcare area of the "Ramón LópezPeña" Polyclinic in Caimanera,
Guantánamo Province, from July to December 2022.
Study Population and Sample
The study population consisted of patients consuming carbamazepine from the Main Municipal Pharmacy
of Caimanera Municipality and the Community Pharmacy in the locality of "Boquerón" in Guantánamo
Province in Cuba. The sample included patients who met the inclusion criteria:
Inclusion Criteria: Patients consuming carbamazepine who gave their consent to participate in the research.
Exclusion Criteria: Patients with any cognitive disorder (dementia, severe mental retardation) that prevents
information gathering, and patients who were hospitalized at the time of the study.
Exit Criteria: Patients who voluntarily decide to discontinue their participation in the study, those who die
during the research, and those who move out of the health area and municipality.
Ethical Considerations
The research was conducted in accordance with the ethical standards of the Declaration of Helsinki
(Williams, 2008) and the regulations stipulated by the Cuban Ministry of Public Health concerning clinical
research. This work was approved by the ethics committee of the "Ramón LópezPeña" Polyclinic in
Caimanera, Guantánamo Province.
Data Collection
Data collection was conducted through the review of medical certificates of patients consuming
carbamazepine who are registered in the National Medication Program (NMP) and dispensed via a control
card. Additionally, data obtained through patient interviews and the analysis of medical histories were
considered.
Sample Characterization
The sample was characterized considering biosocial, clinical, and pharmacotherapeutic variables:
Biosocial Variables:
Gender: Female and Male
Age: in completed years (≤15, 16-39, 40-75)
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Educational level: (Elementary, Secondary, Pre-university, Technical, Higher)
Skin color: Mixed, White, and Black
Unhealthy habits: Coffee, Alcohol, Tobacco, No toxic habits
Clinical Variables:
Reason for prescribing carbamazepine.
Personal pathological history.
Pharmacotherapeutic Variables:
Other consumed medications: generic name and pharmacological group (according to the ATC
classification, from the Anatomical Therapeutic Chemical classification system), dosage, frequency of
administration, and drug interactions.
Classification of Adverse Drug Reactions by Causality, Severity, and Frequency
Adverse drug reactions were classified according to different criteria:
Causality: categorized as definite or certain, probable, possible, conditional, improbable, or unclassifiable
according to the Karch and Lasagna Algorithm.
Severity: classified as mild, moderate, or severe as established by the Cuban Pharmacovigilance System
(CPS).
Frequency of occurrence: classified as frequent, occasional, rare, and not described as per the CPS.
Data Processing
The data obtained were analyzed using descriptive statistics. As summary measures, percentage
calculations and comparisons of absolute and relative frequencies were used.
Results
The sample consisted of 35 patients undergoing treatment with carbamazepine, dispensed at the Main
Municipal Pharmacy of Caimanera and the Community Pharmacy located in the locality of Boquerón in
the same municipality, Guantánamo Province. Table I presents the distribution of patients according to
biosocial variables, where female patients predominated in the age range of 40-75 years, of mixed race,
with a pre-university level of education, and without unhealthy habits.
Table I.
Distribution of patients according to biosocial variables
Biosocial Variables
N
%
Female
18
51.3
Male
17
48.7
≤15 years
8
22.8
16-39 years
11
31.5
40-75 years
16
45.7
Elementary
2
5.7
Secondary
9
25.7
Pre-University
13
20
Technical
7
37.1
Higher education
4
11.5
Mixed
19
54.3
White
9
25.7
Black
7
20
Coffee
13
37.1
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Alcohol
1
2.9
Tobacco
2
5.7
No toxic habits
19
54.3
N: Number of patients
Source: Registered medical certificates of carbamazepine consumers enrolled in the NMP and interviews conducted.
Figure 1 shows the main diagnoses that motivate the use of carbamazepine. The most prevalent pathology
was epilepsy with 24 patients (68.4%), which were classified into: generalized epilepsy 15 patients, tonic-
clonic epilepsy 5 patients, and finally focal epilepsy with 4 patients. Another predominant diagnosis was
trigeminal neuralgia with 5 patients.
Figure 1. Diagnoses motivating the use of carbamazepine.
Source: Medical certificates
Legend: GE: Generalized Epilepsy, TCE: Tonic-Clonic Epilepsy, TN: Trigeminal Neuralgia, FE: Focal
Epilepsy, BPD: Bipolar Affective Disorder, PSCh: Paranoid Schizophrenia, DN: Diabetic Neuropathy
In Figure 2, the concomitant diseases of the studied population group are shown. These include
Hypertension (HT) present in 20% of the patients, followed by Diabetes Mellitus (11.4%) and Bronchial
Asthma (8.5%). It is noteworthy that 60.1% of the patients did not present with any other associated
diseases.
Figure 2 Patients according to concomitant diseases
Source: Medical Certificates
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When analyzing the distribution of the sample according to the pharmacotherapeutic variables studied, it
was observed that antihypertensive medications were the most used, such as hydrochlorothiazide (20%),
and captopril (20%), followed by insulin and salbutamol aerosol. Metamizole (dipyrone) and
acetaminophen appear in 100% of the patients, as they self-medicate with these medications for pain or use
them as antipyretics, the latter more frequently in the children participating in the study.
Table II shows the relationship between the dose used and the diagnosis for which the medication under
study is prescribed. Where the majority of patients present a correct dose at 91.6%, according to the
National Formulary of Medications of Cuba (NFM). Only 8.4% of patients (3) had an inadequate dose.
Table II.
Dose used according to diagnosis and age group
Diagnosis
Age
group(years)
Established dose by the
NFM
Patients with the
right dose
Patients with the
wrong dose
No
%
No
%
Generalized Epilepsy
0-15
100-200mg/day for3 months
up to1year
5
14.4
1
2.8
16-39
100-200mg/day for3 months
up to1year
7
20.2
-
-
40-75
800-1200mg/day
maintenance dose
2
5.7
-
-
Tonic-Clonic Epilepsy
0-15
100-200mg/1-2 times/day/
for3 months up to1 yearaño
1
2.8
1
2.8
16-39
100-200mg/day for3 months
up to1year
3
8.6
Focal Epilepsy
16-39
100-200mg/1-2 times/day/
for3 months up to1 year
1
2.8
40-75
800-1200mg/day
maintenance dose
3
8.6
Bipolar Affective
Disorder
40-75
400mg/day divided into
several doses
2
5.7
Trigeminal Neuralgia
100mgfor 3 month
4
11.5
1
2.8
Paranoid Schizophrenia
200-400mgfor 3 month
2
5.7
Diabetic Neuropathy
200mg/day for 3 month
2
5.7
Total
-
-
32
91.6
3
8.4
Source: Medical certificates.
Classification of Adverse Drug Reactions by Causality, Severity, and Frequency
Table III reflects the ADRs detected in the patients studied during the intervention. Within the central
nervous system disorders, somnolence (21.9%), vertigo (19.1%), blurred vision (13.7%), and loss of
balance (1.3%) were represented; in terms of dermatological reactions, skin rashes were reported at (6.8%);
gastrointestinal system disorders: nausea (10.6%), as well as abdominal pain with the same percentage, and
dry mouth was present in (11%).
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Table III.
Adverse reactions detected in patients consuming carbamazepine.
Affected systems
RAMs
No.
notifications
%
Central nervous system
Somnolence/sleep disorders
16
21.9
Dizziness
14
19.1
Blurred vision
10
13.7
Overbalance
1
1.3
Total
41
56.0
Gastrointestinal system
Dry mouth
11
15.2
Nauseas
8
11
Abdominal pain
8
11
Total
27
37.2
Skin conditions
Skin rash
5
6.8
Total
5
6.8
Grand total
73
100
Source: Clinical histories and patient interviews.
In line with Table IV, we can observe the classification of ADRs according to causality by applying the
Karch-Lasagna algorithm, which has been in use since 1981. These are categorized as possible, definite,
and probable. The results show a considerable number of ADRs classified as probable (34.2%), which
indicates a high correlation that the adverse reaction is related to the medication.
Table IV.
Classification of ADRs by causality, frequency of occurrence, and severity
Classification of ADRs
N
%
Causality assessment
Possible
31
42.5
Probable /likely
25
34.2
Definite/ certain
17
23.3
Frequency of appearance
Frequent
36
49.4
Occasional
27
36.9
Rare
10
13.7
Severity
Mild
43
58.9
Moderate
25
34.3
Severe
5
6.8
Discussion
Carbamazepine has proven effective in treating seizures and mood disorders. However, its use is associated
with a variety of adverse effects, some of which can be serious and potentially life-threatening. Therefore,
monitoring the safety of this drug is essential to ensure its proper use and minimize risks to patients.
In this study, female patients predominated in the age range of 40 to 75 years, a finding consistent with
other authors who have reported an increase in the consumption of carbamazepine among elderly patients
in recent years (Mula, 2009). Similarly, other authors have noted the occurrence of epileptic phenomena
early in life, where carbamazepine, along with valproic acid and lamotrigine, were the most indicated
anticonvulsant drugs (Anderson et al., 2015). This pattern was similarly observed in our research, with a
noteworthy number of patients ≤ 15 years old.
The educational level of the interviewees was predominantly pre-university, aligning with Cuban
educational policy and facilitating comprehension during interviews. Similarly, the prevalence of mixed-
race skin color corresponds with data published by the National Office of Statistics and Information, which
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indicates that regions with the highest levels of mixed ethnicity are Guantánamo, Santiago de Cuba, and
Granma, in that order, with over 54% of their population (Zabala Arguelles, 2021).
Coffee consumption prevailed among the older adults, who claim to drink a cup, preferably in the mornings.
Caffeine is a nervous system stimulant, acting by blocking adenosine A1 and A2a receptors. This blockade
increases excitement, which makes us more "active" when we drink coffee. Epileptic patients are more
susceptible to this neuronal hyperexcitability and, therefore, to experiencing a crisis after consuming
stimulant substances, not only directly but also indirectly if they affect sleep, preventing proper rest.
However, the relationship between caffeine and epileptic seizures is not entirely clear, as large-scale studies
proving this have yet to be conducted. Researchers estimate that high coffee consumption in epileptic
patients is associated with up to twice the risk of suffering focal to bilateral tonic-clonic seizures compared
to moderate coffee consumption in this patient population (Bourgeois-Vionnet et al., 2022).
In Cuba, several studies agree that carbamazepine is the most used antiepileptic drug in monotherapy or
bitherapy and is very effective in treating trigeminal neuralgia, findings that coincide with other studies
reported in the literature which demonstrated a pattern similar to that obtained in this investigation (Adrián,
2022; Ruíz López, 2023; Hernández et al., 2020).
It is important to note the predominance of arterial hypertension as an associated pathology in the studied
patients, a chronic disease with a high incidence in the Guantánamo province of 198.8 per 1000 inhabitants
according to the Cuban Health Statistical Yearbook 2020 (MINSAP, 2020). This results in
antihypertensives like captopril and diuretics such as hydrochlorothiazide being frequently associated with
the therapeutic regimen, as well as NSAIDs like dipyrone and acetaminophen, which are often self-
medicated by the studied patients, leading to various drug interactions.
Considering that carbamazepine is a drug with complex pharmacokinetics that induces CYP3A4 (a family
of cytochrome 450 enzymes playing a key role in the hepatic metabolism of many drugs), glucuronidation,
and epoxide hydroxylation, it consequently favors the metabolism of other drugs and vice versa. One such
drug is acetaminophen; in this regard, carbamazepine accelerates the biotransformation of acetaminophen
into its excretable inactive metabolites, causing a precipitous drop in the latter's plasma levels and the early
disappearance of its analgesic and antipyretic effect, presenting a drug interaction (Hata et al., 2008).
Moreover, the pharmacodynamic drug interaction phase of hydrochlorothiazide and carbamazepine is
pharmacologically based on the anticonvulsant's ability to erratically increase or decrease potassium
currents entering and leaving cells. This effect, combined with the potassium depletion caused by the
diuretic effect of hydrochlorothiazide, synergistically leads to potassium excretion, potentially causing
hyponatremia, especially at high doses of carbamazepine (Flórez et al., 2014).
We highlight that most of the patients studied were administered the correct dosage; only 8.4% of the
patients had an inadequate dose. The majority of these patients who received an inadequate dose were in
pediatric ages (5.6%) under the diagnosis of generalized and tonic-clonic epilepsy, where the prescription
made by the physician for the initiation of treatment was higher than recommended in these cases. This
incorrect prescription poses a severe danger, especially in pediatric ages, where there are significant
differences in drug bioavailability, sensitivity of different target organs, or specific receptors to
medications. Thus, very different treatment guidelines are needed compared to those prescribed for adults.
Children, for ethical reasons, participate very limitedly in clinical studies that test the pharmacokinetics,
safety, and efficacy of a drug, which requires using medications according to very conservative criteria in
this population. Therefore, special attention is needed regarding prescription criteria in this age group. It is
also noteworthy that all patients in the study had monotherapy, and the scientific literature recognizes that
polytherapy with this group of drugs for the treatment of epilepsy is more likely to be associated with
medication toxicity. (Ministerio de Salud Pública, 2014)
The ADRs detected during the intervention were reported in the model 33-36-1 Notification of Suspected
Adverse Drug Reaction by the Cuban Ministry of Public Health. Possible, frequent, and mild adverse
reactions predominated, mostly linked to the CNS. These results coincide with the study of the most
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frequent adverse reactions in different populations (Anderson et al., 2015). Additionally, adverse effects
associated with the consumption of carbamazepine reported in the literature include nystagmus, ataxia,
diplopia, blurred vision, lens opacity, gastrointestinal disorders, serious skin reactions, liver damage, altered
cardiovascular function, and worsening of seizures at high concentrations. Cognitive dysfunction is much
less common than with other anticonvulsants but can occur even within the therapeutic range, especially if
used in polytherapy.
However, it is worth highlighting the detection of five severe adverse reactions, 6.8% of the total,
corresponding to serious mucocutaneous reactions. It is recognized that Stevens-Johnson syndrome and
toxic epidermal necrolysis are associated with the administration of carbamazepine, which eventually led
the FDA to add a warning to this medication in 2007. These reactions are considered immune disorders
induced by carbamazepine. While the exact mechanism is still unknown, it is believed that Stevens-Johnson
syndrome and toxic epidermal necrolysis result from cumulative risks related to the drug's structure and the
patient's genetic predisposition (drug metabolism, immunogenic clonotypes, and T cells) (Noguchi et al.,
2020).
It is noteworthy that the largest percentage of patients in this study was found in the 40-75 years age group.
This group is more vulnerable to ADRs due to physiological changes and diseases that modify
pharmacokinetics and pharmacodynamics, altering drug response, high comorbidity with long-term
treatments, polypharmacy and drug interactions, non-compliance with treatment, self-medication, and
decreased compensatory capacity to pharmacological actions.
Conclusions
In the study, patients between 40-75 years of age (45.7%), female, mixed race, with pre-university
educational level predominated, and 54.2% presented no unhealthy habits. Epilepsy (68.4%) was
highlighted as the main reason for prescribing carbamazepine, and it was estimated that the indications and
therapeutic guidelines for treatment with carbamazepine were appropriate, considering the clinical
individualities of the patients. There were 73 adverse reactions detected, with the nervous system being the
most affected at 56.0%, with possible ADRs being the most common at 42.5%, frequent at 49.4%, and mild
at 58.9%.
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