A Study of Carbamazepine Utilization in the Hospitals in Yogyakarta Special Province

 

Vitarani D. A. Ningrum1*, Priska C. Sukemi2, Khoerul A. Rhidohan2, Endang Yuniarti3,4

1Pharmacy Practice Laboratory, Department of Pharmacy, Universitas Islam Indonesia, Indonesia.

2Research Assistant, Department of Pharmacy, Universitas Islam Indonesia, Indonesia.

3PKU Muhammadiyah Hospital, Yogyakarta, Indonesia.

4STIKES Muhammadiyah Gombong, Central Java, Indonesia.

*Corresponding Author E-mail: vitarani.ningrum@uii.ac.id

 

ABSTRACT:

Therapy to control seizures primarily utilizes drugs to date, including carbamazepine. However, carbamazepine has a narrow therapeutic index and is auto-inductive and potential to induce serious adverse reactions, such as Stevens-Johnson Syndrome. This has placed carbamazepine among the priority drugs for which the utilization should be evaluated to ensure safety and effectiveness. This study analyzed the indication, dose, clinical response, and adverse drug reaction (ADR) of carbamazepine by five hospitals in Yogyakarta. The research employed a retrospective cross-sectional design for patients with epilepsy who received carbamazepine for a minimum of 3 days. Patients’ demographics, diagnosis, carbamazepine dose and clinical response, ADR, and concomitant drugs interacting with carbamazepine were collected from medical records during one year of the study. The study involved 78 patients with a majority of male with age of 44.3±13.3 years. The highest indication of carbamazepine was for secondary-type epilepsy (17.95%) with an average maintenance dose of 423.94±135.65 mg/day. Carbamazepine discrepancy was found in absence-type epileptic with an average dose higher than that for other seizure types. Meanwhile, more than 80% seizures could be controlled by carbamazepine monotherapy or its combination. This study found that 16.67% of patients suffered from ADR, particularly a nervous system disorder, with no serious ADR reported. An effective approach is required to improve the appropriateness of antiepileptic drug selection based on the seizure types. In addition, the average maintenance dose of CBZ found in this study, which is relatively lower than those found in studies involving different populations, needs further pharmacogenetic studies of carbamazepine.

 

KEYWORDS: Carbamazepine, Antiepileptic Drug, Dose, Adverse Drug Reaction, Drug Utilization Study.

 

 


INTRODUCTION:

Carbamazepine (CBZ) is not only affordable but also listed in the Indonesian National Formulary as an oral antiepileptic drug available at all levels of healthcare facilities, thereby encouraging relatively frequent utilization. When clinically compared to other antiepileptic drugs, however, CBZ is more at risk of causing serious adverse drug reactions (ADR) in the form of severe hypersensitivity, such as Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN).

 

Such severe reactions to carbamazepine have been reported in a number of studies, including in those involving Asian populations, which have proved to be influenced by genetic factors1–7.

 

In addition, since CBZ is a drug with a narrow therapeutic index and high variability, it is necessary to take into account the patients’ individual factors to prevent subtherapeutic or toxic effects8. The recent recommendation from WHO states that a careful clinical assessment of CBZ utilization takes precedence over TDM services9. Therefore, the utilization of CBZ for all patients who are either currently or recently starting receiving such therapy should be evaluated10.

 

Studies to evaluate carbamazepine utilization have been previously conducted, but these only involved pediatric patients11,12, examined a particular type of epilepsy13, and focused on metabolic syndrome effects14. Therefore, this present multicenter study analyzes the indication, dose, clinical response, and prevalence of ADR in adult and elderly patients receiving CBZ.

 

METHODS:

Study Design:

This descriptive retrospective cross-sectional study of carbamazepine utilization was conducted in four secondary hospitals in Yogyakarta Special Province (DIY), namely RS PKU Muhammadiyah Yogyakarta, RSUD Kota Yogyakarta, RS Bethesda, RSUD Sleman, and one primary hospital, RS PKU Muhammadiyah Gamping. The study involved patients with epilepsy who received carbamazepine during the study period of one year with a minimum age of 26 years selected through saturation sampling while patients who received CBZ for less than 3 days were excluded from this study. The clinical response was considered under control if there was a decrease in the seizure frequency after CBZ administration. Data of patients’ demographic characteristics, diagnosis, CBZ dose, clinical response, ADR incidence, and other antiepileptic drugs consumed were obtained from the medical records. To minimize the potential for bias towards the assessment of ADR incidence, this study also analyzed the incidence of CBZ-drug interactions if the minimum duration of administration had reached its’ steady state levels and considered patients’ comorbidities. This study has passed the ethical review of the Research Ethics Committee in each hospital.

 

Data Analysis:

A univariate analysis was employed to describe the demographic characteristics, diagnosis, and CBZ doses in the form of mean±SD using the Excel software in Microsoft Office Version 365. Meanwhile, the clinical response and ADR incidence were presented in percentages, and the mean differences in CBZ doses of each age category and epilepsy type were examined using the T test for normally distributed data and otherwise using the Mann-Whitney test in SPSS Version 25.

 

RESULTS AND DISCUSSION:

Distribution of Subject Characteristics:

The subjects from 5 hospitals consist of 78 patients with CBZ utilization amounting to 496 during the study period of one year. The flowchart of patient participation in the study is presented in Figure 1.

 

 

Figure 1. Flowchart of Participants in This Descriptive Retrospective Cross-sectional Study

 

Different from CBZ utilization in other indications, its use to control epileptic seizures requires longer duration except in such particular conditions as hypersensitivity reaction or other intolerable ADR. The patient characteristics according to age, sex, type of seizure, and comorbidity are described in Table 1.

 

Table 1. Distribution of Patient Characteristics

Characteristic

Total

(n)

Percentage

(%)

Sex

Male

41

52.60

Female

37

47.40

Age Category (Years)

Adult (26-65)

73

93.60

Elderly (>65)

5

6.40

Diagnosis of Epilepsy Type

Tonic-Clonic

7

8.97

Absence

2

2.56

Partial

3

3.85

Secondary

14

17.95

Unspecified

52

66.67

Comorbidities

Cardiovascular Disease and/or Type-2 DM and/or Cerebrovascular Disease

 

23

29.49

TTH

7

8.97

Infections and/or arthritis and/or allergy

4

5.13

TGN

2

2.56

Hydrocephalus

1

1.28

None

41

52.56

*Notes: DM: Diabetes Mellitus, TTH: Tension Type Headache, TGN: Trigeminal Neuralgia

 

This study found that the majority of the epileptic patients receiving CBZ were male adult patients. In general, epidemiological studies have found no association between sex and epilepsy incidence. However, a large number of studies and clinicians has stated that there are differences between men and women in the implications for patients’ life and well-being with regard to the complex interactions among anti-epileptic drugs (AEDs), endocrine functions, and the epilepsy itself, which affect the selection of safe, effective, acceptable AEDs 15.

 

In relation to the drug safety factor, this study found that the elderly received considerably less CBZ than the adult group (only <7%). However, a pharmacokinetic study shows that the age has no effects on either the clearance or the volume distribution of CBZ 16. Rather, AEDs with minimal ADR to the cognitive function in particular, low protein binding, and insignificant pharmacokinetic interactions are preferred for elderly patients17,18. However, compared to other AEDs, CBZ has the highest risk of severe cutaneous adverse drug reactions (SCARs) and hyponatremia, possesses high protein binding, and is a strong enzyme inducer 19–21. A 13-year retrospective study in a hospital has found that CBZ becomes the second most common drug administered to elderly patients with newly diagnosed epilepsy 22. Additionally, in a population study of CBZ pharmacokinetics in 121 patients, the pharmacokinetic variability of CBZ in elderly patients is relatively low when given as monotherapy (18.1%) and increases 4-fold when simultaneously administered with phenytoin19. As a result, to date, CBZ prescription remains frequent for controlling epileptic seizures.

 

In general, as one of the long-established AEDs, CBZ effectiveness has been comparable to that of newer generations of AEDs, such as lamotrigine, oxcarbazepine, and gabapentin, but with a higher risk of ADR. Consequently, although the seizure-free effect for 12 months’ duration of observation is comparable, the utilization retention is lower. This is partially affected by the utilization of the immediate-release form and high dose of CBZ23. In addition, the availability of lamotrigine, which is allowed by the Indonesian National Health Insurance policy to be administered to elderly with epilepsy, and that only the conventional dosage form of CBZ is covered can become one of the factors in the low frequency of CBZ prescription for the elderly patients in this study.

 

Meanwhile, the secondary-type epilepsy becomes the highest indication for CBZ. According to The International League Against Epilepsy (ILAE), CBZ is among the preferred drugs for tonic-clonic, partial, and secondary-generalized epilepsy types 24. However, this study found that 2.6% of the patients with absence-type epilepsy were still prescribed CBZ. It is acknowledged that CBZ can exacerbate absence-type seizures, thereby making CBZ utilization contraindicative although the underlying mechanism remains poorly understood 25,26. In addition, more than 60% of the diagnosed epilepsy with CBZ administration was not completed with a specific seizure type, thereby leading to incomprehensive assessment of the appropriateness of CBZ utilization according to the seizure types.

 

The dose of CBZ is known to necessitate consideration for both age and comorbidity. Elderly patients generally experience a decline in organ functions which can lead to a decrease in absorption, protein binding, and drug elimination, thereby changing the pharmacokinetic profile of drugs, including that of CBZ. Consequently, the dose for elderly patients theoretically needs adjustment27,28. Meanwhile, although CBZ rarely induces kidney failure, its disposition can change, especially in a condition of impaired kidney function with proteinuria, making it remain necessary to perform close monitoring. Furthermore, the majority of CBZ elimination works through hepatic biotransformation, which therefore suggests the necessity to avoid its utilization for patients with impaired liver function so as to prevent accumulation 29,30. Patients with kidney and liver failure were not found in this study. The dose of CBZ according to patients’ age and type of epilepsy is presented in Table 2.

 

Table 2. Average Dose of Carbamazepine Based on Age and Epilepsy Type

Indication

Age category

Daily dose (mg/day)

n (visits)

%

Average dose

(mg/day)

Tonic-clonic

Adult

200

2

2.56

393.10±65.08

400

26

33.33

600

1

1.28

Absence

Adult

400

9

11.54

436.36±80.90

600

2

2.56

Partial

Adult

200

7

8.97

326.32±99.12

400

12

15.38

Secondary

Adult

100

4

5.13

325±221.73

200

4

5.13

400

70

89.74

600

17

21.79

Elderly

400

12

15.38

400

Epilepsy*

Adult

25

1

1.28

229.17±227.16

 

50

5

6.41

100

5

6.41

200

47

60.26

400

144

184.62

600

121

155.13

Elderly

200

1

1.28

371.43±75.59

400

6

7.69

*unspecified seizure type

 

This study found that the highest average dose of CBZ was utilized to control absence-type seizures (253.77 mg/day). Although rare, absence-type seizures can occur in adult patients 31,32 as reported by the findings of this study. In fact, CBZ utilization is not recommended, and ethosuximide or valproate becomes the preferred AEDs for such seizure type instead33.

 

The initial dose of CBZ as an antiepileptic drug for adult patients is 200 mg twice per day and can be increased by 200 mg/day at one-week intervals with a maximum dose of 1600 mg/day in 3-4 divided doses 34. Meanwhile, the dose of CBZ as an antiepileptic drug for elderly patients begins at 100 mg twice daily and can be increased by 100 mg/day of each week as required. The results of this study showed that the average doses for adult and elderly groups were 250.18 mg/day and 206.42 mg/day, respectively (p 0.143). In general, the average dose received by Indonesian patients is lower than that for patients with epilepsy from other races who receive a maintenance dose of 400-1200 mg/day35–37.

 

Table 3. Antiepileptic Drugs in Combination with Carbamazepine

Type of epilepsy

Concomitant drugs

Concomitant drug dose (n)

Subtherapeutic dose

Therapeutic dose

Tonic-clonic

VPA

-

3

VPA-CLB*

2

-

VPA, CLB*-PHT

-

1

PHT

-

1

PHT-CLB*

11

-

Absence

VPA

-

1

VPA-CLB*

1

-

VPA-PHT

-

9

Partial

VPA

-

1

VPA, CLB*-PHT

-

4

Secondary

VPA

-

2

VPA-GBP*

1

-

DZP

-

2

DZP*-TPM

5

-

PHT

4

28

TPM

-

5

PHT-CLB*

3

9

PHT-DZP*

1

32

Unspecified seizure type

VPA

-

20

VPA-PHT

-

2

VPA-CLB*

3

-

VPA-PB*

-

8

VPA-PB-LEV*

4

-

LEV-PHT

-

3

LEV-PHT-CZP

-

8

CLB

2

3

DZP

4

3

PHT

6

59

PB-TPM

-

2

PB

19

1

PHT-DZP*

7

2

PHT-CZP*-PB*

2

-

PHT-LEV

-

1

PHT-LEV-DZP

-

1

PHT-PB*

21

1

PHT-PB*-VPA

1

22

PHT-PB*-LEV*

3

-

PHT-PB-LEV-CZP

-

2

Total

100

236

PB                  : Phenobarbital                  PHT      : Phenytoin

CBZ               : Carbamazepine                VPA      : Valproic acid

TPM               : Topiramate                      LEV      : Levetiracetam

DZP               : Diazepam                        CZP      : Clonazepam

CLB               : Clobazam

*Prescribed AEDs with a subtherapeutic dose

 

On the other hand, a significant difference in the mean dose was found with regard to the type of seizures, in which the highest dose was in the absence-type seizures and the lowest was in the partial type (p 0.003). In addition to the type of seizures, the dose of AED is also generally influenced by concomitant medications and patients’ age34. Some CBZ utilization in this study has a dose of lower than 200 mg/day because the patients are undergoing a stage of tapering doses. Tapering off is performed when therapy with a maximum dose of antiepileptic drug has not been effective at controlling seizures, and the medication is therefore switched to another AED. To avoid withdrawal or relapse symptoms, the dose of CBZ is slowly reduced, and the substitute medication commences with dose titration. A number of epileptic patients also undergo a tapering-off process in order to discontinue the medications that have fulfilled particular clinical criteria 38. Meanwhile, the dose of CBZ for tapering off can vary from 50 mg to 100 mg or 150 mg as the dose reduced by approximately 50% from the initial dose prior to the tapering off process 39. This study found 12 cases of CBZ utilization with tapering off doses ranging from 25 to 100 mg/day. Upon re-analysis, by excluding the dose of CBZ data for tapering off, it was revealed that the average dose of CBZ for the elderly patients remained lower than that for adult patients (p 0.083). The AED regimen utilized in this study is presented in Table 3.

 

This study found that nearly 70% of the CBZ utilization was in the form of drug combination, the majority of which was with 1 concomitant drug, including PHT as the most commonly used in combination with AED. It is known that the CBZ-PHT combination, both of which are strong inducers of CYP-450 and glucuronidase enzymes, has the potential to induce pharmacokinetic interactions in metabolic processes, thus leading to decreased drug concentrations in serum. Consequently, further studies are necessary to analyze the clinical impacts of such drug-drug interaction.

 

Although some epileptic patients require rational combination therapy, for the purpose of optimizing clinical response and minimizing adverse effects, it is recommended that the combination is selected according to different mechanisms of action 40. The similarity between CBZ and PHT as part of the sodium channel blockers group in the fast-inactivated state category has made them inadvisable to be combined though they show superior effectiveness when compared to the single use but with higher toxicity 41. Another drug commonly combined with CBZ is valproic acid. A previous study found that the combination of carbamazepine and valproate has caused serious adverse drug reactions associated with hepatic function and hematological disorders in the form of reduced leukocytes and platelets 42. In essence, the goal of AED administration either as monotherapy or in combination is to maintain patients’ seizure-free during treatment. The clinical response to the utilization of CBZ based on the type of seizures is shown in Table 4.


Table 4. Clinical Response to Carbamazepine Utilization Based on Epilepsy Types

Epilepsy type

Therapy

Clinical Response

Dose (mg/day)

n (visits)

% of Each Clinical Response

Tonic-clonic

Monotherapy

Controlled

200

2

2.22

400

9

Uncontrolled

400

1

0.20

Combination

Controlled

400

10

2.42

600

1

Uncontrolled

400

6

1.21

Absence

Combination

Controlled

400

6

1.61

600

2

Uncontrolled

400

3

0.60

Partial

Monotherapy

Controlled

200

2

2.62

400

11

Uncontrolled

400

1

0.20

Combination

Controlled

200

4

0.81

Uncontrolled

200

1

0.20

Secondary

Monotherapy

Controlled

400

11

2.42

Uncontrolled

400

2

0.40

Combination

Controlled

100

1

17.94

200

4

400

70

600

14

Uncontrolled

600

3

0.60

Unspecified epilepsy

Monotherapy

Controlled

25

1

21.57

100

3

200

15

300

2

400

48

600

38

Uncontrolled

100

1

2.62

200

1

400

10

600

1

Combination

Controlled

50

3

36.08

100

1

200

30

400

73

600

72

Uncontrolled

50

2

6.65

200

2

400

19

600

10

 

Table 5.  ADR Incidence from Carbamazepine Utilization

Type of ADR

Complaint/Sign

Sex (n)

Mean Age (years)

Concomitant Drugs

n (%)

A

Dizziness

Female

47

Amlodipine, clobazam, meloxicam, lansoprazole, betahistine mesylate, valproic acid, phenytoin, folic acid, diazepam, paracetamol, dimenhydrinate, phenobarbital

3 (23.08)

Male*

Simvastatin, allopurinol, acetylsalicylic acid

Male

Amlodipine, phenytoin, folic acid, flunarizine HCl, candesartan

Fatigue

Male

29

Phenytoin, phenobarbital, levetiracetam

1 (7.69)

Fatigue, nausea, vomiting, joint pain

Female**

54

Paracetamol, valproic acid, ceftriaxone

1 (7.69)

Dizziness, leg pain

Male**

63

Amlodipine, valproic acid, gemfibrozil, flunarizine HCl, NaCl infuse

1 (7.69)

Pain, nausea, vomiting, fatigue

Male**

63

Phenytoin, folic acid, paracetamol, insulin aspart, tranexamic acid, candesartan

1 (7.69)

Headache

Female

45

Phenytoin, folic acid, paracetamol, flunarizine HCl, diazepam, vitamin B complex, captopril, simvastatin, ranitidine, amlodipine

3 (23.08)

Female**

Phenytoin, folic acid, metamizole

Male*

Simvastatin, allopurinol, acetylsalicylic acid

C

Joint pain

Female

63

Amlodipine, captopril, amitriptyline, folic acid, phenytoin, phenobarbital, valproic acid, meloxicam, diclofenac, alprazolam

3 (23.08)

Female*

Meloxicam, paracetamol, vitamin B, diazepam, gabapentin

Male

Meloxicam, eperisone

Notes: * : Elderly Patients, ** : Inpatients


Table 4 indicates that 87.3% of the clinical responses have been well controlled by the utilization of either carbamazepine monotherapy or its combination. The average dose of carbamazepine which results in controlled and uncontrolled clinical responses in this study is 250.19 mg/day and 236.87 mg/day, respectively (p 0.439). In general, the average dose received by epileptic patients in Indonesia is lower than that among other races, with a maintenance dose of 400-1200 mg/day 35–37.

 

The existence of genetic variations in the ABCB1 gene that encodes P-glycoprotein frequently found among the Indonesian population and CYP3A5 gene polymorphisms can become the contributing factors in the dose of CBZ medication discrepancy 43–45. In addition to the clinical response, this study has also identified the ADR of CBZ as described in Table 5.

 

Table 5 shows that 16.67% of the patients suffered from ADR incidence with dizziness as the highest manifestation categorized as type-A ADR. It indicates that such adverse effect commonly occurs and is associated with the mechanisms of action and the dose of carbamazepine 46. This is in line with the findings of an ADR prospective study among 150 patients, in which type-A ADR was the most frequent with 8.3% incident being caused by the use of antiepileptic drugs47.

 

In addition, this study found that ADR incidence was relatively similar between male and female patients. In contrast, it was found to be different in a study of ADR cases among 270 patients in a tertiary hospital, in which the incidence was more frequent in female patients compared to male48. In general, regardless of the inconsistent findings, reports of ADR incidence indicates that women belong to the group with more frequent ADR experiences, especially those associated with the administration of such specific medication as thyroid hormones, tumor necrosis factor‐α inhibitors, and some psychoanaleptics49.

 

Meanwhile, such CBZ ADR variants as SJS or TEN were not found in this study. A prospective ADR study of dermatological ADR in a tertiary hospital found only one in 105 cases of dermatological ADR due to CBZ utilization manifested as TEN50. Although such incidence is very uncommon, it remains necessary to prevent and monitor this type of ADR.

 

Meanwhile, other ADRs in the form of bone disorders categorized as type-C ADR due to chronic utilization and reversible nature were also found in this study. As a strong inducer, CBZ also affects the enzymes involved in endogenous metabolic pathways and can alter the biochemistry of bone, thus leading to osteoporosis 51. In addition, long-term utilization of CBZ in combination with valproic acid can increase the risk of bone disorders. Previous research found that epileptic patients administered with carbamazepine experience changes in bone metabolism marked by a decrease in vitamin D and calcium levels 52. A case-control study has proved that the administration of AED combinations is a risk factor for metabolic bone diseases thus leading to osteoporosis. The combined administration of CBZ most frequently found in this study requires monitoring, particularly in patients with risk factors53.

 

On the other hand, the findings of a prospective study involving epileptic patients in a tertiary hospital showed that CBZ can induce hyponatremia with a causality score of 6 (probable ADR)54. The implementation of a feasible pharmacovigilance system facilitated by reliable infrastructure and human resources is expected to support the achievement of patient safety goals in drug utilization55. Training, workshops, and continuing professional education for healthcare workers are important to maintain the sustainability of this implementation56.

 

A number of limitations of this study need to be taken into account, such as the non-randomized selection of the hospitals, the high number of epilepsy diagnosis without seizure types, and the absence of a control group. Such limitations indicate that the results of this study have yet to represent the assessment of the appropriateness of CBZ utilization as well as patient-factor correlation which affects the clinical response and incidence of ADR in hospitals as a whole. Furthermore, although this study is multicenter, the retrospective cross-sectional study design with limitations in the laboratory parameters prevents it from completely confirming ADR incidence. Therefore, not only the existence of a control group but also a longitudinal study is required with involving patients of different hospitals over a larger area to reveal actual ADR incidence.

 

CONCLUSION:

The most frequent CBZ utilization is found in the secondary-type epilepsy for adult patients with an average maintenance dose that is relatively lower than those recommended in some reliable literature. There is an inappropriateness in CBZ utilization for absence-type epilepsy. Carbamazepine either as monotherapy or in combination shows 87.3% controlled clinical response. The most frequent ADR type is dizziness with no serious ADR found. This study confirms the importance of monitoring CBZ utilization to ensure its safety, particularly in relation to its interactions with other AEDs. Since the findings of this study shows a lower average dose of CBZ compared to those in other studies involving different races, further research is required to confirm the levels of ADR sensitivity in Indonesian patients receiving CBZ.

 

ACKNOWLEDGEMENT:

The researchers are grateful to the research assistants for helping with data collection. This study is funded by the Department of Pharmacy Universitas Islam Indonesia via Pharmacy Collaborative Research Grant (Hibah Penelitian Kolaborasi Jurusan Farmasi) No. 0163/Kajur.Far/20/Jur.Far./VII/2020

 

CONFLICTS OF INTEREST:

The researchers declare no conflicts of interest.

 

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Received on 12.03.2021           Modified on 12.08.2021

Accepted on 01.11.2021         © RJPT All right reserved

Research J. Pharm. and Tech. 2022; 15(6):2577-2584.

DOI: 10.52711/0974-360X.2022.00431