Clinical management of carbamazepine intoxication during anti-tubercular treatment: a case report
Massimo Calderazzo 1, Pierandrea Rende 2, Paolo Gambardella 1, Manuela Colosimo 3, Giovambattista De Sarro 2, Luca Gallelli 2
1 Department of Infectious Disease, ASP Lamezia Terme, Catanzaro, Italy
2 Department of Health Science, University of Catanzaro and Operative Unit of Clinical Pharmacology and Pharmacovigilance, Azienda Ospedaliera Mater Domini, Catanzaro, Italy
3 Department of Service, Microbiology Unit, Central Lab, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Italy
Abstract
We describe a 67-year-old man with medical history of focal post-stroke seizure and type 2 diabetes mellitus treated with carbamazepine, clobazam, gliclazide, insulin glargine, and omeprazole we visited for the onset in the last 7 days of asthenia, cough with mucus, breathing difficulty, chest pain, and weight loss. After clinical and laboratory tests, pulmonary tuberculosis was diagnosed, and a treatment with isoniazid, ethambutol, pyrazinamide rifampicin, and pyridoxine was started. Therapeutic drug monitoring of tuberculosis treatment documented that all drugs were in normal therapeutic range. Four days after the beginning of the treatment, we documented the improvement of fever, and three days later the patient showed sleepiness, visual disorder and asthenia. Clinical and pharmacological evaluation suggested a carbamazepine toxicity probably related to a drug interaction (Drug Interaction Probability Scale score = 6). The impossibility to switch carbamazepine for another antiepileptic drug, due to a resistant form of seizure, induced the discontinuation of tuberculosis treatment, resulting in the normalization of serum carbamazepine levels in one day (10 µg/ml) and in the worsening of fever, requiring a new clinical and pharmacological evaluation. The titration dosage of carbamazepine and its therapeutic drug monitoring allowed to continue the treatment with both antitubercular drugs and carbamazepine, without the development of adverse drug reactions. To date, tuberculosis treatment was stopped and clinical evaluation, radiology and microbiology assays documented the absence of tubercular infection and no seizures appeared (carbamazepine dosage 800 mg/bid; serum levels 9.5 µg/ml).
Keywords: Carbamazepine; Isoniazid; Rifampicin; Drug-drug interactions; Therapeutic drug monitoring
Gestione clinica di una intossicazione da carbamazepina durante un trattamento anti-tubercolare: un caso clinico
CMI 2015; 9(2): 41-44
http://dx.doi.org/10.7175/cmi.v9i2.1175
Case report
Disclosure
The authors declare they have no competing financial interests concerning the topics of this article
Why we describe this case
Drug-drug interactions are common in patients using multiple drugs. This case report suggests that, when a drug switch is not possible, the therapeutic drug monitoring may help physicians in the management of treatments that usually could not be administered together
Introduction
Drug-drug interactions (DDIs) represent a common cause of adverse drug reactions (ADRs), particularly in patients using multiple drugs [1] inducing an impairment of quality of life and an increase in healthcare costs [2]. Therapeutic drug monitoring (TDM) is useful to improve drug safety reducing the development of ADRs, particularly during the treatment with drugs that have a narrow therapeutic index.
Case report
A 67-year-old man (weight = 65 kg, height = 1.68 m) was referred for evaluation on January the 20th, 2014 owing to the onset in the last 7 days of asthenia, cough with mucus, breathing difficulty, chest pain, and weight loss (1.8 kg). His medical history reported focal post-stroke seizure unresponsive to several antiepileptic drugs (i.e., oxcarbazepine, topiramate, levetiracetam, lamotrigine, valproic acid) and well-controlled type 2 diabetes mellitus (HbA1c < 7%).
Medications included carbamazepine (800 mg/bid), clobazam (100 mg/daily), gliclazide (30 mg/tid), insulin glargine (100 IU), and omeprazole (20 mg/daily). On physical examination, blood pressure was 108/70 mmHg, heart rate = 83 beats/min, respiratory rate = 20 breaths/min, temperature = 38.1°C, SpO2 = 98% on room air; tuberculin skin test was performed.
Laboratory test revealed high levels of C-reactive protein (CRP = 18 mg/l), erythrocyte sedimentation rate (ESR = 62 mm/h) and white blood cells (WBC = 17,910 cells/µl). Other biochemical tests were in normal range (Table I).
|
Blood tests |
January 20th, 2014 |
Normal range |
|
Glucose (mg/dl) |
89 |
70-100 |
|
Creatinine clearance (ml/min) |
87 |
85-130 |
|
Serum creatinine (mg/dl) |
0.75 |
0.7-1.2 |
|
Potassium (mEq/l) |
3.9 |
3.6-5 |
|
Total cholesterol (mg/dl) |
165 |
< 220 |
|
LDL-cholesterol (mg/dl) |
95 |
< 130 |
|
HDL-cholesterol (mg/dl) |
40 |
35-39 |
|
Triglycerides (mg/dl) |
72 |
50-150 |
|
Aspartate aminotransferase (IU/l) |
26 |
8-48 |
|
Alanine aminotransferase (IU/l) |
22 |
7-55 |
|
C-reactive protein (mg/l) |
18 |
0.5-10 |
|
Erythrocyte sedimentation rate (mm/h) |
62 |
0-22 |
|
White blood cells (cells/µl) |
17,910 |
4,500-11,000 |
Table I. Laboratory findings at admission
Chest X-ray showed multifocal opacities in the right upper lobe with thickening and upward shift of the minor fissure, pleural effusion, and hilar lymphadenopathy. Three days later, tuberculin skin test proved positive, as confirmed by interferon-gamma release blood test, while microbiology of sputum documented the presence of Mycobacterium tuberculosis. Pulmonary tuberculosis was diagnosed and a treatment with a fixed-dose combination of isoniazid 75 mg/day, ethambutol 275 mg/day, pyrazinamide 400 mg/day and rifampicin 150 mg/day (Rimstar®) + pyridoxine (50 mg/day) was started. Two days later, the TDM of tuberculosis treatment, performed 2 hours after drug administration, documented that all drugs were in normal therapeutic range: isoniazid = 4.6 µg/ml (normal range = 3-6 µg/ml); ethambutol = 4 µg/ml (normal range = 2-6 µg/ml); pyrazinamide = 32.8 µg/ml (normal range = 20-50 µg/ml); rifampicin = 8.5 µg/ml (normal range = 8-24 µg/ml). Four days after the beginning of drug treatment, we documented the improvement of fever (36.8°C) but, three days later, the patient showed sleepiness, visual disorders, and asthenia. On physical examination, he was conscious and oriented in both time and space and presented somnolence, ataxia, and nystagmus; blood pressure was 97/68 mmHg with a pulse heart rate = 96 beats/min; electrocardiography revealed a cardiac block. Other causes of conscious disorders e.g. trauma, substance abuse, and infections were ruled out. Laboratory analysis and abdominal ultrasound examinations were negative; renal, liver, and heart failures were ruled out. Carbamazepine intoxication was postulated, and TDM confirmed it (serum carbamazepine levels = 16.60 µg/ml; normal range = 6-12 µg/ml). Pharmacological evaluation suggested a possible DDI between tuberculosis treatment and carbamazepine (Drug Interaction Probability Scale score = 6).
The impossibility to switch from carbamazepine to another antiepileptic drug, due to a resistant form of seizure, induced the discontinuation of tuberculosis treatment, resulting in the normalization of serum carbamazepine levels in one day (10 µg/ml). Two days later, we recorded a worsening of fever (37.9°C) that required a new clinical and pharmacological evaluation. Considering history, co-morbidity and drug treatment, tuberculosis treatment was re-administered and carbamazepine was titrated in 3 administrations/day (total = 400 mg/day), resulting in a good control of clinical symptoms. TDM of carbamazepine performed one day later was in normal range (10.1 µg/ml).
One- and two-month follow-up revealed a good control of tubercular disease, while TDM showed normal levels of both carbamazepine (10.0 µg/ml) and tuberculosis drugs (isoniazid = 4.7 µg/ml; ethambutol = l4.2 µg/ml; pyrazinamide = 34.5 µg/ml; rifampicin = 9.1 µg/ml), without the development of seizure or ADRs. Tuberculosis treatment was discontinued and switched to a fixed-dose combinations of isoniazide + rifampicin. In October, tuberculosis treatment was stopped and clinical evaluation, as well as radiology and microbiology assays, documented the absence of tubercular infection. No seizure or ADRs appeared (carbamazepine dosage = 800 mg/bid; serum levels = 9.5 µg/ml). Time course of drug treatment during the study is reported in Table II.
|
Time |
Symptoms/laboratory tests |
Treatment |
|
Admission January 20th, 2014 |
Asthenia, cough with mucus, breathing difficulty, chest pain and weight loss |
Carbamazepine (1,600 mg/day) |
|
January 23rd, 2014 |
Diagnosis of tuberculosis |
Start Rimstar® + pyridoxine |
|
January 25th, 2014 |
TDM of tuberculosis treatment: normal range |
|
|
January 29th, 2014 |
Improvement of fever |
|
|
February 1st, 2014 |
Sleepiness, visual disorder, and asthenia; blood pressure = 97/68 mmHg, pulse heart rate = 96 beats/min; cardiac block Increase in plasma carbamazepine levels |
Stop Rimstar® and pyridoxine |
|
February 2nd, 2014 |
Normal plasma carbamazepine levels |
|
|
February 4th, 2014 |
Worsening of fever |
Start Rimstar® + pyridoxine Reduce carbamazepine (total 400 mg/day) |
|
February 5th, 2014 |
Normal plasma carbamazepine levels |
|
|
March, 2014 |
Normal plasma carbamazepine levels No seizures No adverse drug reactions |
|
|
April, 2014 |
Normal plasma carbamazepine levels No seizures No adverse drug reactions |
Rimstar® switched to isoniazide + rifampicin |
|
October, 2014 |
No tuberculosis |
Stop isoniazide + rifampicin Increase carbamazepine to 1,600 mg/day |
Table II. Time course of drug treatment during the study
Main questions a doctor should ask him/herself in this situation
- Have I excluded other causes able to induce symptoms?
- Can I change the treatment?
- Can I evaluate the plasma levels of each drug?
Discussion
Here we report the case of a 67-year-old man with type 2 diabetes mellitus and resistant epilepsy responsive to carbamazepine and clobazam. Due to the development of tuberculosis, the patient was hospitalized and treated with isoniazid, ethambutol, pyrazinamide, and rifampicin, with a good control of tuberculosis.
It has been reported that in patients with tuberculosis, diabetes contributes to increase severity [3], reducing the response to tuberculosis treatment [4]. In our patient, clinical evaluation documented an improvement of tuberculosis symptoms, while TDM revealed that tuberculosis drugs were in normal range. However, 7 days after the beginning of tuberculosis treatment, the patient lamented sleepiness, visual disorder, and asthenia. Several papers showed that the administration of isoniazid in a patient treated with carbamazepine may induce the development of liver failure [5,6] able to induce conscious disorders.
Laboratory and clinical evaluation excluded secondary causes of conscious disorders (i.e. alcohol and substance abuse, encephalitis, hepatitis, neuroleptic malignant syndrome, drug toxicity).
Pharmacological evaluation hypothesized a carbamazepine intoxication related to a drug-drug interaction. In fact, carbamazepine is highly bound to plasma proteins (75-80%), with an half-life of 12-20 hours, and is metabolized in the liver by cytochrome P450 (CYP3A4) [7]; isoniazid and ethambutol are strong and weak CYP3A4 inhibitors, respectively [8,9]. Therefore, these drugs probably slowed the elimination of carbamazepine in our patient.
In fact, TDM documented high serum carbamazepine levels, and the discontinuation of tuberculosis treatment induced a decrease in serum carbamazepine levels, with a worsening of tuberculosis.
In agreement with our previous papers [10,11], using the Drug Interaction Probability Scale (DIPS), we hypothesized an interaction between tuberculosis treatment and carbamazepine. The titration of carbamazepine dosage and its TDM allowed continuation of combined treatment with a good control both of seizure and tuberculosis and without the development of ADRs.
The Summary of Product Characteristics (SPCs) represents the primary source of information about DDIs for health care professionals. Unfortunately, DDIs cannot be listed exhaustively, consequently the information on potential DDIs may be insufficiently described, due to the limited space in the SPC.
In fact, in the present case, SPC suggests to evaluate carefully the co-administration of carbamazepine during the treatment with isoniazid, but when it is not possible to change the drugs, TDM is needed to optimize the therapeutic efficacy and safety of carbamazepine.
Key points
- Drug-drug interactions (DDIs) may be common during a multiple therapy
- DDIs must be considered during a differential diagnosis
- Clinical conditions as well as therapeutic drug monitoring may be important during the clinical management
References
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