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Case Report Carbamazepine Toxicity Following Oxybutynin And

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Case Report Carbamazepine Toxicity Following Oxybutynin And Spinal Cord (2005) 43, 252–255 & 2005 International Spinal Cord Society All rights reserved 1362-4393/05 $30.00 www.nature.com/sc Case Report Carbamazepine toxicity following Oxybutynin and Dantrolene administration: a case report T Vander*,1, H Odi1, V Bluvstein1, J Ronen1,2 and A Catz1,2 1Department of Spinal Rehabilitation, Loewenstein Rehabilitation Hospital, Raanana, Israel; 2Tel-Aviv University, Tel-Aviv, Israel Objective: To report a case of Carbamazepine toxicity following the administration of Oxybutynin and Dantrolene. Study design: A case report. Setting: The Spinal Rehabilitation Department, Loewenstein Hospital, Raanana, Israel. Methods: A patient with C6D tetraplegia who sustained intoxication because of drug interaction is presented. She had been treated by Carbamazepine 1000 mg/day for neuropathic pain for 2 years without clinical or laboratory signs of toxicity. After administration of Oxybutynin concomitantly with an increase in the dose of Dantrolene, she presented the clinical symptoms and laboratory finding of Carbamazepine intoxication. Trying to adjust the treatment to the patient’s requirements, Carbamazepine together with Oxybutynin and Dantrolene was readministrated in lower doses. Results: The combination of these drugs, even small doses, caused toxicity. Adding Dantrolene and Oxybutynin elevated the blood level of Carbamazepine, possibly by inhibition of cytochrome P450. Conclusion: A possible pharmacokinetic interaction between Dantrolene and Oxybutynin should be borne in mind when considering Carbamazepine medication for a patient with a spinal cord lesion. Spinal Cord (2005) 43, 252–255. doi:10.1038/sj.sc.3101689; Published online 1 February 2005 Keywords: Carbamazepine; Oxybutynin; Dantrolene; drug interaction; cytochrome P450 Introduction Both Oxybutynin chloride and Dantrolene sodium are be required when patients have concomitant post- widely used in patients with spinal cord lesion (SCL). traumatic or postoperative epilepsy, or more frequently Oxybutynin is used for the treatment of detrusor for the treatment of painful or paraesthetic phenom- overactivity1 and Dantrolene to reduce spasticity.2–4 ena.9,10 Carbamazepine intoxication includes nausea, Oxybutynin has both an antimuscarinic and a direct vomiting, dizziness, ataxia, confusion, dysarthria, and muscle relaxant effect and, in addition, a local anesthetic nystagmus,11 and it may also cause liver dysfunction.12 activity.5 It may have anticholinergic side effects, Administration of the three drugs at the same time including dry mouth, blurred vision, somnolence, exposes the patient with SCL to their combined side constipation, and delirium.6 Dantrolene relaxes striated effects. However, the reported case may indicate that the muscles by inhibiting the release of Ca2 þ from the combination may carry an even greater risk because of sarcoplasmic reticulum.7 The drug commonly causes pharmacokinetic interactions. Carbamazepine may in- transient drowsiness, weakness, general malaise, fatigue, teract with various drugs. It is eliminated through the diarrhea, and liver test dysfunction that requires strict hepatic pathway and catalyzed by cytochrome P450 laboratory follow-up.8 The potential liver toxicity (CYP3A subfamily),13 so drugs that inhibit the activity discourages some physicians from using Dantrolene, of this cytochrome may elevate Carbamazepine blood but still many use it for long periods.3,4 Carbamazepine level and cause toxicity.11 These drugs include itricona- is less frequently used in patients with SCL, but it may zole, ketokonazole, clarythromycin, erythromycin, nefazodone, ritonavir,14 isoniazide, propoxyphene, cimetidine,15 fluvoxamine, fluoxetine,16 and acetazola- *Correspondence: T Vander, Department IV, Spinal Rehabilitation, 17 Loewenstein Rehabilitation Hospital, 278 Achuza St., PO Box3, mide. Here we present a case of Carbamazepine Raanana 43100, Israel toxicity related to a pharmacokinetic interaction with Toxicity following Oxybutynin and Dantrolene T Vander et al 253 either Oxybutynin or Dantrolene. To the best of our electrolytes, renal function test, and liver function test knowledge, this is the first such report. were normal. Carbamazepine and Oxybutynin were discontinued and Dantrolene dose was lowered to 25 mg Case report per day. Carbamazepine level fell to 6 mg/ml and the intoxication disappeared, but then the patient was A 37-year-old woman with incomplete tetraplegia due to willing to use these drugs again to relieve her symptoms. cervical spondylosis at the C5–C6 level was admitted to Therefore, readministration of the medication was the spinal department of Loewenstein Rehabilitation attempted again, using a lower dose: Carbamazepine Hospital (Raanana, Israel). At 2 years before this 400 mg per day and Dantrolene 25 mg/day. After a week admission she had had a subtotal excision of a D5–D7 on this regimen the Carbamazepine blood level was ependymoma. Since that operation, she suffered from 8.4 mg/ml. At this stage, 5 mg of Oxybutynin were added; lancinating and burning sensations over the D6–D7 it was followed by a dramatic elevation of Carbamaze- cutaneous dermatomes. Treatment with Gabapentin pine level to 32 mg/ml, and signs of toxicity returned. was unsuccessful, but the patient responded favorably Liver enzymes remained within normal limits. This time to Tab. Carbamazepine 1000 mg daily. She was also Carbamazepine was replaced by Valproic acid 600 mg/ receiving Tab. Baclofen 100 mg/day for spasticity, Tab. day, which also proved to be beneficial against the Atenolol 50 mg/day for hypertension, and Tab. Fluvox- painful sensation and showed no interactions with amine 100 mg/day for depression. Neurological exam- Oxybutynin or Dantrolene. The patient was discharged ination revealed spastic tetraplegia (ASIA D) below the from hospital in an alert state and well oriented, C6 level, with exaggerated tendon reflexes and bilateral independent in self-care, and walking with crutches. pyramidal signs. She needed assistance in self-care, could walk with crutches for a short distance, was voiding by self-catheterization, and had regular bowel Discussion movements. Between catheterizations, urine was leaking into the diaper. Admission laboratory examinations, The clinical presentation and the laboratory finding of including renal (BUN and creatinine) and liver (SGOT, the patient presented here are compatible with Carba- SGPT, GGT) function tests, were normal. Abdominal mazepine toxicity (Figure 1). As no signs of Carbama- sonogram revealed a normal liver and no other zepine overdose were evident during the previous 2 abnormalities. years, during which she received the same dosage of the Owing to the marked spasticity, Cap. Dantrolene was drug, it is plausible that administration of new drugs started and its dosage was elevated gradually. After changed the metabolism of Carbamazepine and elevated urodynamic investigation revealed a hypertonic bladder its blood level concentration. without vesicoureteral reflux, Tab. Oxybutynin 5 mg twice a day was added. At 2 weeks starting Oxybutynin, and while on 125 mg Carbamazepine Interaction with Dantrolene, the patient complained of dizziness and Oxybutinin and Dantrolene repeated vomiting. She was drowsy, unsteady, and confused, and her speech was slurred. Bilateral hor- 32 izontal gaze-evoked nystagmus was found. The EEG record showed a slow background activity compatible 24 with a toxic-metabolic pattern. Hemoglobin, leucocytes, blood electrolytes, liver, and renal function were 16 normal, and Carbamazepine blood concentration was 16 mg/ml (therapeutic range 4–12 mg/ml). 8 Carbamazepine Carbamazepine, Oxybutynin, Fluvoxamine, Baclofen, blood level (µg/ml) and Dantrolene were stopped, the plasma level of 0 Carbamazepine returned to the therapeutic range 123456 (8.3 mg/ml), and the clinical condition of the patient Drug combination gradually improved until she regained her previous Figure 1 The drug combinations: (1) Carbamazepine status. Fluvoxamine, which may elevate the Carbama- 1000 mg/day, Oxybutinine 10 mg/day, Dantrolene 125 mg/ zepine plasma level, was discontinued permanently. day; (2) none; (3) Carbamazepine 600 mg/day, Oxybutinine However, as the pain, urinary frequency, and disturbing 10 mg/day, Dantrolene 100 mg/day; (4) Carbamazepine spasticity reappeared, Carbamazepine, Oxybutynin, and 600 mg/day, Oxybutinine 10 mg/day, Dantrolene 125 mg/day; Dantrolene were readministered in doses of 600, 10, and (5) Carbamazepine 400 mg/day, Dantrolene 25 mg/day; (6) 100 mg daily, respectively. As a Carbamazepine blood Carbamazepine 400 mg/day, Oxybutinine 5 mg/day, Dantro- lene 25 mg/day. The first episode of intoxication followed the level of 9.2 mg/ml was reported under this treatment, and start of Oxybutynin and an increase in Dantrolene dosage to spasticity was still disturbing, Dantrolene dosage was 125 mg/day. The second episode followed Oxybutinine admin- raised to 125 mg daily. After 1 day, the Carbamazepine istration with a similar increase in Dantrolene dosage. The blood level increased to 29 mg/ml and clinical intoxica- third episode appeared with a lower dose of Dantrolene, when tion was again evident. Again, blood count, blood a low dose of Oxybutynin was started Spinal Cord Toxicity following Oxybutynin and Dantrolene T Vander et al 254 During the previous 2 years she was taking, besides and a meticulous clinical observation to reduce the risk Carbamazepine, Baclofen, Atenolol, and Fluvoxamine. associated with interactions. There is no evidence that Baclofen or Atenolol
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