J. Rindone, Chadwick K. Mellen
Nov 23, 2017
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Journal
European Journal of Clinical Pharmacology
Abstract
Primidone has been used for decades, mainly in the treatment of seizure disorders. In the late 1980s, it was found that primidone can be a suitable alternative to propranolol in patients with essential tremor and this has been its major use ever since [1]. Essential tremor is a relatively common disorder, especially in patients ≥ 65 years old [2]. Considering the common nature of this disorder and that many patients may need primidone for tremor control, it is likely to be prescribed in patients taking warfarin [3]. Since primidone is partially metabolized to phenobarbital, this raises the possibility of a primidone/warfarin interaction which heretofore has not been reported in the medical literature. We encountered a case of significant warfarin resistance associated with primidone use in a patient with essential tremor. Our patient is a 63-year-old male who has been using warfarin for several years for the treatment of pulmonary embolus. For months, he was stable on warfarin 52 mg/week with therapeutic International Normalized Ratios (INR) (Fig. 1). In April of 2017, he was seen by a consultant neurologist for essential tremor. The patient was taking propranolol 160 mg/ day with modest results. Primidone was added at 50 mg daily and titrated up to 250 mg three times daily over the next 4 weeks. Three weeks after starting primidone, his INR was 2.0 and no changes were made. He returned to our anticoagulation clinic 6 weeks later with INR 1.0. No other medication or diet changes were made. He denied noncompliance with warfarin. Because of sedation, his primidone dose was lowered to 250 mg twice a day and his warfarin dose was gradually increased over the next 5 weeks to 128 mg/week with an INR of 2.8. Since he had a high degree of sedation, even with a lower primidone dose, a phenobarbital level was measured, which was 15.4 mcg/ml (reference range 15–40). He had good tremor control with the primidone and elected to stay at his current dose of 250 mg twice day. Patient decided to move to another state and he was lost to further follow up. This case highlights the potential problem of prescribing primidone to patients stable on warfarin. A strong temporal relationship between starting primidone and resultant decrease in INR and a 146% increase in warfarin dose is noteworthy. A review of PubMed and Embase databases shows no reports of primidone interacting with warfarin. This interaction is not listed in the package insert for primidone [4]. Primidone is partially metabolized to phenobarbital at varying degrees. Many patients can have therapeutic serum concentrations of phenobarbital with full doses of primidone (as noted in our patient) [5]. Phenobarbital can stimulate the cytochrome P450 system, especially CYP2C9 which is the major CYP enzyme responsible for warfarin metabolism [6]. A study from 5 decades ago showed that phenobarbital can reduce the half-life of warfarin in volunteers by 46% [7]. A trial from the 1970s showed that phenobarbital 100 mg daily for 4 weeks in 10 patients lowered prothrombin times by a mean of only 4.5 s [8]. Contrary to these data, a retrospective review showed that warfarin dosage requirements did not change in 2 patients receiving standard doses of phenobarbital [9]. Since primidone can cause warfarin resistance, we recommend that alternative therapies be used in the treatment of essential tremor when beta-blockers are ineffective. Gabapentin and topiramate may be good alternatives and should not interact with warfarin [10, 11]. Using novel anticoagulants instead of warfarin, such as Xa blockers or dabigatran, should be avoided in patients receiving primidone since phenobarbital may enhance their clearance through induction of CYP 3A4 or increasing Pglycoprotein activity [12]. * Joseph P. Rindone joseph.rindone@va.gov