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Associate Professor, Departments of Clinical Pharmacy and Physical Medicine, Schools of Pharmacy and Medicine, University of Colorado Health Sciences Center, Denver, CO
Associate Professor, Departments of Clinical Pharmacy and Neurology, Schools of Pharmacy and Medicine, University of Colorado Health Sciences Center
Reprints: Dr. Page, UCHSC, School of Pharmacy, Department of Clinical Pharmacy, 4200 E. Ninth Ave., Box C238, Denver, CO 80262-0001, fax 303/315-4630, robert.page{at}uchsc.edu
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CASE SUMMARY: A 61-year-old woman with significant cardiovascular disease was started on topiramate 25 mg daily for lower extremity neuropathy. After 7 days of treatment, she began to experience severe, intractable epistaxis that lasted 8 days, warranting an ED visit. The epistaxis resolved 1 week after topiramate discontinuation. Topiramate was restarted 3 months later, and the patient again developed intractable epistaxis. After 2 days of epistaxis, she returned to the ED with significant anginal pain and was admitted to the hospital, where she received 2 units of packed red blood cells. One week after stopping topiramate, the epistaxis stopped. At the time of writing, she had exhibited no epistaxis for 6 months. According to the Naranjo probability scale, topiramate was the probable cause of epistaxis.
DISCUSSION: Topiramate is a neuromodulatory compound approved for management of migraines, as well as partial and generalized tonic-clonic seizures. Over the past decade, its use has expanded to include many other neuropathic conditions. Currently, epistaxis has been reported in only 1-4% of patients receiving topiramate in clinical trials; however, these data were derived from a young study population. Like topiramate, calcium-channel blockers (CCBs) modulate voltage-gated L type calcium ion channels. These specific channels are located on vascular smooth muscle and non-contractile tissues such as platelets. Due to their possible antiplatelet effects, CCBs have been associated with an increased risk of hemorrhage, epistaxis, and prolonged bleeding time. The same may hold true for topiramate.
CONCLUSIONS: Topiramate, particularly in combination with antiplatelet medications, may be associated with severe, intractable epistaxis. Intractable epistaxis should be added to the list of potentially serious adverse reactions that are monitored when topiramate is administered.
Key Words: epistaxis, topiramate
Published Online, July 5, 2006. www.theannals.com, DOI 10.1345/aph.1H078
As topiramate continues to be prescribed outside its FDA-approved labeling, exposure of a larger patient population augments the emergence of new adverse effects and possible drug-drug interactions. We report a case of severe, intractable epistaxis warranting multiple emergency department (ED) visits and hospital admission in a patient with significant cardiovascular disease after administration of topiramate for relief of neuropathic pain.
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Three months prior to this visit, the woman had been admitted to the hospital for unstable angina; a paclitaxel-eluting stent was placed in her right coronary artery at that time. During that admission, oral therapy consisting of atorvastatin 40 mg at bedtime, metoprolol succinate 150 mg daily, clopidogrel 75 mg daily, and aspirin 325 mg daily was added to the patient's chronic medication regimen. She denied taking any over-the-counter drugs or alternative agents. She had no known drug allergies, had smoked 2 packs of cigarettes a day for 30 years but quit 4 years previously, and consumed no alcohol.
On presentation, the patient's blood pressure was well controlled, at 125/75 mm Hg, with a heart rate of 65 beats/min. Results of all blood tests, including a metabolic panel, complete blood cell count, and liver function tests, were within normal limits. After diagnosing her with diabetic peripheral neuropathy, the patient's physician initiated topiramate 25 mg orally, to be administered at bedtime, and instructed her to increase the dose to twice daily after the first week. Seven days after the 25 mg/day dose was started, the pain slowly decreased in severity; however, the woman began experiencing daily, copious nosebleeds that lasted 1-2 hours. After contacting the physician on the second day of epistaxis, she was instructed to reduce the aspirin dose to 162 mg, initiate nasal saline washes 3 times daily, and use a humidifier in her house and at work.
While self-care therapy provided some mild intermittent relief, the nosebleeds continued. After 8 total days of epistaxis, the patient experienced another episode that lasted 4 hours and was beyond containment. She immediately went to the ED, where an otolaryngologist detected minor mucosal irritation along the middle and interior turbinates and lateral nasal wall. Based on these findings and presentation, he felt that the bleeding was primarily posterior in origin. Trauma, infection, septal deviation, and nasal neoplasm were ruled out as precipitating causes. Both nasal cavities were packed with nasal tampons, and the patient was instructed to follow up with her primary care physician. Three days after the ED visit, the nasal tampons were removed. While antiplatelet therapy was believed to be the culprit for the bleeding, the physician discontinued topiramate due to its temporal association with the epistaxis. He then prescribed gabapentin 300 mg to be taken at bedtime, increasing the dose by 300 mg each week to a total dose of 300 mg 3 times daily. One week after topiramate was stopped, the nosebleeds completely resolved. The patient remained on gabapentin for 3 months with some relief of her neuropathic pain; however, she could not tolerate the sedation associated with gabapentin and requested another trial of topiramate. Reluctantly, the physician agreed and reinitiated topiramate at 25 mg daily.
Four days after topiramate therapy was started, the nosebleeds began again, but with a greater severity and longer duration (>4 h). After 2 days of epistaxis, the patient went to the ED and reported dull, substernal, nonradiating chest pain that she rated as 6 out of 10 on a severity scale. The chest pain was associated with shortness of breath, nausea, and vomiting; there was no diaphoresis. Her blood pressure on admission was 100/75 mm Hg, heart rate was 70 beats/min, and oxygen saturation was 93% on room air. The hemoglobin level was 10.8 g/dL and hematocrit was 26% (baseline values 13 g/dL and 35%, respectively). All other laboratory values, which included a basic metabolic panel, liver function tests, and a complete blood cell count, were within normal limits. An electrocardiogram and serum troponin level were negative for ischemic etiology, and the woman's pain was quickly controlled with morphine after no relief had been shown with sublingual nitroglycerin. Due to the possibility of stent restenosis, the patient was admitted to the cardiology service for evaluation. Immediately, she received 2 units of packed red blood cells (PRBCs), and her volume was restored with intravenous infusion of NaCl 0.9%.
Within 8 hours, these interventions restored the hematocrit level to 33%. The patient was also administered 2 L of oxygen by mask, both nasal cavities were packed with nasal tampons, and topiramate was discontinued (all other chronic medications were continued). At this point, a Medwatch form was completed and submitted to both the hospital's medication safety coordinator and the FDA. On hospital day 2, a pharmacologic stress test revealed no change in her ischemic condition, and a pulmonary embolism, as well as upper and lower gastrointestinal bleeding evaluated with endoscopy, were ruled out. The etiology of the anginal symptoms was attributed to blood loss associated with intractable epistaxis.
Seventy-two hours after the chest pain had resolved, the patient's nasal tampons were removed; she was discharged on hospital day 3. All long-term medications were continued, with the addition of gabapentin 300 mg twice daily and amitriptyline 25 mg at bedtime for neuropathic pain. Three days after hospital discharge and 7 days after stopping topiramate, the patient's nosebleeds ceased. After 6 months, she remained free of chest pain, with no further development of epistaxis, anemia, or neuropathic pain.
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To our knowledge, as of June 23, 2006, this is the first case to document intractable epistaxis warranting hospital admission and administration of PRBCs in a patient receiving topiramate. During controlled clinical trials for adults with epilepsy, epistaxis was reported in 1-2% of patients receiving topiramate, compared with 1% of those receiving placebo.1 In pediatric patients with epilepsy, this percentage increased to 4% for those receiving topiramate, compared with 1% in the control group. Out of 1367 patients who received treatment with topiramate for migraine prophylaxis, more than 1% reported epistaxis. While these numbers appear relatively low, it should be noted that many patients in these clinical trials were younger than 65 years of age and may not have had comorbid cardiovascular or cerebrovascular conditions warranting additional antiplatelet and/or anticoagulant therapy.
The possible etiology behind topiramate-induced epistaxis requires a
comparative analysis of the drug's pharmacology with other L type channel
blockers. Topiramate acts on neuronal transmission in at least 5 different
ways: modulation of voltage-gated sodium channels, potentiation of
-aminobutyric acid inhibition, blockade of excitatory glutamate
neurotransmission, inhibition of carbonic anhydrase, and modulation of
voltage-gated N and L type calcium ion
channels.7
Like topiramate, calcium-channel blockers (CCBs) also modulate voltage-gated L
type calcium ion channels. In fact, animal seizure models have suggested that
pretreatment with verapamil and nifedipine may either attenuate or block
topiramate's anticonvulsant
activity.7,8
CCBs have been associated with an elevated risk of bleeding, epistaxis, and/or
prolonged bleeding times due to their possible antiplatelet effects; however,
these have not been previously reported with
topiramate.9-15
In the CONVINCE (Controlled Onset Verapamil Investigation of Cardiovascular
Endpoints) trial, 16 602 patients with hypertension and one additional
cardiovascular risk factor were randomized to receive controlled-onset,
extended-release verapamil; atenolol; or
hydrochlorothiazide.16
After 3 years, those who received verapamil had a significantly higher risk of
death or hospitalization due to bleeding (HR 1.54; p = 0.003) compared with
those receiving a diuretic or ß-blocker. Studies have shown that adding a
CCB to low-dose aspirin (40-100 mg/day) may also have partial additive
antiplatelet
effects.17,18
However, all of these data are controversial, and other studies have been
published that refute these
findings.17,19-21
While the true antiplatelet etiology of CCBs remains unclear, one possible mechanism may be modulation of trans-membrane calcium fluxes through blockade of platelet L type calcium ion channels.22,23 Therefore, if topiramate blocks L type calcium ion channels like the CCBs, it would seem plausible that topiramate may also exert an antiplatelet effect through a similar mechanism, thereby increasing the risk of epistaxis. However, because topiramate's effects on platelet aggregation have not been evaluated, this is purely hypothetical.
Our case report does have several limitations. First, topiramate's role for the management of diabetic peripheral neuropathy has been questionable. While the drug is used in clinical practice for this disorder, 3 placebo-controlled studies with topiramate did not demonstrate significance in this population.24 Therefore, our patient received therapy that has not been sufficiently studied for her specific type of neuropathic pain. Second, she was receiving concomitant clopidogrel, aspirin, and prednisone, all of which increase the risk of bleeding. However, the patient had been taking prednisone for over a year, as well as clopidogrel, aspirin, and prednisone together for 3 months prior to topiramate exposure, with no report of bleeding and/or epistaxis. Third, it is difficult to distinguish whether this adverse reaction was the result of an interaction between topiramate and clopidogrel, aspirin, and/or prednisone or topiramate acting independently. From a pharmacokinetic standpoint, topiramate does not interfere with the metabolism, distribution, and/or elimination of any of the patient's medications and vice versa.25 However, pharmacodynamically, topiramate could have exerted an additive antiplatelet effect with clopidogrel, aspirin, and/or prednisone. Other than this potential pharmacodynamic interaction, no other drug-drug interaction could be identified. Furthermore, as discussed earlier, our theory relating to an antiplatelet effect of topiramate requires further analysis.
We also cannot exclude the possibility that the epistaxis may have been idiopathic in origin or associated with the patient's hypertension. While hypertension has been cited as a possible risk factor for epistaxis, population-based studies have not confirmed a definite association between elevated blood pressure and the incidence of nosebleeds.6,26 Furthermore, with each epistaxis occurrence, our patient's blood pressure was well controlled according to national guidelines. However, the temporal association of topiramate with the multiple reappearance of epistaxis, along with the lack of other local or systemic causes, strongly suggests topiramate as the culprit. Based on the Naranjo probability scale, topiramate was the probable cause of this adverse reaction.27
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