Key words: Antiepileptic drugs * Carbamazepine * Epilepsy * Erectile dysfunction * Oxcarbazepine
ABSTRACT
Oxcarbazepine is an antiepileptic drug (AED) indicated for use as monotherapy and add-on therapy in adults and children 4 years of age and older. Despite being structurally related to carbamazepine, oxcarbazepine differs substantially in its pharmacokinetic and safety profile; oxcarbazepine has a much lower risk of pharmacokinetic drug-drug interactions than carbamazepine. Carbamazepine has also been shown to induce the hepatic synthesis of sex hormone-binding globulin, thus reducing free serum testosterone levels and possibly causing erectile dysfunction (ED) in some men; these effects have not been observed with oxcarbazepine. This paper provides a discussion of recent clinical experience with men who presented in private clinical practice with complaints of ED while being treated with carbamazepine for seizure disorders. The four illustrative case studies presented in this report suggest that switching AED treatment from carbamazepine to oxcarbazepine in men with epilepsy can reduce the ED side effects observed with carbamazepine.
Introduction
Carbamazepine is a commonly used antiepileptic drug (AED) that is associated with a wide range of adverse reactions, including central nervous system dysfunction; gastrointestinal, hepatic, and endocrine disturbances; and teratogenic effects1. In addition, carbamazepine can increase plasma levels of sex hormone-binding globulin (SHBG), consequently decreasing the unbound biologically active form of testosterone, which leads to sexual dysfunction in some men2,3. In particular, complaints of erectile dysfunction (ED), hypoactive sexual desire disorder, inhibited orgasm, and premature ejaculation have been reported in men taking carbamazepine4-5.
Oxcarbazepine, a more recently developed AED, is indicated for use in the United States as monotherapy or adjunctive therapy in adult and pediatric patients ≥ 4 years old with partial seizures with or without secondary generalization. Oxcarbazepine is a structural variant of carbamazepine, although results from preclinical and clinical studies have demonstrated some distinct differences between the two drugs. In particular, oxcarbazepine is associated with fewer side effects and appears to be better tolerated than carbamazepine6’7. Oxcarbazepine does not increase the risk of sexual side effects; despite observed hormonal changes at high doses in one study, SHBG levels were increased but testosterone activity was unaffected8.
The lack of sexual side effects associated with oxcarbazepine suggests that the ED in men who are taking carbamazepine will improve once they are switched to oxcarbazepine. In fact, normalized endocrine effects, namely restoration of normal SHBG plasma levels, were observed after carbamazepine was replaced with oxcarbazepine9. The following case presentations illustrate the effect of this hormonal normalization after a switch in anticonvulsant regimen; the erectile function in four men who experienced ED while being treated with carbamazepine improved after being switched to oxcarbazepine (see Table 1 for a summary of the most relevant data from these cases). These men were all seen in a neurology epilepsy practice at the University Hospital and were selected for inclusion in this report based on information they volunteered without direct questioning by the physician during follow-up visits. We originally identified these patients in an informal case review, from among those who visited the clinic over the previous two months.
Case 1
This 221-pound, 48-year-old married man (TM; here and later, these are not real patient initials] is a maintenance worker at a large northeastern university. TM has a history since childhood of simple and complex partial seizures progressing to generalized seizures; the etiology of his epilepsy is postnatal meningitis leading to cortical vein thrombosis. Magnetic resonance imaging (MRI) indicated encephalomacia in the right temporal lobe, and a computed tomography scan showed abnormalities in the right frontotemporal-parietal region. An electroencephalogram obtained in 1986 indicated bilateral abnormalities.
The patient’s AED treatment history included primidone, phenobarbital, phenytoin, and carbamazepine; however, the refractory nature of his seizure disorder prompted physicians to perform a right temporal lobectomy. There were no postsurgical complications, and adequate seizure control was achieved with carbamazepine 2200mg/ day monotherapy. However, TM complained of ED and decreased libido during the course of his AED therapy that was most severe with phenytoin and improved only somewhat after he was switched to carbamazepine. Conditions such as vascular disease or major depressive disorder (MDD) were ruled out as the cause of his ED. Nevertheless, TM tolerated the sexual side effect of carbamazepine because his seizures were well controlled by the medication.
Table 1. Summary of data from case studies
TM began to experience intolerable visual side effects (blurring and diplopia) on carbamazepine and was switched to monotherapy with oxcarbazepine dosed initially at 3000mg/day and tapered to 2700mg/ day. His seizures remained well controlled, and the visual abnormalities resolved within a few days after the initiation of oxcarbazepine. Moreover, at the next follow-up visit, TM volunteered that he was experiencing a substantially increased libido and improved erections that enabled satisfactory sexual intercourse. Clinical laboratory analyses conducted after the switch to oxcarbazepine indicated no abnormalities in liver function test results, serum sodium levels, or plasma lipid profile. His most recent serum testosterone level was 306ng/dL (10.6nmol/L), normal range 241-827ng/dL (8.4-28.7nmol/L), and steady-state concentration of oxcarbazepine monohydroxy derivative (MHD) was 34g/mL. TM remains seizure free on oxcarbazepine monotherapy and is satisfied with his sexual function. The treatment plan is to further taper the oxcarbazepine dose to 2400mg/day.
Case 2
This 224-pound, 51-year-old man (SF) works for a pharmaceutical company and has been married for 14 years. He has hypertension that is being controlled with antihypertensive polytherapy. He began experiencing seizures in 2001, most probably secondary to a mild stroke, although an MRI revealed no abnormalities. SF experienced normal erectile function while receiving only antihypertensive therapy, but complained of ED with normal libido upon coadministration of carbamazepine. SF accepted this adverse effect because his seizures were well controlled and, when offered sildenafil as a treatment for his ED, he refused. However, SF subsequently requested the carbamazepine be discontinued because it interfered with his concentration at work.
One year ago, SF was switched to oxcarbazepine 1500-1800 mg/day. The change significantly improved his erectile function but caused dizziness, nausea, and hyponatremia (serum sodium 125mEq/L [125mmol/ L], which improved with fluid restriction to 131mEq/L [131 mmol/ L]); all adverse effects resolved after 3 months of oxcarbazepine treatment. His most recent serum testosterone level was 421 ng/ dL (14.6nmol/L), normal range 241-827ng/dL (8.4-28.7nmol/L), and his MHD concentration was 36g/mL. He remains seizure free with normal erectile function on oxcarbazepine monotherapy.
Case 3
This 225-pound, 50-year-old married man (JD) who works for a delivery service began to experience seizures in 1997, most often simple partial with occasional generalized involvement. His MRI was normal, and his two most recent electroencephalograms revealed normal findings. He had sleep apnea and elevated serum lipids (low- density lipoprotein cholesterol and triglycerides), although his blood pressure was normal. He was also diagnosed with MDD, which was treated unsuccessfully with fluoxetine, escitalopram, and sertraline; he is currently maintained on extended-release venlafaxine 112.5mg/day. While JD’s seizures were controlled on carbamazepine, he experienced ED with normal libido for which he was prescribed 1OO mg sildenafil. After being switched to oxcarbazepine dosed initially at 2400 mg/day and tapered to 1800 mg/day, he experienced improvement in erectile function; his sildenafil dose was reduced to 50 mg and then ultimately discontinued. His most recent testosterone level was 328ng/dL (11.4nmol/L), normal range 241-827ng/dL (8.4-28.7nmol/L), and his MHD concentration was 29g/ mL. His seizures are currently well controlled on oxcarbazepine 1800 mg/day.
Case 4
This 191-pound, divorced, 60-year-old man (BV) works occasionally as a laborer, loading and unloading trucks. He has had partial complex seizures since childhood that were not completely controlled by AED therapy, and he underwent a left temporal lobectomy in 1985. BV has hypertension that is currently managed with ramipril and MDD currently managed with paroxetine SOmg/day.
Postsurgically, BVs seizures were controlled with carbamazepine 1800mg/day, but he experienced ED that was managed with sildenafil 50mg/day. He was switched to oxcarbazepine 2400mg/day 1 year ago, and his ED improved significantly within 3 months. For the past 9 months, he has not required the sildenafil to achieve erections satisfacto\ry enough to engage in sexual intercourse. His most recent MHD concentration was 37g/mL; a testosterone level was not obtained. BVs seizures are currently well controlled on oxcarbazepine 1800mg/day.
Discussion
Because sexual function is an important aspect of the male identity10, ED can significantly affect a man’s quality of life and perception of self. Sexual dysfunction, including ED, occurs in nearly two thirds of people with epilepsy and is attributed to changes in sex hormone levels due to the disease or treatment with AEDs11. In particular, iatrogenic sexual dysfunction in men resulting from carbamazepine has been well documented4’5. As shown in the four cases of men with epilepsy presented in this report, switching from carbamazepine to oxcarbazepine may have significantly improved erectile function in carbamazepine-induced ED.
Carbamazepine has been shown to significantly increase plasma levels of SHBG and consequently decrease free testosterone in men. Brunei et al. measured SHBG levels and free testosterone index in 51 men with epilepsy12. Their results showed that patients receiving carbamazepine monotherapy had higher concentrations of SHBG and lower levels of free testosterone than control subjects; AEDs such as carbamazepine may induce the hepatic synthesis of SHBG, leading to reduced serum testosterone levels. Rtty et al. reported similar results in 22 men recently diagnosed with epilepsy who began treatment with carbamazepine13. These patients had increased serum SHBG levels, reduced dehydroepiandrosterone sulfate, and a decreased free-androgen index. Results from other studies in individuals without epilepsy showed that low levels of free testosterone and elevated concentrations of SHBG are both associated with ED14-16.
Given that oxcarbazepine does not induce hepatic metabolism17, it should have fewer deleterious effects on SHBG than carbamazepine. The results from Rtty et al. suggest that, unlike with carbamazepine, serum testosterone, gonadotropins, and SHBG concentrations were normal in men receiving low doses of oxcarbazepine (
The cases presented here support research findings on the influence of AEDs on sex hormone levels and erectile function. In 3 of the 4 patients, testosterone levels were measured during oxcarbazepine therapy to ensure levels were within the normal range. However, testosterone levels were not measured prior to switching therapy from carbamazepine to oxcarbazepine; such data would have been interesting to have to confirm a hormonal basis for the ED experienced with carbamazepine. Oxcarbazepine and carbamazepine are clinically distinctly different medications, and oxcarbazepine may be preferred for the treatment of men with epilepsy to avoid the potential risk of ED17. More formal studies are needed to evaluate the precise mechanisms involved in anticonvulsant-induced sexual dysfunction, specifically ED and decreased libido.
Acknowledgment
This case study report was supported by an unrestricted educational grant from Novartis Pharmaceuticals.
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http://www.cmrojournal.com
Paper CMRO-2946_4, Accepted for publication: 03 May 2005
Published Online: 03 June 2005
doi: 10.1185/030079905X50561
Rajesh Sachdeo(a) and Revathi R. Sathyan(b)
a Clinical Professor of Neurology, University of Medicine and Dentistry of New Jersey; Director, NJ Comprehensive Epilepsy Center, Saint Peter’s University Hospital, New Brunswick, NJ, USA
b Research Assistant, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ, USA
Address for correspondence: Rajesh Sachdeo, MD, Director, NJ Comprehensive Epilepsy Center, St. Peter’s University Hospital, 254 Easton Avenue, CARES Building, 4th floor, New Brunswick, NJ 08903, USA. Tel.: +1 (732) 565-5478; Fax: +1 (732) 745-2980; email: [email protected]
Copyright Librapharm Jul 2005
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