Erectile dysfunction: Three rare cases of Qsymia side effect

Phentermine and topiramate, sold under the brand name Qsymia, is intended to be used as an adjunct to a reduced-calorie diet along with increased physical activity in patients with obesity (a body mass index (BMI) greater than 30 kg/m² or a BMI of 27 kg/m² or greater and who have at least one weight-related comorbidity) [1]. Phentermine is a sympathomimetic amine that reduces appetite through central nervous system (CNS) effects including releasing norepinephrine via hypothalamus stimulation. For topiramate, it is suspected to suppress appetite and enhance satiety through a combination of mechanisms including blocking neuronal voltage-dependent sodium channels, enhancing GABA(A) activity, antagonizing AMPA/kainite glutamate receptors, and weakly inhibiting carbonic anhydrase [2]. According to the result of the one-year Phase III trial of Qsymia, there is no report of adverse events related to sexual dysfunction (SD). The most frequent adverse events of clinical interest with full-dose were paresthesia (20%), dry mouth (19%), constipation (16%), dysgeusia (9%), insomnia (9%), and dizziness (9%) [3]. Though previous animal study has shown long-term topiramate ingestion produces adverse effects on fertility and reproductive system in adult male rat [4] and limited observational studies indicates 9% patients with psychiatric disorder reported topiramate-associated SD [5], there is no current report of erectile dysfunction (ED) for patients with obesity on Qsymia. In this case report and literature review, we present three extremely rare cases of male patients with obesity experiencing ED after starting Qsymia with two cases demonstrating reversibility.

Case 1

A 50-year-old male with a history of secondary hypogonadism, hypertension, prediabetes, and obesity (BMI 32.7) taking Androgel 3 pumps daily for six years was started on Qsymia; the patient was on Qsymia 7.5 mg/46 mg daily for weight management alongside recommendation for lifestyle and diet modification. During his four-month follow-up, the patient reported decrease in erection frequency (2–3 morning erections per week to 1 per week) and duration as well as difficulty in erection maintenance since he started Qsymia. He also reported other common self-resolved adverse effects noted with Qsymia including exacerbated nearsightedness and dry mouth. His BMI has decreased to 25.8 according to self-report. Despite significant weight loss, the decision was made to taper off Qsymia. In addition, the Androgel dose was increased to 4 pumps daily. Two months after stopping Qsymia and increasing Androgel dose, the patient reported complete resolution of ED. The patient has been managing his obesity well with lifestyle modification, diet modification, and exercise.

Case 2

A 48-year-old male with a history of anxiety, irritable bowel syndrome, insomnia, depression, post-traumatic stress disorder (PTSD), and class II obesity (BMI 36.85) was started on Qsymia. The patient was on Qsymia 7.5 mg/46 mg daily for weight management alongside recommendation for lifestyle and diet modification. During his two-month follow-up appointment, he complained about ED along with constipation and mood swings after starting Qsymia. Since the medication is effective in weight management (15-pound weight loss with BMI of 34.7), we decided to increase Qsymia to maximum dose (15 mg/92 mg) while starting the patient on Viagra 25 mg as needed (PRN) to treat ED. During his six-month follow-up, the patient continued to report constipation as an adverse effect. The Viagra 25 mg PRN treatment is effective in reversing his ED and he continued to benefit from Qsymia (12-pound weight loss since last visit).

Case 3

A 45-year-old male with a history of anxiety, hypertension, gastroesophageal lux disease (GERD), alcohol dependence, and class III obesity (BMI 40.92) that underwent vasectomy taking Sildenafil 25 mg as needed was started on Qsymia. Patient was on Qsymia 7.5 mg/46 mg daily for weight management alongside recommendation for lifestyle and diet modification. During his six-month follow-up appointment, he reported ED while taking Sildenafil as before in addition to the common adverse effect of dry mouth. He lost 15 pounds on Qsymia and is now classified as class II obesity (BMI 39.96). Despite the adverse effect of ED, the patient is satisfied with weight loss and pers to continue Qsymia.

Erectile dysfunction is defined as the failure to achieve or maintain a rigid penile erection suitable for satisfactory sexual intercourse. Penile erection is achieved via the relaxation of the intracavernosal smooth muscle which allows increased blood flow into the corpora cavernosa. Nitric oxide (NO) released by the cavernous nerve terminals initiate the erection process while NO from endothelial cells maintain it [6].

The cause of ED is multifactorial involving underlying psychological causes (i.e., performance anxiety) and/or an organic etiology. Among all causes of ED, prescription medications contribute to one-quarter of them and common medications that have ED listed as a common side effect including most antidepressants, thiazide diuretics, and other antihypertensives [6]. Comorbidities for ED include age, hypertension, obesity, cardiovascular disease (CVD), benign prostate hyperplasia (BPH), and anxiety/depression [7]. For obesity, according to the meta-analysis performed by Pizzol et al., prevalence of ED is 31% higher for overweight men and 60% high for men with obesity. It is hypothesized that adipocytes contain high expression of aromatase which enzymatically converts testosterone to estradiol decreasing circulating androgens level. Androgens not only enhances sexual desire but also positively regulates NO synthase in the penis which both contributes to initiation and maintenance of an erection [8].

Since Qsymia is indicated for obesity, the prevalence of ED is higher in patients who are taking the medication compared to healthy men. In addition, all three patients reported have additional comorbidities for ED (Table 1): hypertension, anxiety/depression, and age (above 40 years old) [6]. While the patients reported are at significantly higher risk in developing ED due to having multiple comorbidities and two out of three patients have ED predispositions (Table 1), all three patients reported ED onset or increase in severity after starting recommended dose of Qsymia and two patients’ ED demonstrated reversibility (Table 1). Theore, it is reasonable to suspect the reported ED is due to Qsymia. However, reversibility of ED after stopping Qsymia alone cannot be established due to only having two patient cases reported here. In addition, Qsymia alone is causing ED as the side effect cannot be established as patients 1 and 2 received additional treatments in addition to discontinuation of Qsymia. Further evidence such as discontinuation of the medication alone or switching to a different weight loss drug lead to ED reversal is needed to confirm the suspicion.

The components of Qsymia are Phentermine and Topiramate. There is no primary literature on Phentermine causing ED except decrease in libido. For Topiramate, there has been one case report of a 52-year-old man taking it for alcohol dependence experiencing ED when the dose was raised to 50 mg and several cases of patients taking it for epilepsy. All of the reported Topiramate-induced ED are dose-dependent (symptom development at 50–300 mg) and reversible with medication discontinuation [9]. The proposed mechanisms of Topiramate causing reversible ED include vasogenic [10] and reducing free testosterone levels or affecting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamatergic pathways impacting penile blood flow [11],[12].

The dosage of Topiramate taken by the patients when they reported ED was 46 mg which is close to the dose that develops symptoms (50 mg). It is also possible that the decrease in libido due to Phentermine enhances the effect of Topiramate-induced ED.

Despite the reported ED, all three patients noted sufficient therapeutic effect (Table 1). Given the effectiveness of Qsymia in treating obesity compared to monotherapy of Phentermine, the limited cases reported for Qsymia-induced ED [13] and the reversibility of the adverse effect, Qsymia should remain as therapy for obesity regardless of whether the patient has additional comorbidities(s) for ED. However, physicians should be informed about this side effects while waiting for future data to confirm causality and guide management.

All in all, ED remains an exceedingly rare adverse effect of Phentermine and Topiramate. The three patients reported are the only ones described in the literature.