Update on drug safety evaluation of naltrexone/bupropion for the treatment of obesity

KEYWORDS:

• Bupropion
• contrave
• naltrexone
• obesity
• psoriasis
• opioid resistant analgesia

1. Introduction

The long-term management of obesity is challenging for patients and health care providers. In addition to lifestyle interventions, there are several pharmacotherapies and bariatric surgical options available. Of the five prescription-only pharmacotherapies currently available on the US market for the long-term management of obesity, three of these medications naltrexone/bupropion extended release (ER), orlistat, and liraglutide, are not scheduled by the DEA as a controlled substance. In 2014, the FDA approved naltrexone/bupropion ER, which is a novel formulation of two generic medications under US patent exclusivity through 2030 and is sold as Contrave® by Nalpropion Pharmaceuticals [1]. This editorial will update the reported adverse effects of naltrexone/bupropion ER since FDA approval. Although the novel formation provides a combination interaction to sustain moderate weight loss (4–5% placebo subtracted) [2,3], the safety profile of naltrexone/bupropion ER is still emerging as the prescription volume increases and the medication becomes more available on the US markets.

2. Safety evaluation of naltrexone/bupropion ER

2.1. Naltrexone as a monotherapy for obesity

The first generic component of Contrave® is naltrexone HCl [(5α)-17-(cyclopropylmethyl)-3,14-dihydroxy-4,5-epoxymorphinan-6-one], which is an opioid receptor antagonist approved by FDA for the treatment of opioid dependence in 1984 [4]. Naltrexone HCl was approved in 1994 for the treatment of alcohol dependence and is currently available as a generic medication (50 mg tablets) [5]. When used as a monotherapy for obesity, however, naltrexone has not produced meaningful weight loss, even at high doses (300 mg/day) [6–8]. In clinical populations, the most frequent (≥ 10%) naltrexone treatment emergent adverse effects (TEAE) are sleep disturbances, anxiety, nervousness, abdominal pains, nausea with or without vomiting, fatigue, joint and muscle pain, and headache [9]. Administration of high doses of naltrexone (200–300 mg/day) for weight loss in obese subjects has resulted in a reversible elevation of hepatic transaminases [7,9]. For the 200 mg/day 10-week treatment (n = 51), three subjects (5%) had a twofold increase in hepatic transaminases [7]. A higher number of obese subjects (19%) reported elevated transaminases with 300 mg/day naltrexone and older adults appear to be more susceptible to the high-dose naltrexone-induced transaminase elevation [10].

2.2. Bupropion as a monotherapy for obesity

The second genic component of Contrave® is bupropion HCl [2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one], which is a nonselective inhibitor of the dopamine transporter (DAT) and norepinephrine transporter (NET) [11]. Approved by FDA for the treatment of major depressive disorder (MDD) in 1985, bupropion was also FDA-approved for smoking cessation in 1997 and seasonal affective disorder in 2006 [11–13]. One randomized placebo-controlled trial in obese subjects (n = 227) indicated that bupropion sustained release (SR; 300 mg/day or 400 mg/day) formulation resulted in a 2.2% (300 mg/day; placebo-subtracted) and 5.1% (400 mg/day; placebo-subtracted) weight loss at 24 weeks [14]. Subjects taking bupropion had an improved lipid profile at 24 weeks, with an increase in high-density lipoprotein (HDL) and reductions in triglyceride levels compared with placebo. Subjects maintained the weight loss for an additional 24 weeks (48 weeks in total) with treatment [14]. The most common (≥ 5%) TEAE with bupropion SR are insomnia, rhinitis, dry mouth, dizziness, nervous disturbance, anxiety, nausea, constipation, and arthralgia [15]. Bupropion immediate release and SR formulations have an FDA-issued neuropsychiatric black box warning label for suicide and suicide ideation [15].

2.3. Safety of naltrexone/bupropion ER for the long-term management of obesity

Contrave® is a fixed-dose, oral tablet, extended release formulation (naltrexone 8 mg/bupropion 90 mg) and patients are uptitrated to 4 tablets/day (naltrexone 32 mg/bupropion 360 mg) by week 4 of treatment [16]. The most common TEAEs (≥ 5%) of Contrave® are nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, and diarrhea [16]. In phase III trials of Contrave®, there were transient increases in heart rate and blood pressure [17,18]. In order to evaluate major adverse cardiovascular events (MACE; cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction) associated with Contrave® (naltrexone 32 mg/bupropion 360 mg/day), a large-scale FDA-mandated randomized noninferiority cardiovascular outcomes trial (n = 4455 Contrave®, 54.7% female; n = 4450 placebo, 54.4% female; NCT01601704) was initiated in June 2012 [19]. Subjects for this trial were obese (Body Mass Index; BMI mean was 36.6 kg/m², range 33.1–40.9 kg/m²; mean age was 61 years old) with an increased managed risk of adverse cardiovascular outcomes (85.2% had noninsulin-dependent diabetes mellitus; NIDDM, 32.1% had established cardiovascular disease, and 17.4% had both conditions) [19]. The primary outcome was time from trial randomization to first occurrence of MACE. The 50% interim analysis revealed that 90 subjects (2%) receiving Contrave® had a MACE, compared with 102 subjects (2.3%) receiving placebo. This resulted in a hazard ratio of 0.88 (0.57–1.34; CI 99.7%) [19]. Nonfatal stroke had a 1.10 hazard ratio (0.44–2.78; CI 99.7%), nonfatal myocardial infarction had a 1.00 hazard ratio (0.57–1.75; CI 99.7%), and cardiovascular death had a 0.50 hazard ratio (0.21–1.19; CI 99.7%) [19]. Data collected at 16 weeks indicated a + 0.9 mm Hg (placebo-subtracted) increase in systolic blood pressure in the Contrave®-treated group (p < 0.01) [19]. TEAE leading to study discontinuation were gastrointestinal (14.2% in Contrave® vs. 1.9% in placebo; p < 0.001), central nervous system (5.1% in Contrave® vs. 1.2% in placebo; p < 0.001), and psychiatric symptoms (3.1% in Contrave® vs. 0.9% in placebo; p < 0.001) [19]. The MACE outcomes study was prematurely terminated at the 50% interim analysis on 12 May 2015, at the recommendation of the executive steering committee of the trial. This recommendation for premature termination was due to the inclusion of the 25% interim analysis on patent publication in March 2015 and potential unblinding of the subject populations. In addition, the FDA concluded that because the 25% interim analysis included the release of ‘patient-level data listings’ to nonessential parties, the MACE outcomes study could not be used as primary data for the postapproval requirements for assessing cardiovascular outcomes. The 25% interim analysis had a 0.59 hazard ratio (0.39–0.90; 95% CI) for major cardiovascular events [19]. Nonetheless, the early termination of the MACE outcomes trial for Contrave® was not completed, and the FDA noninferiority cardiovascular safety criteria were not achieved.

As a consequence of the bupropion component, Contrave® has an FDA-issued neuropsychiatric black box warning label for suicide and suicide ideation [16]. In a pooled post-hoc analysis from five randomized clinical trials (1 Phase II, 4 Phase III), psychiatric adverse effects were evaluated by major subtopics, such as anxiety, depression, and sleep disorders. Additional evaluations were performed on depressive symptomology (Inventory of the Depressive Symptomatology Self Report; IDS-R) and suicidal ideation (Columbia Classification Algorithm of Suicide Assessment; C-CASA) structured assessments [20]. Pooled subjects had a mean BMI of 36.2 kg/m² (82.4% female) and were receiving naltrexone (32 mg)/bupropion (360–400 mg) ER (n = 2545) or placebo (n = 1515) [20]. Overall, psychiatric TEAE were more frequent with naltrexone/bupropion ER (22.2%) than with placebo (15.5%). The most commonly reported psychiatric TEAE were insomnia, anxiety, and irritability. When the reported TEAE were evaluated based on subtopics, only sleep disorders were significantly different for naltrexone/bupropion ER (13.8%) compared with placebo (8.4%) (p < 0.001) [20]. The mean duration for sleep disorders was 5 weeks for naltrexone/bupropion ER compared with 6 weeks for placebo. The IDS-R treatment emergent depression scores indicated sadness was 3.5% for naltrexone/bupropion ER compared with 3.4% for placebo. Anxiety/tension scores were observed in 6.4% for naltrexone/bupropion ER compared with 4.8% for placebo, which were not significantly different [20]. From the pooled analysis, there were four events of suicide (one in the naltrexone/bupropion ER group vs. three in the placebo group). Treatment emergent suicide ideation was not endorsed by C-CASA for naltrexone/bupropion ER and strongly suggested no overall difference in risk compared with placebo (−0.00018) [20]. Overall, the pooled analyses of the clinical trials of Contrave® suggest higher frequency of psychiatric TEAE than placebo, specifically for sleep disorders, but the data do not indicate an increased risk for suicide or suicide ideation. It should be noted that the patients in the pooled analyses were excluded if they had a serious psychiatric illness and needed psychiatric medications in the previous 6 months. Subjects were also excluded if they had a history of drug or alcohol use within the past year. As such, the subject population in the pooled analysis may not be entirely representative of clinical populations seeking pharmacotherapy for obesity.

2.4. Additional reported safety concerns with naltrexone/bupropion ER

Since FDA approval, only two case reports have reported adverse effects associated with Contrave® [21,22]. The first case was of a 55 year-old obese (BMI 47.75 kg/m²) woman presenting with a body-wide rash with an onset 3 week after initiating Contrave®. During the 3 week uptitration period, she was taking three tablets of Contrave® per day (two tablets in the morning/one tablet at night; 24 mg naltrexone/270 mg bupropion/day). She was also taking esomeprazole (40 mg) for gastric reflux, calciferol, and cyanocobalamin. Patient had no history of psoriasis. Her rash was characterized as a generalized and erythrodermic pustular psoriasis. Contrave® was discontinued and the patient was prescribed cyclosporine for immunosuppression [22]. Rare skin reactions have been associated bupropion [15]. As such, the bupropion component of Contrave® was speculated to have caused the skin reaction reported in this case. The second case was a 42 year-old obese (BMI 30.2 kg/m²) woman that was presented for spine surgery of cervical radiculopathy. She had been taking Contrave® for 6 months prior to surgery for the long-term management of obesity and she was also taking alprazolam for anxiety. Both medications were discontinued 12 h prior to surgery. The patient experienced increased postoperative pain that was managed by a hydromorphone patient-controlled analgesic (PCA; 0.3 mg bolus/8 min) intravenous pump. A single episode of oxygen desaturation (82% oxygen) was observed while managing the patient’s pain in a step-down unit. The hydromorphone PCA was discontinued on postoperative day 1, and pain was managed by oral hydromorphone on postoperative day 2 before discharge [21]. Opioid antagonist reversal regimens for pain management are recommended for patients receiving naltrexone for the management of alcoholism [14]. Because of this, similar opioid antagonist reversal regimens are recommended for use with Contrave® in clinical pain management settings [16].

3. Expert opinion

Naltrexone/bupropion ER is a well-tolerated safe medication for the long-term management of obesity. Despite being FDA-approved in 2014, several important safety concerns are still unanswered for use of the medication by the general population. Because obesity is a chronic disease and requires, in some cases, long-term management (i.e. > 52 weeks), data regarding the longer-term efficacy and safety for naltrexone/bupropion ER are needed in the postapproval phase. Only one double-blind placebo-controlled study has examined naltrexone/bupropion ER beyond the year (> 52-week) period needed to obtain FDA approval [19]. In the large-scale randomized noninferiority cardiovascular outcomes trial that was prematurely discontinued, naltrexone/bupropion ER resulted in 2.5% (placebo-subtracted) weight loss at 104 weeks (n = 2408 naltrexone/bupropion-treated subjects, n = 2264 placebo-treated subjects) [19]. Interestingly, the reported efficacy in this longer-term study is about half of the reported mean efficacy weight loss reported in the phase III clinical trials of naltrexone/bupropion ER for FDA approval [21]. In the 104 week study, however, MACE was the primary study endpoint, not weight loss [19]. Despite the large-scale efforts of the randomized noninferiority cardiovascular outcomes trial [19], the FDA requirement for cardiovascular safety still has not been met. Longer-term studies are also needed to fully characterize the potential of naltrexone/bupropion ER-induced hepatic dysfunction, because liver diseases and hepatic impairment are often associated with obesity [23]. While there is a stated hepatic risk on the labeling for naltrexone/bupropion ER, longer evaluation periods are needed. Although elevated hepatic transaminases were reported with high-dose naltrexone (≥ 200 mg/day) in obese subjects treated in the short-term (≤ 10 weeks) [7–10]. It is unclear whether naltrexone (32 mg) in Contrave® for longer periods (≥ 52 weeks) would result in hepatic impairments in obese individuals.

Contrave® has a real challenge for increasing its 5-year trajectory for patient care. The ill-advised or management misstep of the public release of 25% interim analysis of naltrexone/bupropion ER has certainly diminished the long-term impact of Contrave® on US markets and the continuing financial outlook. In addition, a head-to head comparison with other medications, such as liraglutide or orlistat, would be beneficial for assessing the comparative safety profile of Contrave® in the current obesity medication landscape.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are a speaker for Novo Nordisk and Jansen Pharmaceuticals and are a shareholder in Zafgen and Vivus. All other peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Acknowledgments

The author would like to thank Dr. Kathy Manger for her editorial assistance.

Additional information

Funding

This paper was not funded.