Vyvanse (Lisdexamfetamine) After Bariatric Surgery: What Clinicians and Patients Need to Know

How Vyvanse is absorbed and switched on

Lisdexamfetamine is an inactive prodrug. The capsule delivers a molecule that has to be split before dextroamphetamine, the active stimulant, appears in the body [1]. The Vyvanse label places that split mainly in the blood, carried out by red blood cells, and states that cytochrome P450 enzymes are not involved; in vitro the parent drug does not bind norepinephrine or dopamine reuptake sites [1].

About 96% of an oral dose is recovered in urine: 42% as amphetamine, 25% as hippuric acid and 2% as unchanged lisdexamfetamine [1]. In children aged 6 to 12 taking a capsule fasted, lisdexamfetamine peaks at about 1 hour and dextroamphetamine at about 3.5 hours; food moves the dextroamphetamine peak about an hour later without changing AUC or Cmax [1]. In a phase 1 study of six healthy adults given a single 70 mg oral dose in solution after a fast, median time to peak dextroamphetamine was 3.0 hours and terminal half-life was 10.39 hours [4]. The label gives average dextroamphetamine half-lives of about 10 to 11.3 hours in healthy adults and 8.6 to 9.5 hours in children 6 to 12 [1].

Does a bypassed duodenum stop the conversion?

Roux-en-Y gastric bypass sends food past the entire duodenum [5]. It is easy to assume this removes the enzymes that switch Vyvanse on. The label does not describe conversion as a gut-wall process; it describes conversion in red blood cells, after the prodrug has been absorbed [1].

What surgery does to oral absorption in general

A systematic review of 26 studies of drug absorption after bariatric surgery found that the effect is drug-specific rather than uniform. Evidence for diminished absorption was found in 15 of 22 jejunoileal bypass studies, 1 of 3 gastric bypass or gastroplasty studies and 0 of 1 biliopancreatic diversion study. The strongest evidence involved cyclosporine, thyroxine, phenytoin and rifampin, and the authors noted that drugs that are intrinsically poorly absorbed, highly lipophilic or subject to enterohepatic recirculation carry the greatest risk [6].

A separate review of Roux-en-Y pharmacokinetics concluded that drugs needing an acidic environment for absorption or activation, or relying on intestinal transporters concentrated in the duodenum, are the ones most likely to be affected, and that the primary literature offers little help in predicting the effect for an individual drug [5].

Sleeve gastrectomy leaves the duodenum in the food stream but speeds transit. In a prospective study of 21 patients given semisolid radiolabeled meals before surgery and again four months after, the times to 10% and 50% gastric emptying were shorter, duodenal-to-terminal-ileum transit shortened, and the meal reached the terminal ileum sooner [7].

Roux-en-Y and sleeve gastrectomy compared

Roux-en-Y gastric bypass dramatically decreases stomach size and bypasses the entire duodenum [5]. The documented functional change after sleeve gastrectomy is faster gastric emptying and faster small bowel transit [7].

Taking the dose after surgery: capsule, chewable, liquid

The label gives several ways to take the drug. Capsules are swallowed whole, or opened and the entire contents mixed with yogurt, water or orange juice and consumed immediately, with no storing of the mixture; a spoon may be used to break up compacted powder. Chewable tablets must be chewed thoroughly, and capsules and chewable tablets can be substituted milligram for milligram. A single dose should not be divided, and nothing less than one capsule or tablet is taken [1]. The label directs that the dose be taken in the morning with or without food, and that afternoon doses be avoided because of insomnia [1].

A separate lisdexamfetamine product, Arynta, is approved as a 10 mg/mL oral solution and has its own labeling [2].

Dosing: fixed milligrams, renal caps and urinary pH

For ADHD, the label starts adults and children 6 and older at 30 mg every morning, adjusts by 10 mg or 20 mg at about weekly intervals, and gives a recommended range of 30 to 70 mg a day with a maximum of 70 mg [1]. For binge eating disorder in adults, it starts at 30 mg, titrates by 20 mg at about weekly intervals to a target of 50 to 70 mg a day, caps at 70 mg, and says to discontinue if binge eating does not improve [1].

The label's renal adjustments are a maximum of 50 mg a day at a GFR of 15 to under 30, and 30 mg a day in end-stage renal disease [1]. It also says to adjust the dose when agents that change urinary pH are used (see below) [1]. Before starting, the label calls for an assessment for cardiac disease (history, family history of sudden death or ventricular arrhythmia, and a physical exam) and for family history or signs of tics or Tourette syndrome [1].

Interactions that matter when the medication list gets longer

The label's pH warning concerns urine, not stomach contents. Urinary acidifying agents such as ascorbic acid lower amphetamine blood levels and efficacy, and the label says to increase the dose based on clinical response; urinary alkalinizing agents such as sodium bicarbonate raise blood levels and potentiate the effects, and co-administration should be avoided [1].

Monoamine oxidase inhibitors are contraindicated during use and within 14 days of stopping one, including linezolid and intravenous methylene blue, because of hypertensive crisis risk [1]. Serotonergic drugs raise the risk of serotonin syndrome, so the label advises a lower starting dose and monitoring, particularly at initiation or dose increase [1]. CYP2D6 inhibitors increase exposure to dextroamphetamine and may add to serotonin syndrome risk [1]. Tricyclic antidepressants can potentiate cardiovascular effects and call for frequent monitoring [1]. Vyvanse can also interfere with the dopamine transporter imaging agent ioflupane I-123, so the label calls for a washout before that scan [1].

Blood pressure, heart rate and the boxed warning

The boxed warning on Vyvanse is for abuse, misuse and addiction. It states that the drug has a high potential for abuse and misuse, that this can lead to a substance use disorder including addiction, that misuse and abuse can cause overdose and death, and that risk rises with higher doses or unapproved routes such as snorting or injection. It directs prescribers to assess each patient's risk before prescribing, educate patients and families about storage and disposal, and reassess risk throughout treatment [1]. Lisdexamfetamine is a Schedule II controlled substance [1].

CNS stimulants raise blood pressure by a mean of about 2 to 4 mm Hg and heart rate by a mean of about 3 to 6 bpm, with larger increases in some patients, and the label directs monitoring of blood pressure and pulse in everyone treated [1]. The label also says to avoid Vyvanse in people with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease or other serious cardiac disease, because sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease treated with CNS stimulants at usual ADHD doses [1]. It directs screening for risk factors for mania before starting, and notes that new psychotic or manic symptoms occurred in about 0.1% of stimulant-treated patients versus 0% on placebo in pooled short-term trials [1].

Alcohol and drug use after surgery

In a prospective cohort of 1,945 adults who had bariatric surgery, past-year alcohol use disorder symptoms were present in 7.6% one year before surgery and 7.3% one year after (not a significant change), and in 9.6% in the second postoperative year, which was significantly higher. Preoperative alcohol use disorder, recreational drug use and Roux-en-Y gastric bypass (odds ratio 2.07 versus adjustable band) were among the factors independently associated with alcohol use disorder after surgery [8].

That background is relevant to a Schedule II stimulant whose label already calls for assessing abuse risk before prescribing and reassessing it during treatment [1]. In an abuse liability study in 38 people with a history of drug abuse, Vyvanse 150 mg produced drug liking similar to immediate-release d-amphetamine 40 mg, and intravenous lisdexamfetamine 50 mg produced positive subjective effects greater than placebo, so the prodrug design does not remove the risk [1].

Binge eating disorder and the weight question

Binge eating disorder is common in this population: a meta-analysis of 59 publications covering 65,363 patients seeking or undergoing bariatric surgery estimated a prevalence of 17% (95% CI 13% to 21%) [3]. Lisdexamfetamine is approved for moderate to severe binge eating disorder in adults, and the label's target dose is 50 to 70 mg a day [1].

In the two pivotal 12-week trials (383 and 390 adults), lisdexamfetamine 50 or 70 mg a day reduced binge eating days per week more than placebo, with treatment differences of 1.35 days (95% CI 1.01 to 1.70) and 1.66 days (1.28 to 2.04), both P<0.001. Dry mouth, insomnia and headache were the common adverse events, and mean pulse rose 4.41 to 6.31 bpm [9]. In a randomized withdrawal trial, 418 adults entered 12 weeks of open-label treatment, 275 responders were randomized, and relapse occurred in 3.7% (5 of 136) of those who continued versus 32.1% (42 of 131) of those switched to placebo (hazard ratio 0.09, 95% CI 0.04 to 0.23) [10].

The label is explicit that Vyvanse is not indicated for weight loss and that its safety and effectiveness in obesity have not been established [1]. Substantial weight change is expected after surgery: in a multicenter cohort, Roux-en-Y patients lost a median 31.5% of baseline weight by three years and adjustable band patients 15.9% [11]. The labeled doses are fixed milligram amounts [1].

Dose-response and duration of effect

In the adult ADHD trial, 420 adults were randomized to 30, 50 or 70 mg a day or placebo. ADHD rating scale scores fell by 8.2 points on placebo and 16.2, 17.4 and 18.6 points at 30, 50 and 70 mg, all significantly better than placebo with no differences between doses [12]. In a laboratory school study that randomized 117 children aged 6 to 12, lisdexamfetamine separated from placebo on attention and deportment measures at every time point tested from 1.5 through 13 hours after dosing [13].