Vyvanse Plateau and Non-Response Troubleshooting

Two different problems hide under the word plateau

A plateau is a response that was there and faded. Non-response is a benefit that never arrived. Vyvanse is lisdexamfetamine, an inactive prodrug that is converted to dextroamphetamine mainly in red blood cells, not by cytochrome P450 enzymes [1]. Several label items bear on a weak response: the dose prescribed, when it is taken, what else is taken with it, and how well the kidneys are clearing amphetamine [1].

Check the total daily dose against the label schedule

In adults and children 6 and older, the label starts Vyvanse at 30 mg every morning and adjusts by 10 mg or 20 mg at approximately weekly intervals, with a recommended range of 30 to 70 mg per day and a maximum of 70 mg per day [1]. For moderate to severe binge eating disorder in adults, it starts at 30 mg and titrates in 20 mg steps at about weekly intervals to a target of 50 to 70 mg per day, with the same 70 mg ceiling [1].

The trial data on going higher are modest. In a 4-week double-blind trial of 420 adults with moderate to severe ADHD, ADHD-RS score changes were -8.2 on placebo and -16.2, -17.4 and -18.6 at 30, 50 and 70 mg per day — all significant against placebo, with no differences between doses [2]. In a 4-week trial of 290 children aged 6 to 12, every dose (30, 50 and 70 mg) improved ADHD-RS-IV scores more than placebo, and discontinuations for adverse events were 9% at 30 mg, 5% at 50 mg and 14% at 70 mg, versus 1% on placebo [3].

The adult trial compared doses against placebo over 4 weeks; it did not test whether increasing a dose restores a response that has faded [2].

Confirm the prescribed dose is taken as the label directs

The label's administration rules matter when a response seems thin. The dose is taken in the morning with or without food, and afternoon doses are to be avoided because of insomnia [1]. A single dose should not be divided, and nothing less than one full capsule or tablet is taken [1]. Capsules may be swallowed whole or opened and mixed with yogurt, water or orange juice — the mixture is consumed immediately and not stored [1]. Chewable tablets must be chewed thoroughly, and capsules and chewable tablets can be substituted milligram for milligram [1].

Food and timing change the clock, not the amount

The label notes that food prolongs the time to peak dextroamphetamine concentration by about 1 hour without changing total exposure (AUC) or peak concentration (Cmax) [1]. After a capsule taken fasted in children aged 6 to 12, lisdexamfetamine peaks at about 1 hour and dextroamphetamine at about 3.5 hours [1]. Dextroamphetamine's half-life averages about 10 to 11.3 hours in healthy adults and 8.6 to 9.5 hours in children 6 to 12 [1].

Urinary pH and other drugs are dose-modifying

The label treats urinary pH as a dose-modifying variable, not a minor detail. Acidifying agents such as ascorbic acid lower amphetamine blood levels and efficacy, and the label's instruction is to increase the dose based on clinical response; alkalinizing agents such as sodium bicarbonate raise levels and potentiate effects, and coadministration should be avoided [1].

Other label interactions worth ruling out: CYP2D6 inhibitors may increase exposure to dextroamphetamine and raise serotonin syndrome risk, and serotonergic drugs (SSRIs, SNRIs, triptans) carry the same serotonin syndrome warning, with lower starting doses and monitoring around initiation and dose increases [1].

Kidney function can cap the dose

The label sets a maximum of 50 mg per day in severe renal impairment (GFR 15 to under 30) and 30 mg per day in end-stage renal disease [1]. If kidney function has changed since the dose was set, these ceilings may now sit below the prescribed dose.

Is it tolerance?

The label says that physical dependence and tolerance may occur with Vyvanse, and that withdrawal after prolonged use can include dysphoric mood, depression, fatigue, vivid unpleasant dreams, insomnia or hypersomnia, increased appetite and psychomotor changes [1]. This appears in the abuse and dependence section of the label. The boxed warning on the label is for abuse, misuse and addiction [1].

What to monitor while the picture is sorted out

The label says to monitor all treated patients for tachycardia and hypertension, because central nervous system stimulants raise blood pressure by a mean of about 2 to 4 mm Hg and heart rate by about 3 to 6 bpm, with larger rises in some patients [1]. In the 4-week adult ADHD trial, increased blood pressure was reported in 3% on Vyvanse versus 0% on placebo, and increased heart rate in 2% versus 0% [1]. The label says to avoid use in known structural cardiac abnormalities, cardiomyopathy, serious arrhythmia, coronary artery disease or other serious cardiac disease [1]. New psychotic or manic symptoms occurred in about 0.1% of stimulant-treated patients versus 0% on placebo in pooled short-term trials [1].

If the reason for Vyvanse is binge eating disorder

The BED schedule targets 50 to 70 mg per day, and the label says to discontinue Vyvanse if binge eating does not improve [1]. In two 12-week placebo-controlled trials, the treatment differences in change in binge eating days per week were -1.35 days (95% CI -1.70 to -1.01) and -1.66 days (95% CI -2.04 to -1.28), both favoring lisdexamfetamine, both P<0.001 [4].

The maintenance study is the more useful one for a plateau question. Of 418 adults who entered a 12-week open-label phase at 50 or 70 mg, 275 responders were randomized to continue lisdexamfetamine or switch to placebo for up to 26 weeks. Relapse occurred in 3.7% of those who continued lisdexamfetamine versus 32.1% of those switched to placebo (hazard ratio 0.09, 95% CI 0.04 to 0.23) [5]. Only responders were randomized, so the comparison concerns holding a response already achieved, not regaining one.