Vyvanse

Pregnancy

Advise patients of the potential fetal effects from the use of VYVANSE during pregnancy. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with VYVANSE [see Use in Specific Populations (8.1)].

Limitations of Use:

• The use of VYVANSE is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.5), Use in Specific Populations (8.4)].
• VYVANSE is not indicated or recommended for weight loss. Use of other sympathomimetic drugs for weight loss has been associated with serious cardiovascular adverse events. The safety and effectiveness of VYVANSE for the treatment of obesity have not been established [see Warnings and Precautions (5.2)].

Lactation

Advise women not to breastfeed if they are taking VYVANSE [see Use in Specific Populations (8.2)].

VYVANSE has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1)]. VYVANSE can be diverted for non-medical use into illicit channels or distribution.

Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of lisdexamfetamine, a prodrug of amphetamine, may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including VYVANSE, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

VYVANSE (lisdexamfetamine dimesylate), a CNS stimulant, is for once-a-day oral administration. The chemical designation for lisdexamfetamine dimesylate is (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl] hexanamide dimethanesulfonate. The molecular formula is C₁₅H₂₅N₃O∙(CH₄O₃S)₂, which corresponds to a molecular weight of 455.60. The chemical structure is:

Lisdexamfetamine dimesylate is a white to off-white powder that is soluble in water (792 mg/mL).

Clinical studies of VYVANSE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience and pharmacokinetic data [see Clinical Pharmacology (12.3)] have not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

VYVANSE is contraindicated in patients with:

• Known hypersensitivity to amphetamine products or other ingredients of VYVANSE. Anaphylactic reactions, Stevens-Johnson Syndrome, angioedema, and urticaria have been observed in postmarketing reports [see Adverse Reactions (6.2)].
• Patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis [see Warnings and Precautions (5.7) and Drug Interactions (7.1)].

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Known hypersensitivity to amphetamine products or other ingredients of VYVANSE [see Contraindications (4)]
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) and Drug Interactions (7.1)]
• Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)]
• Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)]
• Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)]
• Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
• Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.5)]
• Peripheral Vasculopathy, including Raynaud's phenomenon [see Warnings and Precautions (5.6)]
• Serotonin Syndrome [see Warnings and Precautions (5.7)]
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome [see Warnings and Precautions (5.8)]

Acidifying and Alkalinizing Agents: Agents that alter urinary pH can alter blood levels of amphetamine. Acidifying agents decrease amphetamine blood levels, while alkalinizing agents increase amphetamine blood levels. Adjust VYVANSE dosage accordingly. (2.6, 7.1)

Due to reduced clearance in patients with severe renal impairment (GFR 15 to <30 mL/min/1.73 m²), the maximum dose should not exceed 50 mg/day. The maximum recommended dose in ESRD (GFR <15 mL/min/1.73 m²) patients is 30 mg/day [see Clinical Pharmacology (12.3)].

Lisdexamfetamine and d-amphetamine are not dialyzable.

Amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. The parent drug, lisdexamfetamine, does not bind to the sites responsible for the reuptake of norepinephrine and dopamine in vitro.

Pharmacokinetic studies after oral administration of lisdexamfetamine dimesylate have been conducted in healthy adult (capsule and chewable tablet formulations) and pediatric (6 to 12 years) patients with ADHD (capsule formulation). After single dose administration of lisdexamfetamine dimesylate, pharmacokinetics of dextroamphetamine was found to be linear between 30 mg and 70 mg in a pediatric study (6 to 12 years), and between 50 mg and 250 mg in an adult study. Dextroamphetamine pharmacokinetic parameters following administration of lisdexamfetamine dimesylate in adults exhibited low inter-subject (<25%) and intra-subject (<8%) variability. There is no accumulation of lisdexamfetamine and dextroamphetamine at steady state in healthy adults.

Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort [see Drug Interactions (7.1)]. The co-administration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to the active metabolite of VYVANSE (dextroamphetamine). In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6 [see Drug Interactions (7.1)].

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Concomitant use of VYVANSE with MAOI drugs is contraindicated [see Contraindications (4)].

Discontinue treatment with VYVANSE and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment. If concomitant use of VYVANSE with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate VYVANSE with lower doses, monitor patients for the emergence of serotonin syndrome during drug initiation or titration, and inform patients of the increased risk for serotonin syndrome.

VYVANSE^® is indicated for the treatment of:

• Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years and older [see Clinical Studies (14.1)].
• Moderate to severe binge eating disorder (BED) in adults [see Clinical Studies (14.2)].

Lisdexamfetamine is a prodrug of dextroamphetamine. Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The exact mode of therapeutic action in ADHD and BED is not known.

VYVANSE contains lisdexamfetamine, a prodrug of amphetamine, a Schedule II controlled substance.

Dispense in a tight, light-resistant container as defined in the USP.

Store at room temperature, 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Prior to treating patients with VYVANSE, assess:

• for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)].
• the family history and clinically evaluate patients for motor or verbal tics or Tourette's syndrome before initiating VYVANSE [see Warnings and Precautions (5.8)].

• Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease (5.2)
• Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. (5.3)
• Psychiatric Adverse Reactions: Prior to initiating VYVANSE, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing VYVANSE. (5.4)
• Long-Term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. (5.5)
• Peripheral Vasculopathy, including Raynaud's phenomenon: Careful observation for digital changes is necessary during VYVANSE treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. (5.6)
• Serotonin Syndrome: Increased risk when co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue VYVANSE and initiate supportive treatment. (4, 5.7, 10)
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome: Before initiating VYVANSE, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette's syndrome. Discontinue treatment if clinically appropriate. (5.8)

• Prior to treatment, assess for presence of cardiac disease (2.4)
• Severe renal impairment: Maximum dose is 50 mg/day (2.5)
• End stage renal disease (ESRD): Maximum dose is 30 mg/day (2.5)

• Capsules: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg (3)
• Chewable tablets: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg (3)

The following adverse reactions have been identified during post-approval use of VYVANSE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events are as follows: cardiomyopathy, mydriasis, diplopia, difficulties with visual accommodation, blurred vision, eosinophilic hepatitis, anaphylactic reaction, hypersensitivity, dyskinesia, dysgeusia, motor and verbal tics, bruxism, depression, dermatillomania, alopecia, aggression, Stevens-Johnson Syndrome, chest pain, angioedema, urticaria, seizures, libido changes, frequent or prolonged erections, constipation, rhabdomyolysis, and intestinal ischemia.

• Pregnancy: May cause fetal harm (8.1)
• Lactation: Breastfeeding not recommended (8.2)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A phase 2 study evaluated the efficacy of VYVANSE 30, 50 and 70 mg/day compared to placebo in reducing the number of binge days/week in adults with at least moderate to severe BED. This randomized, double-blind, parallel-group, placebo-controlled, forced-dose titration study (Study 10) consisted of an 11-week double-blind treatment period (3 weeks of forced-dose titration followed by 8 weeks of dose maintenance). VYVANSE 30 mg/day was not statistically different from placebo on the primary endpoint. The 50 and 70 mg/day doses were statistically superior to placebo on the primary endpoint.

The efficacy of VYVANSE in the treatment of BED was demonstrated in two 12-week randomized, double-blind, multi-center, parallel-group, placebo-controlled, dose-optimization studies (Study 11 and Study 12) in adults aged 18-55 years (Study 11: N=374, Study 12: N=350) with moderate to severe BED. A diagnosis of BED was confirmed using DSM-IV criteria for BED. Severity of BED was determined based on having at least 3 binge days per week for 2 weeks prior to the baseline visit and on having a Clinical Global Impression Severity (CGI-S) score of ≥4 at the baseline visit. For both studies, a binge day was defined as a day with at least 1 binge episode, as determined from the subject's daily binge diary.

Both 12-week studies consisted of a 4-week dose-optimization period and an 8-week dose-maintenance period. During dose-optimization, subjects assigned to VYVANSE began treatment at the titration dose of 30 mg/day and, after 1 week of treatment, were subsequently titrated to 50 mg/day. Additional increases to 70 mg/day were made as tolerated and clinically indicated. Following the dose-optimization period, subjects continued on their optimized dose for the duration of the dose-maintenance period.

The primary efficacy outcome for the two studies was defined as the change from baseline at Week 12 in the number of binge days per week. Baseline is defined as the weekly average of the number of binge days per week for the 14 days prior to the baseline visit. Subjects from both studies on VYVANSE had a statistically significantly greater reduction from baseline in mean number of binge days per week at Week 12. In addition, subjects on VYVANSE showed greater improvement as compared to placebo across key secondary outcomes with higher proportion of subjects rated improved on the CGI-I rating scale, higher proportion of subjects with 4-week binge cessation, and greater reduction in the Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (Y-BOCS-BE) total score.

A double-blind, placebo controlled, randomized withdrawal design study (Study 13) was conducted to evaluate maintenance of efficacy based on time to relapse between VYVANSE and placebo in adults aged 18 to 55 (N=267) with moderate to severe BED. In this longer-term study patients who had responded to VYVANSE in the preceding 12-week open-label treatment phase were randomized to continuation of VYVANSE or placebo for up to 26 weeks of observation for relapse. Response in the open-label phase was defined as 1 or fewer binge days each week for four consecutive weeks prior to the last visit at the end of the 12-week open-label phase and a CGI-S score of 2 or less at the same visit. Relapse during the double-blind phase was defined as having 2 or more binge days each week for two consecutive weeks (14 days) prior to any visit and having an increase in CGI-S score of 2 or more points compared to the randomized-withdrawal baseline. Maintenance of efficacy for patients who had an initial response during the open-label period and then continued on VYVANSE during the 26-week double-blind randomized-withdrawal phase was demonstrated with VYVANSE being superior over placebo as measured by time to relapse.

Figure 8 Kaplan-Meier Estimated Proportions of Subjects with Relapse in Adults with BED (Study 13)

Examination of population subgroups based on age (there were no patients over 65), gender, and race did not reveal any clear evidence of differential responsiveness in the treatment of BED.

The recommended starting dosage in adults and pediatric patients 6 years and older is 30 mg once daily in the morning. Dosage may be adjusted in increments of 10 mg or 20 mg at approximately weekly intervals up to maximum recommended dosage of 70 mg once daily [see Clinical Studies (14.1)].

VYVANSE has a high potential for abuse and misuse. The use of VYVANSE exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. VYVANSE can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2)]. Misuse and abuse of CNS stimulants, including VYVANSE, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing VYVANSE, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store VYVANSE in a safe place, preferably locked, and instruct patients to not give VYVANSE to anyone else. Throughout VYVANSE treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

VYVANSE has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including VYVANSE, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing VYVANSE, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout VYVANSE treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2)].

Take VYVANSE orally in the morning with or without food; avoid afternoon doses because of the potential for insomnia. VYVANSE may be administered in one of the following ways:

Acute administration of high doses of amphetamine (d- or d, l-) has been shown to produce long-lasting neurotoxic effects, including irreversible nerve fiber damage, in rodents. The significance of these findings to humans is unknown.

CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Some patients may have larger increases.

Monitor all VYVANSE-treated patients for potential tachycardia and hypertension.

In patients with severe renal impairment (GFR 15 to <30 mL/min/1.73 m²), the maximum dosage should not exceed 50 mg once daily. In patients with end stage renal disease (ESRD, GFR <15 mL/min/1.73 m²), the maximum recommended dosage is 30 mg once daily [see Use in Specific Populations (8.6)].

Agents that alter urinary pH can impact urinary excretion and alter blood levels of amphetamine. Acidifying agents (e.g., ascorbic acid) decrease blood levels, while alkalinizing agents (e.g., sodium bicarbonate) increase blood levels. Adjust VYVANSE dosage accordingly [see Drug Interactions (7.1)].

Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid VYVANSE use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

NDC 59417-115-01

Vyvanse ^®

(lisdexamfetamine

dimesylate) chewable tablets

10 mg

100 CHEWABLE

TABLETS

Chew tablets completely

before swallowing. Do

not swallow tablets whole.

CII

Rx only

Takeda

NDC 59417-116-01

Vyvanse ^®

(lisdexamfetamine

dimesylate) chewable tablets

20 mg

100 CHEWABLE

TABLETS

Chew tablets completely

before swallowing. Do

not swallow tablets whole.

CII

Rx only

Takeda

NDC 59417-117-01

Vyvanse ^®

(lisdexamfetamine

dimesylate) chewable tablets

30 mg

100 CHEWABLE

TABLETS

Chew tablets completely

before swallowing. Do

not swallow tablets whole.

CII

Rx only

Takeda

NDC 59417-118-01

Vyvanse ^®

(lisdexamfetamine

dimesylate) chewable tablets

40 mg

100 CHEWABLE

TABLETS

Chew tablets completely

before swallowing. Do

not swallow tablets whole.

CII

Rx only

Takeda

NDC 59417-119-01

Vyvanse ^®

(lisdexamfetamine

dimesylate) chewable tablets

50 mg

100 CHEWABLE

TABLETS

Chew tablets completely

before swallowing. Do

not swallow tablets whole.

CII

Rx only

Takeda

NDC 59417-120-01

Vyvanse ^®

(lisdexamfetamine

dimesylate) chewable tablets

60 mg

100 CHEWABLE

TABLETS

Chew tablets completely

before swallowing. Do

not swallow tablets whole.

CII

Rx only

Takeda

NDC 59417-101-10

Vyvanse ^®

(lisdexamfetamine

dimesylate) capsules

10 mg

CII

Rx only

100 CAPSULES

Takeda

NDC 59417-102-10

Vyvanse ^®

(lisdexamfetamine

dimesylate) capsules

20 mg

CII

Rx only

100 CAPSULES

Takeda

NDC 59417-103-10

Vyvanse ^®

(lisdexamfetamine

dimesylate) capsules

30 mg

CII

Rx only

100 CAPSULES

Takeda

NDC 59417-104-10

Vyvanse ^®

(lisdexamfetamine

dimesylate) capsules

40 mg

CII

Rx only

100 CAPSULES

Takeda

NDC 59417-105-10

Vyvanse ^®

(lisdexamfetamine

dimesylate) capsules

50 mg

CII

Rx only

100 CAPSULES

Takeda

NDC 59417-106-10

Vyvanse ^®

(lisdexamfetamine

dimesylate) capsules

60 mg

CII

Rx only

100 CAPSULES

Takeda

NDC 59417-107-10

Vyvanse ^®

(lisdexamfetamine

dimesylate) capsules

70 mg

CII

Rx only

100 CAPSULES

Takeda

VYVANSE is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4)].

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

In a 4-week, placebo-controlled trial of VYVANSE in pediatric patients ages 6 to 12 years old with ADHD, there was a dose-related decrease in weight in the VYVANSE groups compared to weight gain in the placebo group. Additionally, in studies of another stimulant, there was slowing of the increase in height [see Adverse Reactions (6.1)].

Closely monitor growth (weight and height) in VYVANSE-treated pediatric patients. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

CNS stimulants, including VYVANSE, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant.

Careful observation for digital changes is necessary during VYVANSE treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for VYVANSE-treated patients who develop signs or symptoms of peripheral vasculopathy.

The recommended starting dosage in adults is 30 mg once daily to be titrated in increments of 20 mg at approximately weekly intervals to achieve the recommended target dose of 50 mg to 70 mg once daily. The maximum recommended dosage is 70 mg once daily [see Clinical Studies (14.2)]. Discontinue VYVANSE if binge eating does not improve.

CNS stimulants, including amphetamine, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette's syndrome has also been reported [see Adverse Reactions (6.2)].

Before initiating VYVANSE, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor VYVANSE-treated patients for the emergence or worsening of tics or Tourette's syndrome, and discontinue treatment if clinically appropriate.

From a pharmacokinetic perspective, no dose adjustment of VYVANSE is necessary when VYVANSE is co-administered with guanfacine, venlafaxine, or omeprazole. In addition, no dose adjustment of guanfacine or venlafaxine is needed when VYVANSE is co-administered [see Clinical Pharmacology (12.3)].

From a pharmacokinetic perspective, no dose adjustment for drugs that are substrates of CYP1A2 (e.g., theophylline, duloxetine, melatonin), CYP2D6 (e.g., atomoxetine, desipramine, venlafaxine), CYP2C19 (e.g., omeprazole, lansoprazole, clobazam), and CYP3A4 (e.g., midazolam, pimozide, simvastatin) is necessary when VYVANSE is co-administered [see Clinical Pharmacology (12.3)].

Pregnancy

Advise patients of the potential fetal effects from the use of VYVANSE during pregnancy. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with VYVANSE [see Use in Specific Populations (8.1)].

Limitations of Use:

• The use of VYVANSE is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.5), Use in Specific Populations (8.4)].
• VYVANSE is not indicated or recommended for weight loss. Use of other sympathomimetic drugs for weight loss has been associated with serious cardiovascular adverse events. The safety and effectiveness of VYVANSE for the treatment of obesity have not been established [see Warnings and Precautions (5.2)].

Lactation

Advise women not to breastfeed if they are taking VYVANSE [see Use in Specific Populations (8.2)].

VYVANSE has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1)]. VYVANSE can be diverted for non-medical use into illicit channels or distribution.

Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of lisdexamfetamine, a prodrug of amphetamine, may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including VYVANSE, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

VYVANSE (lisdexamfetamine dimesylate), a CNS stimulant, is for once-a-day oral administration. The chemical designation for lisdexamfetamine dimesylate is (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl] hexanamide dimethanesulfonate. The molecular formula is C₁₅H₂₅N₃O∙(CH₄O₃S)₂, which corresponds to a molecular weight of 455.60. The chemical structure is:

Lisdexamfetamine dimesylate is a white to off-white powder that is soluble in water (792 mg/mL).

Clinical studies of VYVANSE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience and pharmacokinetic data [see Clinical Pharmacology (12.3)] have not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

VYVANSE is contraindicated in patients with:

• Known hypersensitivity to amphetamine products or other ingredients of VYVANSE. Anaphylactic reactions, Stevens-Johnson Syndrome, angioedema, and urticaria have been observed in postmarketing reports [see Adverse Reactions (6.2)].
• Patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis [see Warnings and Precautions (5.7) and Drug Interactions (7.1)].

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Known hypersensitivity to amphetamine products or other ingredients of VYVANSE [see Contraindications (4)]
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) and Drug Interactions (7.1)]
• Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)]
• Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)]
• Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)]
• Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
• Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.5)]
• Peripheral Vasculopathy, including Raynaud's phenomenon [see Warnings and Precautions (5.6)]
• Serotonin Syndrome [see Warnings and Precautions (5.7)]
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome [see Warnings and Precautions (5.8)]

Acidifying and Alkalinizing Agents: Agents that alter urinary pH can alter blood levels of amphetamine. Acidifying agents decrease amphetamine blood levels, while alkalinizing agents increase amphetamine blood levels. Adjust VYVANSE dosage accordingly. (2.6, 7.1)

Due to reduced clearance in patients with severe renal impairment (GFR 15 to <30 mL/min/1.73 m²), the maximum dose should not exceed 50 mg/day. The maximum recommended dose in ESRD (GFR <15 mL/min/1.73 m²) patients is 30 mg/day [see Clinical Pharmacology (12.3)].

Lisdexamfetamine and d-amphetamine are not dialyzable.

Amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. The parent drug, lisdexamfetamine, does not bind to the sites responsible for the reuptake of norepinephrine and dopamine in vitro.

Pharmacokinetic studies after oral administration of lisdexamfetamine dimesylate have been conducted in healthy adult (capsule and chewable tablet formulations) and pediatric (6 to 12 years) patients with ADHD (capsule formulation). After single dose administration of lisdexamfetamine dimesylate, pharmacokinetics of dextroamphetamine was found to be linear between 30 mg and 70 mg in a pediatric study (6 to 12 years), and between 50 mg and 250 mg in an adult study. Dextroamphetamine pharmacokinetic parameters following administration of lisdexamfetamine dimesylate in adults exhibited low inter-subject (<25%) and intra-subject (<8%) variability. There is no accumulation of lisdexamfetamine and dextroamphetamine at steady state in healthy adults.

Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort [see Drug Interactions (7.1)]. The co-administration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to the active metabolite of VYVANSE (dextroamphetamine). In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6 [see Drug Interactions (7.1)].

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Concomitant use of VYVANSE with MAOI drugs is contraindicated [see Contraindications (4)].

Discontinue treatment with VYVANSE and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment. If concomitant use of VYVANSE with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate VYVANSE with lower doses, monitor patients for the emergence of serotonin syndrome during drug initiation or titration, and inform patients of the increased risk for serotonin syndrome.

VYVANSE^® is indicated for the treatment of:

• Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years and older [see Clinical Studies (14.1)].
• Moderate to severe binge eating disorder (BED) in adults [see Clinical Studies (14.2)].

Lisdexamfetamine is a prodrug of dextroamphetamine. Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The exact mode of therapeutic action in ADHD and BED is not known.

VYVANSE contains lisdexamfetamine, a prodrug of amphetamine, a Schedule II controlled substance.

Dispense in a tight, light-resistant container as defined in the USP.

Store at room temperature, 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Prior to treating patients with VYVANSE, assess:

• for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)].
• the family history and clinically evaluate patients for motor or verbal tics or Tourette's syndrome before initiating VYVANSE [see Warnings and Precautions (5.8)].

• Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease (5.2)
• Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. (5.3)
• Psychiatric Adverse Reactions: Prior to initiating VYVANSE, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing VYVANSE. (5.4)
• Long-Term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. (5.5)
• Peripheral Vasculopathy, including Raynaud's phenomenon: Careful observation for digital changes is necessary during VYVANSE treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. (5.6)
• Serotonin Syndrome: Increased risk when co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue VYVANSE and initiate supportive treatment. (4, 5.7, 10)
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome: Before initiating VYVANSE, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette's syndrome. Discontinue treatment if clinically appropriate. (5.8)

• Prior to treatment, assess for presence of cardiac disease (2.4)
• Severe renal impairment: Maximum dose is 50 mg/day (2.5)
• End stage renal disease (ESRD): Maximum dose is 30 mg/day (2.5)

• Capsules: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg (3)
• Chewable tablets: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg (3)

The following adverse reactions have been identified during post-approval use of VYVANSE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events are as follows: cardiomyopathy, mydriasis, diplopia, difficulties with visual accommodation, blurred vision, eosinophilic hepatitis, anaphylactic reaction, hypersensitivity, dyskinesia, dysgeusia, motor and verbal tics, bruxism, depression, dermatillomania, alopecia, aggression, Stevens-Johnson Syndrome, chest pain, angioedema, urticaria, seizures, libido changes, frequent or prolonged erections, constipation, rhabdomyolysis, and intestinal ischemia.

• Pregnancy: May cause fetal harm (8.1)
• Lactation: Breastfeeding not recommended (8.2)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A phase 2 study evaluated the efficacy of VYVANSE 30, 50 and 70 mg/day compared to placebo in reducing the number of binge days/week in adults with at least moderate to severe BED. This randomized, double-blind, parallel-group, placebo-controlled, forced-dose titration study (Study 10) consisted of an 11-week double-blind treatment period (3 weeks of forced-dose titration followed by 8 weeks of dose maintenance). VYVANSE 30 mg/day was not statistically different from placebo on the primary endpoint. The 50 and 70 mg/day doses were statistically superior to placebo on the primary endpoint.

The efficacy of VYVANSE in the treatment of BED was demonstrated in two 12-week randomized, double-blind, multi-center, parallel-group, placebo-controlled, dose-optimization studies (Study 11 and Study 12) in adults aged 18-55 years (Study 11: N=374, Study 12: N=350) with moderate to severe BED. A diagnosis of BED was confirmed using DSM-IV criteria for BED. Severity of BED was determined based on having at least 3 binge days per week for 2 weeks prior to the baseline visit and on having a Clinical Global Impression Severity (CGI-S) score of ≥4 at the baseline visit. For both studies, a binge day was defined as a day with at least 1 binge episode, as determined from the subject's daily binge diary.

Both 12-week studies consisted of a 4-week dose-optimization period and an 8-week dose-maintenance period. During dose-optimization, subjects assigned to VYVANSE began treatment at the titration dose of 30 mg/day and, after 1 week of treatment, were subsequently titrated to 50 mg/day. Additional increases to 70 mg/day were made as tolerated and clinically indicated. Following the dose-optimization period, subjects continued on their optimized dose for the duration of the dose-maintenance period.

The primary efficacy outcome for the two studies was defined as the change from baseline at Week 12 in the number of binge days per week. Baseline is defined as the weekly average of the number of binge days per week for the 14 days prior to the baseline visit. Subjects from both studies on VYVANSE had a statistically significantly greater reduction from baseline in mean number of binge days per week at Week 12. In addition, subjects on VYVANSE showed greater improvement as compared to placebo across key secondary outcomes with higher proportion of subjects rated improved on the CGI-I rating scale, higher proportion of subjects with 4-week binge cessation, and greater reduction in the Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (Y-BOCS-BE) total score.

A double-blind, placebo controlled, randomized withdrawal design study (Study 13) was conducted to evaluate maintenance of efficacy based on time to relapse between VYVANSE and placebo in adults aged 18 to 55 (N=267) with moderate to severe BED. In this longer-term study patients who had responded to VYVANSE in the preceding 12-week open-label treatment phase were randomized to continuation of VYVANSE or placebo for up to 26 weeks of observation for relapse. Response in the open-label phase was defined as 1 or fewer binge days each week for four consecutive weeks prior to the last visit at the end of the 12-week open-label phase and a CGI-S score of 2 or less at the same visit. Relapse during the double-blind phase was defined as having 2 or more binge days each week for two consecutive weeks (14 days) prior to any visit and having an increase in CGI-S score of 2 or more points compared to the randomized-withdrawal baseline. Maintenance of efficacy for patients who had an initial response during the open-label period and then continued on VYVANSE during the 26-week double-blind randomized-withdrawal phase was demonstrated with VYVANSE being superior over placebo as measured by time to relapse.

Figure 8 Kaplan-Meier Estimated Proportions of Subjects with Relapse in Adults with BED (Study 13)

Examination of population subgroups based on age (there were no patients over 65), gender, and race did not reveal any clear evidence of differential responsiveness in the treatment of BED.

The recommended starting dosage in adults and pediatric patients 6 years and older is 30 mg once daily in the morning. Dosage may be adjusted in increments of 10 mg or 20 mg at approximately weekly intervals up to maximum recommended dosage of 70 mg once daily [see Clinical Studies (14.1)].

VYVANSE has a high potential for abuse and misuse. The use of VYVANSE exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. VYVANSE can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2)]. Misuse and abuse of CNS stimulants, including VYVANSE, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing VYVANSE, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store VYVANSE in a safe place, preferably locked, and instruct patients to not give VYVANSE to anyone else. Throughout VYVANSE treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

VYVANSE has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including VYVANSE, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing VYVANSE, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout VYVANSE treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2)].

Take VYVANSE orally in the morning with or without food; avoid afternoon doses because of the potential for insomnia. VYVANSE may be administered in one of the following ways:

Acute administration of high doses of amphetamine (d- or d, l-) has been shown to produce long-lasting neurotoxic effects, including irreversible nerve fiber damage, in rodents. The significance of these findings to humans is unknown.

CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Some patients may have larger increases.

Monitor all VYVANSE-treated patients for potential tachycardia and hypertension.

In patients with severe renal impairment (GFR 15 to <30 mL/min/1.73 m²), the maximum dosage should not exceed 50 mg once daily. In patients with end stage renal disease (ESRD, GFR <15 mL/min/1.73 m²), the maximum recommended dosage is 30 mg once daily [see Use in Specific Populations (8.6)].

Agents that alter urinary pH can impact urinary excretion and alter blood levels of amphetamine. Acidifying agents (e.g., ascorbic acid) decrease blood levels, while alkalinizing agents (e.g., sodium bicarbonate) increase blood levels. Adjust VYVANSE dosage accordingly [see Drug Interactions (7.1)].

Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid VYVANSE use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

NDC 59417-115-01

Vyvanse ^®

(lisdexamfetamine

dimesylate) chewable tablets

10 mg

100 CHEWABLE

TABLETS

Chew tablets completely

before swallowing. Do

not swallow tablets whole.

CII

Rx only

Takeda

NDC 59417-116-01

Vyvanse ^®

(lisdexamfetamine

dimesylate) chewable tablets

20 mg

100 CHEWABLE

TABLETS

Chew tablets completely

before swallowing. Do

not swallow tablets whole.

CII

Rx only

Takeda

NDC 59417-117-01

Vyvanse ^®

(lisdexamfetamine

dimesylate) chewable tablets

30 mg

100 CHEWABLE

TABLETS

Chew tablets completely

before swallowing. Do

not swallow tablets whole.

CII

Rx only

Takeda

NDC 59417-118-01

Vyvanse ^®

(lisdexamfetamine

dimesylate) chewable tablets

40 mg

100 CHEWABLE

TABLETS

Chew tablets completely

before swallowing. Do

not swallow tablets whole.

CII

Rx only

Takeda

NDC 59417-119-01

Vyvanse ^®

(lisdexamfetamine

dimesylate) chewable tablets

50 mg

100 CHEWABLE

TABLETS

Chew tablets completely

before swallowing. Do

not swallow tablets whole.

CII

Rx only

Takeda

NDC 59417-120-01

Vyvanse ^®

(lisdexamfetamine

dimesylate) chewable tablets

60 mg

100 CHEWABLE

TABLETS

Chew tablets completely

before swallowing. Do

not swallow tablets whole.

CII

Rx only

Takeda

NDC 59417-101-10

Vyvanse ^®

(lisdexamfetamine

dimesylate) capsules

10 mg

CII

Rx only

100 CAPSULES

Takeda

NDC 59417-102-10

Vyvanse ^®

(lisdexamfetamine

dimesylate) capsules

20 mg

CII

Rx only

100 CAPSULES

Takeda

NDC 59417-103-10

Vyvanse ^®

(lisdexamfetamine

dimesylate) capsules

30 mg

CII

Rx only

100 CAPSULES

Takeda

NDC 59417-104-10

Vyvanse ^®

(lisdexamfetamine

dimesylate) capsules

40 mg

CII

Rx only

100 CAPSULES

Takeda

NDC 59417-105-10

Vyvanse ^®

(lisdexamfetamine

dimesylate) capsules

50 mg

CII

Rx only

100 CAPSULES

Takeda

NDC 59417-106-10

Vyvanse ^®

(lisdexamfetamine

dimesylate) capsules

60 mg

CII

Rx only

100 CAPSULES

Takeda

NDC 59417-107-10

Vyvanse ^®

(lisdexamfetamine

dimesylate) capsules

70 mg

CII

Rx only

100 CAPSULES

Takeda

VYVANSE is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4)].

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

In a 4-week, placebo-controlled trial of VYVANSE in pediatric patients ages 6 to 12 years old with ADHD, there was a dose-related decrease in weight in the VYVANSE groups compared to weight gain in the placebo group. Additionally, in studies of another stimulant, there was slowing of the increase in height [see Adverse Reactions (6.1)].

Closely monitor growth (weight and height) in VYVANSE-treated pediatric patients. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

CNS stimulants, including VYVANSE, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant.

Careful observation for digital changes is necessary during VYVANSE treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for VYVANSE-treated patients who develop signs or symptoms of peripheral vasculopathy.

The recommended starting dosage in adults is 30 mg once daily to be titrated in increments of 20 mg at approximately weekly intervals to achieve the recommended target dose of 50 mg to 70 mg once daily. The maximum recommended dosage is 70 mg once daily [see Clinical Studies (14.2)]. Discontinue VYVANSE if binge eating does not improve.

CNS stimulants, including amphetamine, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette's syndrome has also been reported [see Adverse Reactions (6.2)].

Before initiating VYVANSE, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor VYVANSE-treated patients for the emergence or worsening of tics or Tourette's syndrome, and discontinue treatment if clinically appropriate.

From a pharmacokinetic perspective, no dose adjustment of VYVANSE is necessary when VYVANSE is co-administered with guanfacine, venlafaxine, or omeprazole. In addition, no dose adjustment of guanfacine or venlafaxine is needed when VYVANSE is co-administered [see Clinical Pharmacology (12.3)].

From a pharmacokinetic perspective, no dose adjustment for drugs that are substrates of CYP1A2 (e.g., theophylline, duloxetine, melatonin), CYP2D6 (e.g., atomoxetine, desipramine, venlafaxine), CYP2C19 (e.g., omeprazole, lansoprazole, clobazam), and CYP3A4 (e.g., midazolam, pimozide, simvastatin) is necessary when VYVANSE is co-administered [see Clinical Pharmacology (12.3)].