Vyvanse

Dosage Forms And Strengths

Information For VYVANSE Capsules:

• Capsules 10 mg: pink body/pink cap (imprinted with S489 and 10 mg)
• Capsules 20 mg: ivory body/ivory cap (imprinted with S489 and 20 mg)
• Capsules 30 mg: white body/orange cap (imprinted with S489 and 30 mg)
• Capsules 40 mg: white body/blue green cap (imprinted with S489 and 40 mg)
• Capsules 50 mg: white body/blue cap (imprinted with S489 and 50 mg)
• Capsules 60 mg: aqua blue body/aqua blue cap (imprinted with S489 and 60 mg)
• Capsules 70 mg: blue body/orange cap (imprinted with S489 and 70 mg)

Information For VYVANSE Chewable Tablets:

• Chewable tablets 10 mg: White to off-white round shaped tablet debossed with ‘10’ on one side and ‘S489’ on the other
• Chewable tablets 20 mg: White to off-white hexagonal shaped tablet debossed with ‘20’ on one side and ‘S489’ on the other
• Chewable tablets 30 mg: White to off-white arc triangular shaped tablet debossed with ‘30’ on one side and ‘S489’ on the other
• Chewable tablets 40 mg: White to off-white capsule shaped tablet debossed with ‘40’ on one side and ‘S489’ on the other
• Chewable tablets 50 mg: White to off-white arc square shaped tablet debossed with ‘50’ on one side and ‘S489’ on the other
• Chewable tablets 60 mg: White to off-white arc diamond shaped tablet debossed with ‘60’ on one side and ‘S489’ on the other

Storage And Handling

Information For VYVANSE Capsules:

• VYVANSE capsules 10 mg: pink body/pink cap (imprinted with S489 and 10 mg), bottles of 100, NDC 59417-101-10
• VYVANSE capsules 20 mg: ivory body/ivory cap (imprinted with S489 and 20 mg), bottles of 100, NDC 59417-102-10
• VYVANSE capsules 30 mg: white body/orange cap (imprinted with S489 and 30 mg), bottles of 100, NDC 59417-103-10
• VYVANSE capsules 40 mg: white body/blue green cap (imprinted with S489 and 40 mg), bottles of 100, NDC 59417-104-10
• VYVANSE capsules 50 mg: white body/blue cap (imprinted with S489 and 50 mg), bottles of 100, NDC 59417-105-10
• VYVANSE capsules 60 mg: aqua blue body/aqua blue cap (imprinted with S489 and 60 mg), bottles of 100, NDC 59417-106-10
• VYVANSE capsules 70 mg: blue body/orange cap (imprinted with S489 and 70 mg), bottles of 100, NDC 59417-107-10

Information For VYVANSE Chewable Tablets:

• VYVANSE chewable tablets 10 mg: White to off-white round shaped tablet debossed with ‘10’ on one side and ‘S489’ on the other, bottles of 100, NDC 59417-115-01
• VYVANSE chewable tablets 20 mg: White to off-white hexagonal shaped tablet debossed with ‘20’ on one side and ‘S489’ on the other, bottles of 100, NDC 59417-11601
• VYVANSE chewable tablets 30 mg: White to off-white arc triangular shaped tablet debossed with ‘30’ on one side and ‘S489’ on the other, bottles of 100, NDC 59417-11701
• VYVANSE chewable tablets 40 mg: White to off-white capsule shaped tablet debossed with ‘40’ on one side and ‘S489’ on the other, bottles of 100, NDC 59417-118-01
• VYVANSE chewable tablets 50 mg: White to off-white arc square shaped tablet debossed with ‘50’ on one side and ‘S489’ on the other, bottles of 100, NDC 59417-11901
• VYVANSE chewable tablets 60 mg: White to off-white arc diamond shaped tablet debossed with ‘60’ on one side and ‘S489’ on the other, bottles of 100, NDC 59417-12001

Storage And Handling

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 to 86° F).

Disposal

Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired VYVANSE by a medicine take-back program.

Manufactured for: Shire US Inc., 300 Shire Way, Lexington, MA 02421. Revised: Jul 2017

VYVANSE^® is indicated for the treatment of:

• Attention Deficit Hyperactivity Disorder (ADHD)
• Moderate to Severe Binge Eating Disorder (BED) in adults.

Limitation Of Use

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.

Pre-Treatment Screening

Prior to treating children, adolescents, and adults with CNS stimulants, including VYVANSE, assess for the presence of cardiac disease (e.g., a careful history, family history of sudden death or ventricular arrhythmia, and physical exam).

To reduce the abuse of CNS stimulants including VYVANSE, assess the risk of abuse, prior to prescribing. After prescribing, keep careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and re-evaluate the need for VYVANSE use.

General Instructions For Use

Take VYVANSE by mouth 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:

Information For VYVANSE Capsules:

• Swallow VYVANSE capsules whole, or
• Open capsules, empty and mix the entire contents with yogurt, water, or orange juice. If the contents of the capsule include any compacted powder, a spoon may be used to break apart the powder. The contents should be mixed until completely dispersed. Consume the entire mixture immediately. It should not be stored. The active ingredient dissolves completely once dispersed; however, a film containing the inactive ingredients may remain in the glass or container once the mixture is consumed.

Information For VYVANSE Chewable Tablets:

• VYVANSE chewable tablets must be chewed thoroughly before swallowing.

VYVANSE capsules can be substituted with VYVANSE chewable tablets on a unit per unit/ mg per mg basis (for example, 30 mg capsules for 30 mg chewable tablet).

Do not take anything less than one capsule or chewable tablet per day. A single dose should not be divided.

Dosage For Treatment Of ADHD

The recommended starting dose is 30 mg once daily in the morning in patients ages 6 and above. Dosage may be adjusted in increments of 10 mg or 20 mg at approximately weekly intervals up to maximum dose of 70 mg/day.

Dosage For Treatment Of Moderate To Severe BED In Adults

The recommended starting dose is 30 mg/day to be titrated in increments of 20 mg at approximately weekly intervals to achieve the recommended target dose of 50 to 70 mg/day. The maximum dose is 70 mg/day. Discontinue VYVANSE if binge eating does not improve.

Dosage In Patients With Renal Impairment

In patients with severe renal impairment (GFR 15 to < 30 mL/min/1.73 m²), the maximum dose should not exceed 50 mg/day. In patients with end stage renal disease (ESRD, GFR < 15 mL/min/1.73 m²), the maximum recommended dose is 30 mg/day.

Dosage Modifications Due To Drug Interactions

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.

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.
• 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.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Potential For Abuse And Dependence

CNS stimulants (amphetamines and methylphenidate-containing products), including VYVANSE, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy.

Serious Cardiovascular Reactions

Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in children and adolescents with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during VYVANSE treatment.

Blood Pressure And Heart Rate Increases

CNS stimulants cause an increase in blood pressure (mean increase about 2-4 mm Hg) and heart rate (mean increase about 3-6 bpm). Monitor all patients for potential tachycardia and hypertension.

Psychiatric Adverse Reactions

Exacerbation Of Pre-Existing Psychosis

CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.

Induction Of A Manic Episode In Patients With Bipolar Disorder

CNS stimulants may induce a mixed/manic episode in patients with bipolar disorder. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, and depression).

New Psychotic Or Manic Symptoms

CNS stimulants, at recommended doses, may cause psychotic or manic symptoms, e.g. hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing VYVANSE. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in 0.1% of CNS stimulant-treated patients compared to 0% in placebo-treated patients.

Suppression Of Growth

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including VYVANSE. In a 4-week, placebo-controlled trial of VYVANSE in 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.

Peripheral Vasculopathy, Including Raynaud’s Phenomenon

Stimulants, including VYVANSE, are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Serotonin Syndrome

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. Amphetamines and amphetamine derivatives are known to be metabolized, to some degree, by cytochrome P450 2D6 (CYP2D6) and display minor inhibition of CYP2D6 metabolism. The potential for a pharmacokinetic interaction exists with the co-administration of CYP2D6 inhibitors which may 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. 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.

Discontinue treatment with VYVANSE and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment. Concomitant use of VYVANSE with other serotonergic drugs or CYP2D6 inhibitors should be used only if the potential benefit justifies the potential risk. If clinically warranted, consider initiating VYVANSE with lower doses, monitoring patients for the emergence of serotonin syndrome during drug initiation or titration, and informing patients of the increased risk for serotonin syndrome.

Patient Counseling Information

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

Controlled Substance Status/High Potential For Abuse And Dependence

Advise patients that VYVANSE is a controlled substance and it can be abused and lead to dependence and not to give VYVANSE to anyone else. Advise patients to store VYVANSE in a safe place, preferably locked, to prevent abuse. Advise patients to dispose of remaining, unused, or expired VYVANSE by a medicine take-back program.

Serious Cardiovascular Risks

Advise patients that there is a potential serious cardiovascular risk including sudden death, myocardial infarction, stroke, and hypertension with VYVANSE use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease.

Hypertension And Tachycardia

Instruct patients that VYVANSE can cause elevations of their blood pressure and pulse rate and they should be monitored for such effects.

Psychiatric Risks

Advise patients that VYVANSE at recommended doses may cause psychotic or manic symptoms even in patients without prior history of psychotic symptoms or mania.

Suppression Of Growth

Advise patients that VYVANSE may cause slowing of growth including weight loss.

Impairment In Ability To Operate Machinery Or Vehicles

Advise patients that VYVANSE may impair their ability to engage in potentially dangerous activities such as operating machinery or vehicles. Instruct patients to find out how VYVANSE will affect them before engaging in potentially dangerous activities.

Circulation Problems In Fingers And Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon]

Instruct patients beginning treatment with VYVANSE about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking VYVANSE. Further clinical evaluation (e.g. rheumatology referral) may be appropriate for certain patients.

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with concomitant use of VYVANSE and other serotonergic drugs including SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others such as linezolid. Advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.

Concomitant Medications

Advise patients to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs because there is a potential for interactions.

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.

Lactation

Advise women not to breastfeed if they are taking VYVANSE.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, And Impairment Of Fertility

Carcinogenesis

Carcinogenicity studies of lisdexamfetamine dimesylate have not been performed. No evidence of carcinogenicity was found in studies in which d-, l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats.

Mutagenesis

Lisdexamfetamine dimesylate was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli and S. typhimurium components of the Ames test and in the L5178Y/TK^+-mouse lymphoma assay in vitro.

Impairment Of Fertility

Amphetamine (d-to l-enantiomer ratio of 3:1) did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day.

Use In Specific Populations

Pregnancy

Risk Summary

The limited available data from published literature and postmarketing reports on use of VYVANSE in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. Adverse pregnancy outcomes, including premature delivery and low birth weight, have been seen in infants born to mothers dependent on amphetamines [see Clinical Considerations]. In animal reproduction studies, lisdexamfetamine dimesylate (a prodrug of d-amphetamine) had no effects on embryo-fetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis. Pre-and postnatal studies were not conducted with lisdexamfetamine dimesylate. However, amphetamine (d-to l-ratio of 3:1) administration to pregnant rats during gestation and lactation caused a decrease in pup survival and a decrease in pup body weight that correlated with a delay in developmental landmarks at clinically relevant doses of amphetamine. In addition, adverse effects on reproductive performance were observed in pups whose mothers were treated with amphetamine. Long-term neurochemical and behavioral effects have also been reported in animal developmental studies using clinically relevant doses of amphetamine [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Amphetamines, such as VYVANSE, cause vasoconstriction and thereby may decrease placental perfusion. In addition, amphetamines can stimulate uterine contractions increasing the risk of premature delivery. Infants born to amphetamine-dependent mothers have an increased risk of premature delivery and low birth weight.

Monitor infants born to mothers taking amphetamines for symptoms of withdrawal such as feeding difficulties, irritability, agitation, and excessive drowsiness.

Data

Animal Data

Lisdexamfetamine dimesylate had no apparent effects on embryo-fetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 40 and 120 mg/kg/day, respectively. These doses are approximately 4 and 27 times, respectively, the maximum recommended human dose (MRHD) of 70 mg/day given to adolescents, on a mg/m² body surface area basis.

A study was conducted with amphetamine (d-to l-enantiomer ratio of 3:1) in which pregnant rats received daily oral doses of 2, 6, and 10 mg/kg from gestation day 6 to lactation day 20. These doses are approximately 0.8, 2, and 4 times the MRHD of amphetamine (d-to l-ratio of 3:1) for adolescents of 20 mg/day, on a mg/m² basis. All doses caused hyperactivity and decreased weight gain in the dams. A decrease in pup survival was seen at all doses. A decrease in pup body weight was seen at 6 and 10 mg/kg which correlated with delays in developmental landmarks, such as preputial separation and vaginal opening. Increased pup locomotor activity was seen at 10 mg/kg on day 22 postpartum but not at 5 weeks postweaning. When pups were tested for reproductive performance at maturation, gestational weight gain, number of implantations, and number of delivered pups were decreased in the group whose mothers had been given 10 mg/kg.

A number of studies from the literature in rodents indicate that prenatal or early postnatal exposure to amphetamine (d-or d,l-) at doses similar to those used clinically can result in longterm neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function.

Lactation

Risk Summary

Lisdexamfetamine is a pro-drug of dextroamphetamine. Based on limited case reports in published literature, amphetamine (d-or d, l-) is present in human milk, at relative infant doses of 2% to 13.8% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.9 and 7.5. There are no reports of adverse effects on the breastfed infant. Long-term neurodevelopmental effects on infants from amphetamine exposure are unknown. It is possible that large dosages of dextroamphetamine might interfere with milk production, especially in women whose lactation is not well established. Because of the potential for serious adverse reactions in nursing infants, including serious cardiovascular reactions, blood pressure and heart rate increase, suppression of growth, and peripheral vasculopathy, advise patients that breastfeeding is not recommended during treatment with VYVANSE.

Pediatric Use

ADHD

Safety and effectiveness have been established in pediatric patients with ADHD ages 6 to 17 years. Safety and efficacy in pediatric patients below the age of 6 years have not been established.

BED

Safety and effectiveness in patients less than 18 years of age have not been established.

Growth Suppression

Growth should be monitored during treatment with stimulants, including VYVANSE, and children who are not growing or gaining weight as expected may need to have their treatment interrupted.

Juvenile Animal Data

Studies conducted in juvenile rats and dogs at clinically relevant doses showed growth suppression that partially or fully reversed in dogs and female rats but not in male rats after a four-week drug-free recovery period.

A study was conducted in which juvenile rats received oral doses of 4, 10, or 40 mg/kg/day of lisdexamfetamine dimesylate from day 7 to day 63 of age. These doses are approximately 0.3, 0.7, and 3 times the maximum recommended human daily dose of 70 mg on a mg/m² basis for a child. Dose-related decreases in food consumption, bodyweight gain, and crown-rump length were seen; after a four-week drug-free recovery period, bodyweights and crown-rump lengths had significantly recovered in females but were still substantially reduced in males. Time to vaginal opening was delayed in females at the highest dose, but there were no drug effects on fertility when the animals were mated beginning on day 85 of age.

In a study in which juvenile dogs received lisdexamfetamine dimesylate for 6 months beginning at 10 weeks of age, decreased bodyweight gain was seen at all doses tested (2, 5, and 12 mg/kg/day, which are approximately 0.5, 1, and 3 times the maximum recommended human daily dose on a mg/m² basis for a child). This effect partially or fully reversed during a four-week drug-free recovery period.

Geriatric Use

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 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.

Renal Impairment

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.

Lisdexamfetamine and d-amphetamine are not dialyzable.

Gender

No dosage adjustment of VYVANSE is necessary on the basis of gender.

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.

HOW SUPPLIED

Dosage Forms And Strengths

Information For VYVANSE Capsules:

• Capsules 10 mg: pink body/pink cap (imprinted with S489 and 10 mg)
• Capsules 20 mg: ivory body/ivory cap (imprinted with S489 and 20 mg)
• Capsules 30 mg: white body/orange cap (imprinted with S489 and 30 mg)
• Capsules 40 mg: white body/blue green cap (imprinted with S489 and 40 mg)
• Capsules 50 mg: white body/blue cap (imprinted with S489 and 50 mg)
• Capsules 60 mg: aqua blue body/aqua blue cap (imprinted with S489 and 60 mg)
• Capsules 70 mg: blue body/orange cap (imprinted with S489 and 70 mg)

Information For VYVANSE Chewable Tablets:

• Chewable tablets 10 mg: White to off-white round shaped tablet debossed with ‘10’ on one side and ‘S489’ on the other
• Chewable tablets 20 mg: White to off-white hexagonal shaped tablet debossed with ‘20’ on one side and ‘S489’ on the other
• Chewable tablets 30 mg: White to off-white arc triangular shaped tablet debossed with ‘30’ on one side and ‘S489’ on the other
• Chewable tablets 40 mg: White to off-white capsule shaped tablet debossed with ‘40’ on one side and ‘S489’ on the other
• Chewable tablets 50 mg: White to off-white arc square shaped tablet debossed with ‘50’ on one side and ‘S489’ on the other
• Chewable tablets 60 mg: White to off-white arc diamond shaped tablet debossed with ‘60’ on one side and ‘S489’ on the other

Storage And Handling

Information For VYVANSE Capsules:

• VYVANSE capsules 10 mg: pink body/pink cap (imprinted with S489 and 10 mg), bottles of 100, NDC 59417-101-10
• VYVANSE capsules 20 mg: ivory body/ivory cap (imprinted with S489 and 20 mg), bottles of 100, NDC 59417-102-10
• VYVANSE capsules 30 mg: white body/orange cap (imprinted with S489 and 30 mg), bottles of 100, NDC 59417-103-10
• VYVANSE capsules 40 mg: white body/blue green cap (imprinted with S489 and 40 mg), bottles of 100, NDC 59417-104-10
• VYVANSE capsules 50 mg: white body/blue cap (imprinted with S489 and 50 mg), bottles of 100, NDC 59417-105-10
• VYVANSE capsules 60 mg: aqua blue body/aqua blue cap (imprinted with S489 and 60 mg), bottles of 100, NDC 59417-106-10
• VYVANSE capsules 70 mg: blue body/orange cap (imprinted with S489 and 70 mg), bottles of 100, NDC 59417-107-10

Information For VYVANSE Chewable Tablets:

• VYVANSE chewable tablets 10 mg: White to off-white round shaped tablet debossed with ‘10’ on one side and ‘S489’ on the other, bottles of 100, NDC 59417-115-01
• VYVANSE chewable tablets 20 mg: White to off-white hexagonal shaped tablet debossed with ‘20’ on one side and ‘S489’ on the other, bottles of 100, NDC 59417-11601
• VYVANSE chewable tablets 30 mg: White to off-white arc triangular shaped tablet debossed with ‘30’ on one side and ‘S489’ on the other, bottles of 100, NDC 59417-11701
• VYVANSE chewable tablets 40 mg: White to off-white capsule shaped tablet debossed with ‘40’ on one side and ‘S489’ on the other, bottles of 100, NDC 59417-118-01
• VYVANSE chewable tablets 50 mg: White to off-white arc square shaped tablet debossed with ‘50’ on one side and ‘S489’ on the other, bottles of 100, NDC 59417-11901
• VYVANSE chewable tablets 60 mg: White to off-white arc diamond shaped tablet debossed with ‘60’ on one side and ‘S489’ on the other, bottles of 100, NDC 59417-12001

Storage And Handling

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 to 86° F).

Disposal

Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired VYVANSE by a medicine take-back program.

Manufactured for: Shire US Inc., 300 Shire Way, Lexington, MA 02421. Revised: Jul 2017

SIDE EFFECTS

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
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors
• Drug Dependence
• Serious Cardiovascular Reactions
• Blood Pressure and Heart Rate Increases
• Psychiatric Adverse Reactions
• Suppression of Growth
• Peripheral Vasculopathy, including Raynaud’s phenomenon
• Serotonin Syndrome

Clinical Trial Experience

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.

Attention Deficit Hyperactivity Disorder

The safety data in this section is based on data from the 4-week parallel-group controlled clinical studies of VYVANSE in pediatric and adult patients with ADHD.

Adverse Reactions Associated with Discontinuation of Treatment in ADHD Clinical Trials

In the controlled trial in patients ages 6 to 12 years (Study 1), 8% (18/218) of VYVANSE-treated patients discontinued due to adverse reactions compared to 0% (0/72) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were ECG voltage criteria for ventricular hypertrophy, tic, vomiting, psychomotor hyperactivity, insomnia, decreased appetite and rash [2 instances for each adverse reaction, i.e., 2/218 (1%)]. Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included abdominal pain upper, dry mouth, weight decreased, dizziness, somnolence, logorrhea, chest pain, anger and hypertension.

In the controlled trial in patients ages 13 to 17 years (Study 4), 3% (7/233) of VYVANSE-treated patients discontinued due to adverse reactions compared to 1% (1/77) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were decreased appetite (2/233; 1%) and insomnia (2/233; 1%). Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included irritability, dermatillomania, mood swings, and dyspnea.

In the controlled adult trial (Study 7), 6% (21/358) of VYVANSE-treated patients discontinued due to adverse reactions compared to 2% (1/62) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were insomnia (8/358; 2%), tachycardia (3/358; 1%), irritability (2/358; 1%), hypertension (4/358; 1%), headache (2/358; 1%), anxiety (2/358; 1%), and dyspnea (3/358; 1%). Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included palpitations, diarrhea, nausea, decreased appetite, dizziness, agitation, depression, paranoia and restlessness.

Adverse Reactions Occurring at an Incidence of ≥5% or More Among VYVANSE Treated Patients with ADHD in Clinical Trials

The most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) reported in children, adolescents, and/or adults were anorexia, anxiety, decreased appetite, decreased weight, diarrhea, dizziness, dry mouth, irritability, insomnia, nausea, upper abdominal pain, and vomiting.

Adverse Reactions Occurring at an Incidence of 2% or More Among VYVANSE Treated Patients with ADHD in Clinical Trials

Adverse reactions reported in the controlled trials in pediatric patients ages 6 to 12 years (Study 1), adolescent patients ages 13 to 17 years (Study 4), and adult patients (Study 7) treated with VYVANSE or placebo are presented in Tables 1, 2, and 3 below.

Table 1: Adverse Reactions Reported by 2% or More of Children (Ages 6 to 12 Years) with ADHD Taking VYVANSE and at least Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 1)

Table 2: Adverse Reactions Reported by 2% or More of Adolescent (Ages 13 to 17 Years) Patients with ADHD Taking VYVANSE and at least Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 4)

Table 3: Adverse Reactions Reported by 2% or More of Adult Patients with ADHD Taking VYVANSE and at least Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 7)

In addition, in the adult population erectile dysfunction was observed in 2.6% of males on VYVANSE and 0% on placebo; decreased libido was observed in 1.4% of subjects on VYVANSE and 0% on placebo.

Weight Loss and Slowing Growth Rate in Pediatric Patients with ADHD

In a controlled trial of VYVANSE in children ages 6 to 12 years (Study 1), mean weight loss from baseline after 4 weeks of therapy was -0.9, -1.9, and -2.5 pounds, respectively, for patients receiving 30 mg, 50 mg, and 70 mg of VYVANSE, compared to a 1 pound weight gain for patients receiving placebo. Higher doses were associated with greater weight loss with 4 weeks of treatment. Careful follow-up for weight in children ages 6 to 12 years who received VYVANSE over 12 months suggests that consistently medicated children (i.e. treatment for 7 days per week throughout the year) have a slowing in growth rate, measured by body weight as demonstrated by an age-and sex-normalized mean change from baseline in percentile, of -13.4 over 1 year (average percentiles at baseline and 12 months were 60.9 and 47.2, respectively). In a 4-week controlled trial of VYVANSE in adolescents ages 13 to 17 years, mean weight loss from baseline to endpoint was -2.7, -4.3, and -4.8 lbs., respectively, for patients receiving 30 mg, 50 mg, and 70 mg of VYVANSE, compared to a 2.0 pound weight gain for patients receiving placebo.

Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e. treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. In a controlled trial of amphetamine (d-to l-enantiomer ratio of 3:1) in adolescents, mean weight change from baseline within the initial 4 weeks of therapy was -1.1 pounds and -2.8 pounds, respectively, for patients receiving 10 mg and 20 mg of amphetamine. Higher doses were associated with greater weight loss within the initial 4 weeks of treatment.

Weight Loss in Adults with ADHD

In the controlled adult trial (Study 7), mean weight loss after 4 weeks of therapy was 2.8 pounds, 3.1 pounds, and 4.3 pounds, for patients receiving final doses of 30 mg, 50 mg, and 70 mg of VYVANSE, respectively, compared to a mean weight gain of 0.5 pounds for patients receiving placebo.

Binge Eating Disorder

The safety data in this section is based on data from two 12 week parallel group, flexible-dose, placebo-controlled studies in adults with BED. Patients with cardiovascular risk factors other than obesity and smoking were excluded.

Adverse Reactions Associated with Discontinuation of Treatment in BED Clinical Trials

In controlled trials of patients ages 18 to 55 years, 5.1% (19/373) of VYVANSE-treated patients discontinued due to adverse reactions compared to 2.4% (9/372) of placebo-treated patients. No single adverse reaction led to discontinuation in 1% or more of VYVANSE-treated patients. Less commonly reported adverse reactions (less than 1% or less than twice rate of placebo) included increased heart rate, headache, abdominal pain upper, dyspnea, rash, insomnia, irritability, feeling jittery and anxiety.

The most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) reported in adults were dry mouth, insomnia, decreased appetite, increased heart rate, constipation, feeling jittery, and anxiety.

Adverse reactions reported in the pooled controlled trials in adult patients (Study 11 and 12) treated with VYVANSE or placebo are presented in Table 4 below.

Table 4: Adverse Reactions Reported by 2% or More of Adult Patients with BED Taking VYVANSE and at least Twice the Incidence in Patients Taking Placebo in 12-Week Clinical Trials (Study 11 and 12)

Postmarketing Experience

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 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, tics, bruxism, depression, dermatillomania, alopecia, aggression, Stevens-Johnson Syndrome, chest pain, angioedema, urticaria, seizures, libido changes, frequent or prolonged erections, constipation, and rhabdomyolysis.

DRUG INTERACTIONS

Drugs Having Clinically Important Interactions With Amphetamines

Table 5: Drugs having clinically important interactions with amphetamines.

Drugs Having No Clinically Important Interactions With VYVANSE

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.

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.

Drug Abuse And Dependence

Controlled Substance

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

Abuse

CNS stimulants, including VYVANSE, other amphetamines, and methylphenidate-containing products have a high potential for abuse. Abuse is characterized by impaired control over drug use, compulsive use, continued use despite harm, and craving.

Signs and symptoms of CNS stimulant abuse may include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, suicidal or homicidal ideation have also been seen. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which can result in overdose and death.

To reduce the abuse of CNS stimulants, including VYVANSE, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants, monitor for signs of abuse while on therapy, and re-evaluate the need for VYVANSE use.

Studies Of VYVANSE In Drug Abusers

A randomized, double-blind, placebo-control, cross-over, abuse liability study in 38 patients with a history of drug abuse was conducted with single-doses of 50, 100, or 150 mg of VYVANSE, 40 mg of immediate-release d-amphetamine sulphate (a controlled II substance), and 200 mg of diethylpropion hydrochloride (a controlled IV substance). VYVANSE 100 mg produced significantly less “Drug Liking Effects” as measured by the Drug Rating Questionnaire-Subject score, compared to d-amphetamine 40 mg; and 150 mg of VYVANSE demonstrated similar “Drug-Liking Effects” compared to 40 mg of d-amphetamine and 200 mg of diethylpropion.

Intravenous administration of 50 mg lisdexamfetamine dimesylate to individuals with a history of drug abuse produced positive subjective responses on scales measuring "Drug Liking", "Euphoria", "Amphetamine Effects", and "Benzedrine Effects" that were greater than placebo but less than those produced by an equivalent dose (20 mg) of intravenous d-amphetamine.

Dependence

Tolerance

Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug’s desired and/or undesired effects over time) may occur during the chronic therapy of CNS stimulants including VYVANSE.

Dependence

Physical dependence (a state of adaptation manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants including VYVANSE. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include extreme fatigue and depression.

Risk Summary

The limited available data from published literature and postmarketing reports on use of VYVANSE in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. Adverse pregnancy outcomes, including premature delivery and low birth weight, have been seen in infants born to mothers dependent on amphetamines [see Clinical Considerations]. In animal reproduction studies, lisdexamfetamine dimesylate (a prodrug of d-amphetamine) had no effects on embryo-fetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis. Pre-and postnatal studies were not conducted with lisdexamfetamine dimesylate. However, amphetamine (d-to l-ratio of 3:1) administration to pregnant rats during gestation and lactation caused a decrease in pup survival and a decrease in pup body weight that correlated with a delay in developmental landmarks at clinically relevant doses of amphetamine. In addition, adverse effects on reproductive performance were observed in pups whose mothers were treated with amphetamine. Long-term neurochemical and behavioral effects have also been reported in animal developmental studies using clinically relevant doses of amphetamine [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Amphetamines, such as VYVANSE, cause vasoconstriction and thereby may decrease placental perfusion. In addition, amphetamines can stimulate uterine contractions increasing the risk of premature delivery. Infants born to amphetamine-dependent mothers have an increased risk of premature delivery and low birth weight.

Monitor infants born to mothers taking amphetamines for symptoms of withdrawal such as feeding difficulties, irritability, agitation, and excessive drowsiness.

Data

Animal Data

Lisdexamfetamine dimesylate had no apparent effects on embryo-fetal morphological development or survival when administered orally to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 40 and 120 mg/kg/day, respectively. These doses are approximately 4 and 27 times, respectively, the maximum recommended human dose (MRHD) of 70 mg/day given to adolescents, on a mg/m² body surface area basis.

A study was conducted with amphetamine (d-to l-enantiomer ratio of 3:1) in which pregnant rats received daily oral doses of 2, 6, and 10 mg/kg from gestation day 6 to lactation day 20. These doses are approximately 0.8, 2, and 4 times the MRHD of amphetamine (d-to l-ratio of 3:1) for adolescents of 20 mg/day, on a mg/m² basis. All doses caused hyperactivity and decreased weight gain in the dams. A decrease in pup survival was seen at all doses. A decrease in pup body weight was seen at 6 and 10 mg/kg which correlated with delays in developmental landmarks, such as preputial separation and vaginal opening. Increased pup locomotor activity was seen at 10 mg/kg on day 22 postpartum but not at 5 weeks postweaning. When pups were tested for reproductive performance at maturation, gestational weight gain, number of implantations, and number of delivered pups were decreased in the group whose mothers had been given 10 mg/kg.

A number of studies from the literature in rodents indicate that prenatal or early postnatal exposure to amphetamine (d-or d,l-) at doses similar to those used clinically can result in longterm neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function.

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
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors
• Drug Dependence
• Serious Cardiovascular Reactions
• Blood Pressure and Heart Rate Increases
• Psychiatric Adverse Reactions
• Suppression of Growth
• Peripheral Vasculopathy, including Raynaud’s phenomenon
• Serotonin Syndrome

Clinical Trial Experience

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.

Attention Deficit Hyperactivity Disorder

The safety data in this section is based on data from the 4-week parallel-group controlled clinical studies of VYVANSE in pediatric and adult patients with ADHD.

Adverse Reactions Associated with Discontinuation of Treatment in ADHD Clinical Trials

In the controlled trial in patients ages 6 to 12 years (Study 1), 8% (18/218) of VYVANSE-treated patients discontinued due to adverse reactions compared to 0% (0/72) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were ECG voltage criteria for ventricular hypertrophy, tic, vomiting, psychomotor hyperactivity, insomnia, decreased appetite and rash [2 instances for each adverse reaction, i.e., 2/218 (1%)]. Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included abdominal pain upper, dry mouth, weight decreased, dizziness, somnolence, logorrhea, chest pain, anger and hypertension.

In the controlled trial in patients ages 13 to 17 years (Study 4), 3% (7/233) of VYVANSE-treated patients discontinued due to adverse reactions compared to 1% (1/77) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were decreased appetite (2/233; 1%) and insomnia (2/233; 1%). Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included irritability, dermatillomania, mood swings, and dyspnea.

In the controlled adult trial (Study 7), 6% (21/358) of VYVANSE-treated patients discontinued due to adverse reactions compared to 2% (1/62) of placebo-treated patients. The most frequently reported adverse reactions (1% or more and twice rate of placebo) were insomnia (8/358; 2%), tachycardia (3/358; 1%), irritability (2/358; 1%), hypertension (4/358; 1%), headache (2/358; 1%), anxiety (2/358; 1%), and dyspnea (3/358; 1%). Less frequently reported adverse reactions (less than 1% or less than twice rate of placebo) included palpitations, diarrhea, nausea, decreased appetite, dizziness, agitation, depression, paranoia and restlessness.

Adverse Reactions Occurring at an Incidence of ≥5% or More Among VYVANSE Treated Patients with ADHD in Clinical Trials

The most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) reported in children, adolescents, and/or adults were anorexia, anxiety, decreased appetite, decreased weight, diarrhea, dizziness, dry mouth, irritability, insomnia, nausea, upper abdominal pain, and vomiting.

Adverse Reactions Occurring at an Incidence of 2% or More Among VYVANSE Treated Patients with ADHD in Clinical Trials

Adverse reactions reported in the controlled trials in pediatric patients ages 6 to 12 years (Study 1), adolescent patients ages 13 to 17 years (Study 4), and adult patients (Study 7) treated with VYVANSE or placebo are presented in Tables 1, 2, and 3 below.

Table 1: Adverse Reactions Reported by 2% or More of Children (Ages 6 to 12 Years) with ADHD Taking VYVANSE and at least Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 1)

Table 2: Adverse Reactions Reported by 2% or More of Adolescent (Ages 13 to 17 Years) Patients with ADHD Taking VYVANSE and at least Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 4)

Table 3: Adverse Reactions Reported by 2% or More of Adult Patients with ADHD Taking VYVANSE and at least Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 7)

In addition, in the adult population erectile dysfunction was observed in 2.6% of males on VYVANSE and 0% on placebo; decreased libido was observed in 1.4% of subjects on VYVANSE and 0% on placebo.

Weight Loss and Slowing Growth Rate in Pediatric Patients with ADHD

In a controlled trial of VYVANSE in children ages 6 to 12 years (Study 1), mean weight loss from baseline after 4 weeks of therapy was -0.9, -1.9, and -2.5 pounds, respectively, for patients receiving 30 mg, 50 mg, and 70 mg of VYVANSE, compared to a 1 pound weight gain for patients receiving placebo. Higher doses were associated with greater weight loss with 4 weeks of treatment. Careful follow-up for weight in children ages 6 to 12 years who received VYVANSE over 12 months suggests that consistently medicated children (i.e. treatment for 7 days per week throughout the year) have a slowing in growth rate, measured by body weight as demonstrated by an age-and sex-normalized mean change from baseline in percentile, of -13.4 over 1 year (average percentiles at baseline and 12 months were 60.9 and 47.2, respectively). In a 4-week controlled trial of VYVANSE in adolescents ages 13 to 17 years, mean weight loss from baseline to endpoint was -2.7, -4.3, and -4.8 lbs., respectively, for patients receiving 30 mg, 50 mg, and 70 mg of VYVANSE, compared to a 2.0 pound weight gain for patients receiving placebo.

Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e. treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. In a controlled trial of amphetamine (d-to l-enantiomer ratio of 3:1) in adolescents, mean weight change from baseline within the initial 4 weeks of therapy was -1.1 pounds and -2.8 pounds, respectively, for patients receiving 10 mg and 20 mg of amphetamine. Higher doses were associated with greater weight loss within the initial 4 weeks of treatment.

Weight Loss in Adults with ADHD

In the controlled adult trial (Study 7), mean weight loss after 4 weeks of therapy was 2.8 pounds, 3.1 pounds, and 4.3 pounds, for patients receiving final doses of 30 mg, 50 mg, and 70 mg of VYVANSE, respectively, compared to a mean weight gain of 0.5 pounds for patients receiving placebo.

Binge Eating Disorder

The safety data in this section is based on data from two 12 week parallel group, flexible-dose, placebo-controlled studies in adults with BED. Patients with cardiovascular risk factors other than obesity and smoking were excluded.

Adverse Reactions Associated with Discontinuation of Treatment in BED Clinical Trials

In controlled trials of patients ages 18 to 55 years, 5.1% (19/373) of VYVANSE-treated patients discontinued due to adverse reactions compared to 2.4% (9/372) of placebo-treated patients. No single adverse reaction led to discontinuation in 1% or more of VYVANSE-treated patients. Less commonly reported adverse reactions (less than 1% or less than twice rate of placebo) included increased heart rate, headache, abdominal pain upper, dyspnea, rash, insomnia, irritability, feeling jittery and anxiety.

The most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) reported in adults were dry mouth, insomnia, decreased appetite, increased heart rate, constipation, feeling jittery, and anxiety.

Adverse reactions reported in the pooled controlled trials in adult patients (Study 11 and 12) treated with VYVANSE or placebo are presented in Table 4 below.

Table 4: Adverse Reactions Reported by 2% or More of Adult Patients with BED Taking VYVANSE and at least Twice the Incidence in Patients Taking Placebo in 12-Week Clinical Trials (Study 11 and 12)

Postmarketing Experience

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 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, tics, bruxism, depression, dermatillomania, alopecia, aggression, Stevens-Johnson Syndrome, chest pain, angioedema, urticaria, seizures, libido changes, frequent or prolonged erections, constipation, and rhabdomyolysis.

Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice for treatment of overdosage. Individual patient response to amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses.

Manifestations of amphetamine overdose include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Serotonin syndrome has been reported with amphetamine use, including VYVANSE. Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma.

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, 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.

Safety and efficacy have not been studied above the maximum recommended dose of 70 mg.

Absorption

Capsule Formulation

Following single-dose oral administration of VYVANSE capsule (30 mg, 50 mg, or 70 mg) in patients ages 6 to 12 years with ADHD under fasted conditions, Tmax of lisdexamfetamine and dextroamphetamine was reached at approximately 1 hour and 3.5 hour post dose, respectively. Weight/Dose normalized AUC and Cmax values were the same in pediatric patients ages 6 to 12 years as the adults following single doses of 30 mg to 70 mg VYVANSE capsule.

Food Effect On Capsule Formulation

Neither food (a high fat meal or yogurt) nor orange juice affects the observed AUC and Cmax of dextroamphetamine in healthy adults after single-dose oral administration of 70 mg of VYVANSE capsules. Food prolongs Tmax by approximately 1 hour (from 3.8 hour at fasted state to 4.7 hour after a high fat meal or to 4.2 hour with yogurt). After an 8-hour fast, the AUC for dextroamphetamine following oral administration of lisdexamfetamine dimesylate in solution and as intact capsules were equivalent.

Chewable Tablet Formulation

After a single dose administration of 60 mg VYVANSE chewable tablet in healthy subjects under fasted conditions, Tmax of lisdexamfetamine and dextroamphetamine was reached at approximately 1 hour and 4.4 hour post dose, respectively. Compared to 60 mg VYVANSE capsule, exposure (Cmax and AUC) to lisdexamfetamine was about 15% lower. The exposure (Cmax and AUCinf) of dextroamphetamine is similar between VYVANSE chewable tablet and VYVANSE capsule.

Food Effect on Tablet Formulation

Administration of 60 mg VYVANSE chewable tablet with food (a high-fat meal) decreases the exposure (Cmax and AUCinf) of dextroamphetamine by about 5% to 7%, and prolongs mean Tmax by approximately 1 hour (from 3.9 hrs at fasted state to 4.9 hours).

Elimination

Plasma concentrations of unconverted lisdexamfetamine are low and transient, generally becoming non-quantifiable by 8 hours after administration. The plasma elimination half-life of lisdexamfetamine typically averaged less than one hour in studies of lisdexamfetamine dimesylate in volunteers. The mean plasma elimination half-life of dextroamphetamine was about 12 hours after oral administration of lisdexamfetamine dimesylate.

Metabolism

Lisdexamfetamine is converted to dextroamphetamine and l-lysine primarily in blood due to the hydrolytic activity of red blood cells after oral administration of lisdexamfetamine dimesylate. In vitro data demonstrated that red blood cells have a high capacity for metabolism of lisdexamfetamine; substantial hydrolysis occurred even at low hematocrit levels (33% of normal). Lisdexamfetamine is not metabolized by cytochrome P450 enzymes.

Excretion

Following oral administration of a 70 mg dose of radiolabeled lisdexamfetamine dimesylate to 6 healthy subjects, approximately 96% of the oral dose radioactivity was recovered in the urine and only 0.3% recovered in the feces over a period of 120 hours. Of the radioactivity recovered in the urine, 42% of the dose was related to amphetamine, 25% to hippuric acid, and 2% to intact lisdexamfetamine.