Lisdexamfetamine dimesylate 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) [see Clinical Pharmacology (12.3)].
Do not take anything less than one capsule per day. A single dose should not be divided.
- Capsules 10 mg: Size 3 hard gelatin capsule with Opaque pink cap and body (imprinted with E0550 in black ink on cap and 10 mg on body)
- Capsules 20 mg: Size 3 hard gelatin capsule with Opaque Ivory cap and body (imprinted with E0551 in black ink on cap and 20 mg on body)
- Capsules 30 mg: Size 3 hard gelatin capsule with Opaque orange cap and white body (imprinted with E0552 in black ink on cap and 30 mg on body)
- Capsules 40 mg: Size 3 hard gelatin capsule with Opaque blue green cap and white body (imprinted with E0553 in black ink on cap and 40 mg on body)
- Capsules 50 mg: Size 3 hard gelatin capsule with Opaque blue cap and white body (imprinted with E0554 in black ink on cap and 50 mg on body)
- Capsules 60 mg: Size 3 hard gelatin capsule with Opaque Aqua blue cap and body (imprinted with E0555 in black ink on cap and 60 mg on body)
- Capsules 70 mg: Size 3 hard gelatin capsule with Opaque blue cap and orange body (imprinted with E0556 in black ink on cap and 70 mg on body)
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 manic or mixed episode. Prior to initiating lisdexamfetamine dimesylate capsule 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 the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing lisdexamfetamine dimesylate capsules.
Attention Deficit Hyperactivity Disorder
The safety data in this section is based on data from the 4-week controlled parallel-group clinical studies of lisdexamfetamine dimesylate in pediatric and adult patients with ADHD [see Clinical Studies (14.1)].
Adverse Reactions Associated with Discontinuation of Treatment in ADHD Clinical Trials
In the controlled trial in pediatric patients ages 6 to 12 years (Study 1), 8% (18/218) of lisdexamfetamine dimesylate-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 pediatric patients ages 13 to 17 years (Study 4), 3% (7/233) of lisdexamfetamine dimesylate-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 lisdexamfetamine dimesylate-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 Lisdexamfetamine Dimesylate Treated Patients with ADHD in Clinical Trials
The most common adverse reactions (incidence ≥5% and at a rate at least twice placebo) reported in pediatric patients ages 6 to 17 years, 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 Lisdexamfetamine Dimesylate Treated Patients with ADHD in Clinical Trials
Adverse reactions reported in the controlled trials in pediatric patients ages, 6 to 12 years (Study 1), pediatric patients ages 13 to 17 years (Study 4), and adult patients (Study 7) treated with lisdexamfetamine dimesylate or placebo are presented in Tables 1, 2 and 3 below.
Table 1 Adverse Reactions Reported by 2% or More of Pediatric Patients Ages 6 to 12 Years with ADHD Taking Lisdexamfetamine Dimesylate and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 1) | Lisdexamfetamine Dimesylate
(n=218) | Placebo
(n=72) |
|---|
| Decreased Appetite | 39% | 4% |
| Insomnia | 22% | 3% |
| Abdominal Pain Upper | 12% | 6% |
| Irritability | 10% | 0% |
| Vomiting | 9% | 4% |
| Weight Decreased | 9% | 1% |
| Nausea | 6% | 3% |
| Dry Mouth | 5% | 0% |
| Dizziness | 5% | 0% |
| Affect lability | 3% | 0% |
| Rash | 3% | 0% |
| Pyrexia | 2% | 1% |
| Somnolence | 2% | 1% |
| Tic | 2% | 0% |
| Anorexia | 2% | 0% |
Table 2 Adverse Reactions Reported by 2% or More of Pediatric Patients Ages 13 to 17 Years with ADHD Taking Lisdexamfetamine Dimesylate and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 4) | Lisdexamfetamine Dimesylate
(n=233) | Placebo
(n=77) |
|---|
| Decreased Appetite | 34% | 3% |
| Insomnia | 13% | 4% |
| Weight Decreased | 9% | 0% |
| Dry Mouth | 4% | 1% |
| Palpitations | 2% | 1% |
| Anorexia | 2% | 0% |
| Tremor | 2% | 0% |
Table 3 Adverse Reactions Reported by 2% or More of Adult Patients with ADHD Taking Lisdexamfetamine Dimesylate and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in a 4-Week Clinical Trial (Study 7) | Lisdexamfetamine Dimesylate
(n=358) | Placebo
(n=62) |
|---|
| Decreased Appetite | 27% | 2% |
| Insomnia | 27% | 8% |
| Dry Mouth | 26% | 3% |
| Diarrhea | 7% | 0% |
| Nausea | 7% | 0% |
| Anxiety | 6% | 0% |
| Anorexia | 5% | 0% |
| Feeling Jittery | 4% | 0% |
| Agitation | 3% | 0% |
| Increased Blood Pressure | 3% | 0% |
| Hyperhidrosis | 3% | 0% |
| Restlessness | 3% | 0% |
| Decreased Weight | 3% | 0% |
| Dyspnea | 2% | 0% |
| Increased Heart Rate | 2% | 0% |
| Tremor | 2% | 0% |
| Palpitations | 2% | 0% |
In addition, in the adult population erectile dysfunction was observed in 2.6% of males on lisdexamfetamine dimesylate and 0% on placebo; decreased libido was observed in 1.4% of subjects on lisdexamfetamine dimesylate and 0% on placebo.
Weight Loss and Slowing Growth Rate in Pediatric Patients with ADHD
In a controlled trial of lisdexamfetamine dimesylate in pediatric patients 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 lisdexamfetamine dimesylate, 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 pediatric patients ages 6 to 12 years who received lisdexamfetamine dimesylate over 12 months suggests that consistently medicated pediatric patients (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 lisdexamfetamine dimesylate in pediatric patients 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 lisdexamfetamine dimesylate, compared to a 2.0 pound weight gain for patients receiving placebo.
Careful follow-up of weight and height in pediatric patients 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 pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated pediatric patients ages 7 to 13 years (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 pediatric patients ages 13 to 17 years, 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 [see Warnings and Precautions (5.5)].
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 lisdexamfetamine dimesylate, 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 [see Clinical Studies 14.2]. 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 lisdexamfetamine dimesylate-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 lisdexamfetamine dimesylate-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.
Adverse Reactions Occurring at an Incidence of 5% or More and At Least Twice Placebo Among Lisdexamfetamine Dimesylate Treated Patients with BED in Clinical Trials
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 Occurring at an Incidence of 2% or More and At Least Twice Placebo Among Lisdexamfetamine Dimesylate Treated Patients with BED in Clinical Trials
Adverse reactions reported in the pooled controlled trials in adult patients (Study 11 and 12) treated with lisdexamfetamine dimesylate or placebo are presented in Table 4 below.
Table 4 Adverse Reactions Reported by 2% or More of Adult Patients with BED Taking Lisdexamfetamine Dimesylate and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in 12-Week Clinical Trials (Study 11 and 12) | Lisdexamfetamine Dimesylate
(N=373) | Placebo
(N=372) |
|---|
| Dry Mouth | 36% | 7% |
| Insomnia Includes all preferred terms containing the word "insomnia." | 20% | 8% |
| Decreased Appetite | 8% | 2% |
| Increased Heart Rate Includes the preferred terms "heart rate increased" and "tachycardia." | 7% | 1% |
| Feeling Jittery | 6% | 1% |
| Constipation | 6% | 1% |
| Anxiety | 5% | 1% |
| Diarrhea | 4% | 2% |
| Decreased Weight | 4% | 0% |
| Hyperhidrosis | 4% | 0% |
| Vomiting | 2% | 1% |
| Gastroenteritis | 2% | 1% |
| Paresthesia | 2% | 1% |
| Pruritus | 2% | 1% |
| Upper Abdominal Pain | 2% | 0% |
| Energy Increased | 2% | 0% |
| Urinary Tract Infection | 2% | 0% |
| Nightmare | 2% | 0% |
| Restlessness | 2% | 0% |
| Oropharyngeal Pain | 2% | 0% |
Risk Summary
The limited available data from published literature and postmarketing reports on use of lisdexamfetamine dimesylate capsules 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 lisdexamfetamine dimesylate capsules, 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 5.5 and 33 times, respectively, the maximum recommended human dose (MRHD) of 70 mg/day given to adults, 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. 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 long-term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function.
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 lisdexamfetamine dimesylate capsules.
ADHD
Safety and effectiveness of lisdexamfetamine dimesylate capsules have been established in pediatric patients with ADHD ages 6 to 17 years [see Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].
Safety and effectiveness of lisdexamfetamine dimesylate capsules have not been established in pediatric patients below the age of 6 years.
Safety and efficacy of lisdexamfetamine dimesylate were evaluated in a double-blind, randomized, parallel-group, placebo-controlled, fixed-dose study in pediatric patients ages 4 to 5 years with ADHD, followed by a 1-year open-label extension study. In these studies, patients experienced elevated rates of adverse reactions, including weight loss, decreased BMI, decreased appetite, insomnia, infections (upper respiratory and nasopharyngitis), irritability, and affect lability.
With the same lisdexamfetamine dimesylate dose, mean steady state exposure of dextroamphetamine was approximately 44% higher in pediatric patients ages 4 to 5 years compared to the pediatric patients ages 6 to 11 years.
BED
Safety and effectiveness of lisdexamfetamine dimesylate capsules have not been established in patients less than 18 years of age.
Growth Suppression
Growth should be monitored during treatment with stimulants, including lisdexamfetamine dimesylate capsules, and pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].
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.
Studies of Lisdexamfetamine Dimesylate 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 lisdexamfetamine dimesylate, 40 mg of immediate-release d-amphetamine sulphate (a controlled II substance), and 200 mg of diethylpropion hydrochloride (a controlled IV substance). Lisdexamfetamine dimesylate 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 lisdexamfetamine dimesylate 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.
Physical Dependence
Lisdexamfetamine dimesylate capsules may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including lisdexamfetamine dimesylate capsules include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.
Tolerance
Lisdexamfetamine dimesylate capsules may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
Information for Lisdexamfetamine Dimesylate Capsules:
Lisdexamfetamine Dimesylate capsules contain 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg of lisdexamfetamine dimesylate (equivalent to 5.8 mg, 11.6 mg, 17.3 mg, 23.1 mg, 28.9 mg, 34.7 mg, and 40.5 mg of lisdexamfetamine) and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and microcrystalline cellulose.
The capsule shells contain gelatin, titanium dioxide, shellac, black iron oxide and potassium hydroxide.
In addition, the 10 mg capsule contains FD&C blue #1 and FD&C red #3; 20mg capsule contains iron oxide yellow; 30mg capsule contains FD&C red #3 and FD&C yellow #6; 40mg contains FD&C blue #1, iron oxide yellow and iron oxide black; 50mg and 60mg contains FD&C blue #1; and 70mg contains FD&C blue#1, FD&C red #3 and FD&C yellow #6.
Absorption
Capsule formulation
Following single-dose oral administration of lisdexamfetamine dimesylate 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 hours 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 lisdexamfetamine dimesylate capsule.
Effect of food 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 lisdexamfetamine dimesylate capsules. Food prolongs Tmax by approximately 1 hour (from 3.8 hours at fasted state to 4.7 hours after a high fat meal or to 4.2 hours 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.
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 volunteers ages 6 years and older. The plasma elimination half-life of dextroamphetamine was approximately 8.6 to 9.5 hours in pediatric patients 6 to 12 years and 10 to 11.3 hours in healthy adults.
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.
Specific Populations
Exposures of dextroamphetamine in specific populations are summarized in Figure 1.
| Figure 1: Specific Populations Figure 1 shows the geometric mean ratios and the 90% confidence limits for Cmax and AUC of d-amphetamine. Comparison for gender uses males as the reference. Comparison for age uses 55-64 years as the reference. : |
|
Drug Interaction Studies
Effects of other drugs on the exposures of dextroamphetamine are summarized in Figure 2.
| Figure 2: Effect of Other Drugs on Lisdexamfetamine Dimesylate Capsules: |
|
The effects of lisdexamfetamine dimesylate capsules on the exposures of other drugs are summarized in Figure 3.
| Figure 3: Effect of Lisdexamfetamine Dimesylate Capsules on Other Drugs: |
|
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.
Pediatric Patients Ages 6 to 12 Years with ADHD
A double-blind, randomized, placebo-controlled, parallel-group study (Study 1) was conducted in pediatric patients ages 6 to 12 years (N=290) who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type). Patients were randomized to receive final doses of 30 mg, 50 mg, or 70 mg of lisdexamfetamine dimesylate or placebo once daily in the morning for a total of four weeks of treatment. All patients receiving lisdexamfetamine dimesylate were initiated on 30 mg for the first week of treatment. Patients assigned to the 50 mg and 70 mg dose groups were titrated by 20 mg per week until they achieved their assigned dose. The primary efficacy outcome was change in Total Score from baseline to endpoint in investigator ratings on the ADHD Rating Scale (ADHD-RS), an 18-item questionnaire with a score range of 0-54 points that measures the core symptoms of ADHD which includes both hyperactive/impulsive and inattentive subscales. Endpoint was defined as the last post-randomization treatment week (i.e., Weeks 1 through 4) for which a valid score was obtained. All lisdexamfetamine dimesylate dose groups were superior to placebo in the primary efficacy outcome. Mean effects at all doses were similar; however, the highest dose (70 mg/day) was numerically superior to both lower doses (Study 1 in Table 6). The effects were maintained throughout the day based on parent ratings (Conners' Parent Rating Scale) in the morning (approximately 10 am), afternoon (approximately 2 pm), and early evening (approximately 6 pm).
A double-blind, placebo-controlled, randomized, crossover design, analog classroom study (Study 2) was conducted in pediatric patients ages 6 to 12 years (N=52) who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type). Following a 3-week open-label dose optimization with Adderall XR®, patients were randomly assigned to continue their optimized dose of Adderall XR (10 mg, 20 mg, or 30 mg), lisdexamfetamine dimesylate (30 mg, 50 mg, or 70 mg), or placebo once daily in the morning for 1 week each treatment. Efficacy assessments were conducted at 1, 2, 3, 4.5, 6, 8, 10, and 12 hours post-dose using the Swanson, Kotkin, Agler, M.Flynn, and Pelham Deportment scores (SKAMP-DS), a 4-item subscale of the SKAMP with scores ranging from 0 to 24 points that measures deportment problems leading to classroom disruptions. A significant difference in patient behavior, based upon the average of investigator ratings on the SKAMP-DS across the 8 assessments were observed between patients when they received lisdexamfetamine dimesylate compared to patients when they received placebo (Study 2 in Table 6). The drug effect reached statistical significance from hours 2 to 12 post-dose, but was not significant at 1 hour.
A second double-blind, placebo-controlled, randomized, crossover design, analog classroom study (Study 3) was conducted in pediatric patients ages 6 to 12 years (N=129) who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type). Following a 4-week open-label dose optimization with lisdexamfetamine dimesylate (30 mg, 50 mg, 70 mg), patients were randomly assigned to continue their optimized dose of lisdexamfetamine dimesylate or placebo once daily in the morning for 1 week each treatment. A significant difference in patient behavior, based upon the average of investigator ratings on the SKAMP-Deportment scores across all 7 assessments conducted at 1.5, 2.5, 5.0, 7.5, 10.0, 12.0, and 13.0 hours post-dose, were observed between patients when they received lisdexamfetamine dimesylate compared to patients when they received placebo (Study 3 in Table 6, Figure 4).
Pediatric Patients Ages 13 to 17 Years with ADHD
A double-blind, randomized, placebo-controlled, parallel-group study (Study 4) was conducted in pediatric patients ages 13 to 17 years (N=314) who met DSM-IV criteria for ADHD. In this study, patients were randomized in a 1:1:1:1 ratio to a daily morning dose of lisdexamfetamine dimesylate (30 mg/day, 50 mg/day or 70 mg/day) or placebo for a total of four weeks of treatment. All patients receiving lisdexamfetamine dimesylate were initiated on 30 mg for the first week of treatment. Patients assigned to the 50 mg and 70 mg dose groups were titrated by 20 mg per week until they achieved their assigned dose. The primary efficacy outcome was change in Total Score from baseline to endpoint in investigator ratings on the ADHD Rating Scale (ADHD-RS). Endpoint was defined as the last post-randomization treatment week (i.e., Weeks 1 through 4) for which a valid score was obtained. All lisdexamfetamine dimesylate dose groups were superior to placebo in the primary efficacy outcome (Study 4 in Table 6).
Pediatric Patients Ages 6 to 17 Years: Short-Term Treatment in ADHD
A double-blind, randomized, placebo- and active-controlled parallel-group, dose-optimization study (Study 5) was conducted in pediatric patients ages 6 to 17 years (n=336) who met DSM-IV criteria for ADHD. In this eight-week study, patients were randomized to a daily morning dose of lisdexamfetamine dimesylate (30, 50 or 70 mg/day), an active control, or placebo (1:1:1). The study consisted of a Screening and Washout Period (up to 42 days), a 7-week Double-blind Evaluation Period (consisting of a 4-week Dose-Optimization Period followed by a 3-week Dose-Maintenance Period), and a 1-week Washout and Follow-up Period. During the Dose Optimization Period, subjects were titrated until an optimal dose, based on tolerability and investigator's judgment, was reached. Lisdexamfetamine dimesylate showed significantly greater efficacy than placebo. The placebo-adjusted mean reduction from baseline in the ADHD-RS-IV total score was 18.6. Subjects on lisdexamfetamine dimesylate also showed greater improvement on the Clinical Global Impression-Improvement (CGI-I) rating scale compared to subjects on placebo (Study 5 in Table 6).
Pediatric Patients Ages 6 to 17 Years: Maintenance Treatment in ADHD
Maintenance of Efficacy Study (Study 6) - A double-blind, placebo-controlled, randomized withdrawal study was conducted in pediatric patients ages 6 to 17 years (N=276) who met the diagnosis of ADHD (DSM-IV criteria). A total of 276 patients were enrolled into the study, 236 patients participated in Study 5 and 40 subjects directly enrolled. Subjects were treated with open-label lisdexamfetamine dimesylate for at least 26 weeks prior to being assessed for entry into the randomized withdrawal period. Eligible patients had to demonstrate treatment response as defined by CGI-S <3 and Total Score on the ADHD-RS ≤22. Patients that maintained treatment response for 2 weeks at the end of the open label treatment period were eligible to be randomized to ongoing treatment with the same dose of lisdexamfetamine dimesylate (N=78) or switched to placebo (N=79) during the double-blind phase. Patients were observed for relapse (treatment failure) during the 6 week double blind phase. A significantly lower proportion of treatment failures occurred among lisdexamfetamine dimesylate subjects (15.8%) compared to placebo (67.5%) at endpoint of the randomized withdrawal period. The endpoint measurement was defined as the last post-randomization treatment week at which a valid ADHD-RS Total Score and CGI-S were observed. Treatment failure was defined as a ≥50% increase (worsening) in the ADHD-RS Total Score and a ≥2-point increase in the CGI-S score compared to scores at entry into the double-blind randomized withdrawal phase. Subjects who withdrew from the randomized withdrawal period and who did not provide efficacy data at their last on-treatment visit were classified as treatment failures (Study 6, Figure 5).
Adults: Short-Term Treatment in ADHD
A double-blind, randomized, placebo-controlled, parallel-group study (Study 7) was conducted in adults ages 18 to 55 (N=420) who met DSM-IV criteria for ADHD. In this study, patients were randomized to receive final doses of 30 mg, 50 mg, or 70 mg of lisdexamfetamine dimesylate or placebo for a total of four weeks of treatment. All patients receiving lisdexamfetamine dimesylate were initiated on 30 mg for the first week of treatment. Patients assigned to the 50 mg and 70 mg dose groups were titrated by 20 mg per week until they achieved their assigned dose. The primary efficacy outcome was change in Total Score from baseline to endpoint in investigator ratings on the ADHD Rating Scale (ADHD-RS). Endpoint was defined as the last post-randomization treatment week (i.e., Weeks 1 through 4) for which a valid score was obtained. All lisdexamfetamine dimesylate dose groups were superior to placebo in the primary efficacy outcome (Study 7 in Table 6).
The second study was a multi-center, randomized, double-blind, placebo-controlled, cross-over, modified analog classroom study (Study 8) of lisdexamfetamine dimesylate to simulate a workplace environment in 142 adults ages 18 to 55 who met DSM-IV-TR criteria for ADHD. There was a 4-week open-label, dose optimization phase with lisdexamfetamine dimesylate (30 mg/day, 50 mg/day, or 70 mg/day in the morning). Patients were then randomized to one of two treatment sequences: 1) lisdexamfetamine dimesylate (optimized dose) followed by placebo, each for one week, or 2) placebo followed by lisdexamfetamine dimesylate, each for one week. Efficacy assessments occurred at the end of each week, using the Permanent Product Measure of Performance (PERMP), a skill-adjusted math test that measures attention in ADHD. PERMP total score results from the sum of the number of math problems attempted plus the number of math problems answered correctly. Lisdexamfetamine dimesylate treatment, compared to placebo, resulted in a statistically significant improvement in attention across all post-dose time points, as measured by average PERMP total scores over the course of one assessment day, as well as at each time point measured. The PERMP assessments were administered at pre-dose (-0.5 hours) and at 2, 4, 8,10,12, and 14 hours post-dose (Study 8 in Table 6, Figure 6).
Adults: Maintenance Treatment in ADHD
A double-blind, placebo-controlled, randomized withdrawal design study (Study 9) was conducted in adults ages 18 to 55 (N=123) who had a documented diagnosis of ADHD or met DSM-IV criteria for ADHD. At study entry, patients must have had documentation of treatment with lisdexamfetamine dimesylate for a minimum of 6 months and had to demonstrate treatment response as defined by Clinical Global Impression Severity (CGI-S) ≤3 and Total Score on the ADHD-RS <22. ADHD-RS Total Score is a measure of core symptoms of ADHD. The CGI-S score assesses the clinician's impression of the patient's current illness state and ranges from 1 (not at all ill) to 7 (extremely ill). Patients that maintained treatment response at Week 3 of the open label treatment phase (N=116) were eligible to be randomized to ongoing treatment with the same dose of lisdexamfetamine dimesylate (N=56) or switched to placebo (N=60) during the double-blind phase. Patients were observed for relapse (treatment failure) during the 6-week double-blind phase. The efficacy endpoint was the proportion of patients with treatment failure during the double-blind phase. Treatment failure was defined as a ≥50% increase (worsening) in the ADHD-RS Total Score and ≥2-point increase in the CGI-S score compared to scores at entry into the double-blind phase. Maintenance of efficacy for patients treated with lisdexamfetamine dimesylate was demonstrated by the significantly lower proportion of patients with treatment failure (9%) compared to patients receiving placebo (75%) at endpoint during the double-blind phase (Study 9, Figure 7).
Table 6: Summary of Primary Efficacy Results from Short-term Studies of Lisdexamfetamine Dimesylate Capsules in Pediatric Patients (Ages 6 to 17) and Adults with ADHD| Study Number (Age range) | Primary Endpoint | Treatment Group | Mean Baseline Score (SD) | LS Mean Change from Baseline (SE) | Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. (95% CI) |
|---|
| SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval. |
Study 1
(6 - 12 years) | ADHD-RS-IV | Lisdexamfetamine Dimesylate Capsules (30 mg/day) Doses statistically significantly superior to placebo. | 43.2 (6.7) | -21.8 (1.6) | -15.6 (-19.9, -11.2) |
| Lisdexamfetamine Dimesylate Capsules (50 mg/day) | 43.3 (6.7) | -23.4 (1.6) | -17.2 (-21.5, -12.9) |
| Lisdexamfetamine Dimesylate Capsules (70 mg/day) | 45.1(6.8) | -26.7 (1.5) | -20.5 (-24.8, -16.2) |
| Placebo | 42.4 (7.1) | -6.2 (1.6) | -- |
Study 2
(6 - 12 years) | Average SKAMP-DS | Lisdexamfetamine Dimesylate Capsules (30, 50 or 70 mg/day) | -- Pre-dose SKAMP-DS was not collected. | 0.8 (0.1) LS Mean for SKAMP-DS (Study 2 and 3) or PERMP (Study 8) is post-dose average score over all sessions of the treatment day, rather than change from baseline. | -0.9 (-1.1, -0.7) |
| Placebo | -- | 1.7 (0.1) | -- |
Study 3
(6 - 12 years) | Average SKAMP-DS | Lisdexamfetamine Dimesylate Capsules (30, 50 or 70 mg/day) | 0.9 (1.0) Pre-dose SKAMP-DS (Study 3) or PERMP (Study 8) total score, averaged over both periods. | 0.7 (0.1) | -0.7 (-0.9, -0.6) |
| Placebo | 0.7 (0.9) | 1.4 (0.1) | -- |
Study 4
(13 - 17 years) | ADHD-RS-IV | Lisdexamfetamine Dimesylate Capsules (30 mg/day) | 38.3 (6.7) | -18.3 (1.2) | -5.5 (-9.0, -2.0) |
| Lisdexamfetamine Dimesylate Capsules (50 mg/day) | 37.3 (6.3) | -21.1 (1.3) | -8.3 (-11.8, -4.8) |
| Lisdexamfetamine Dimesylate Capsules (70 mg/day) | 37.0 (7.3) | -20.7 (1.3) | -7.9 (-11.4, -4.5) |
| Placebo | 38.5 (7.1) | -12.8 (1.2) | -- |
Study 5
(6 - 17 years) | ADHD-RS-IV | Lisdexamfetamine Dimesylate Capsules (30, 50 or 70 mg/day) | 40.7 (7.3) | -24.3 (1.2) | -18.6 (-21.5, -15.7) |
| Placebo | 41.0 (7.1) | -5.7 (1.1) | -- |
Study 7
(18 - 55 years) | ADHD-RS-IV | Lisdexamfetamine Dimesylate Capsules (30 mg/day) | 40.5 (6.2) | -16.2 (1.1) | -8.0 (-11.5, -4.6) |
| Lisdexamfetamine Dimesylate Capsules (50 mg/day) | 40.8 (7.3) | -17.4 (1.0) | -9.2 (-12.6, -5.7) |
| Lisdexamfetamine Dimesylate Capsules (70 mg/day) | 41.0 (6.0) | -18.6 (1.0) | -10.4 (-13.9, -6.9) |
| Placebo | 39.4 (6.4) | -8.2 (1.4) | -- |
Study 8
(18 - 55 years) | Average PERMP | Lisdexamfetamine Dimesylate Capsules (30, 50 or 70 mg/day) | 260.1 (86.2) | 312.9 (8.6) | 23.4 (15.6, 31.2) |
| Placebo | 261.4 (75.0) | 289.5 (8.6) | -- |
Figure 4 LS Mean SKAMP Deportment Subscale Score by Treatment and Time-point for Pediatric Patients Ages 6 to 12 with ADHD after 1 Week of Double Blind Treatment (Study 3)
Higher score on the SKAMP-Deportment scale indicates more severe symptoms
Figure 5 Kaplan-Meier Estimated Proportion of Patients with Treatment Failure for Pediatric Patients Ages 6 to 17 (Study 6)
Figure 6 LS Mean (SE) PERMP Total Score by Treatment and Time-point for Adults Ages 18 to 55 with ADHD after 1 Week of Double Blind Treatment (Study 8)
Higher score on the PERMP scale indicates less severe symptoms
Figure 7 Kaplan-Meier Estimated Proportion of Subjects with Relapse in Adults with ADHD (Study 9)
Lisdexamfetamine Dimesylate Capsules:
- Lisdexamfetamine Dimesylate Capsules 10 mg: Opaque pink cap and body, Hard gelatin capsules, imprinted with black ink E0550 on cap and 10 mg on body, Bottles of 100, NDC 64850-550-01
- Lisdexamfetamine Dimesylate Capsules 20 mg: Opaque ivory cap and body, Hard gelatin capsules, imprinted with black ink E0551 on cap and 20 mg on body, Bottles of 100, NDC 64850-551-01
- Lisdexamfetamine Dimesylate Capsules 30 mg: Opaque orange cap and white body, Hard gelatin capsules, imprinted with black ink E0552 on cap and 30 mg on body, Bottles of 100, NDC 64850-552-01
- Lisdexamfetamine Dimesylate Capsules 40 mg: Opaque blue green cap and white body, Hard gelatin capsules, imprinted with black ink E0553 on cap and 40 mg on body, Bottles of 100, NDC 64850-553-01
- Lisdexamfetamine Dimesylate Capsules 50 mg: Opaque blue cap and white body, Hard gelatin capsule, imprinted with black ink E0554 on cap and 50 mg on body, Bottles of 100, NDC 64850-554-01
- Lisdexamfetamine Dimesylate Capsules 60 mg: Opaque aqua blue cap and body, Hard gelatin capsule, imprinted with black ink E0555 on cap and 60 mg on body, Bottles of 100, NDC 64850-555-01
- Lisdexamfetamine Dimesylate Capsules 70 mg: Opaque blue cap and orange body, Hard gelatin capsule, imprinted with black ink E0556 on cap and 70 mg on body, Bottles of 100, NDC 64850-556-01
Abuse, Misuse, and Addiction
Educate patients and their families about the risks of abuse, misuse, and addiction of lisdexamfetamine dimesylate capsules, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2), Overdosage (10)]. Advise patients to store lisdexamfetamine dimesylate capsules in a safe place, preferably locked, and instruct patients to not give lisdexamfetamine dimesylate capsules to anyone else.
Risks to Patients with Serious Cardiac Disease
Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with lisdexamfetamine dimesylate capsules 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 [see Warnings and Precautions (5.2)].
Increased Blood Pressure and Heart Rate
Instruct patients that lisdexamfetamine dimesylate capsules can cause elevations of their blood pressure and pulse rate and they should be monitored for such effects.
Psychiatric Adverse Reactions
Advise patients that lisdexamfetamine dimesylate capsules at recommended doses may cause psychotic or manic symptoms even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)].
Long-Term Suppression of Growth in Pediatric Patients
Advise patients that lisdexamfetamine dimesylate capsules may cause slowing of growth including weight loss [see Warnings and Precautions (5.5)].
Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud's phenomenon]
Instruct patients beginning treatment with lisdexamfetamine dimesylate capsules 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 lisdexamfetamine dimesylate capsules. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6)].
Serotonin Syndrome
Caution patients about the risk of serotonin syndrome with concomitant use of lisdexamfetamine dimesylate capsules 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 [see Contraindications (4), Warnings and Precautions (5.7) and Drug Interactions (7.1)]. 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 [see Drug Interactions (7.1)].
Motor and Verbal Tics, and Worsening of Tourette’s Syndrome
Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with lisdexamfetamine dimesylate capsules. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions (5.8)].
Administration Instructions
- Capsules: Advise patients to take the capsules whole or empty and mix the entire contents with yogurt, water, or orange juice. Advise patients to consume the mixture immediately and not to store for future use [see Dosage and Administration (2.2)].
Manufactured by:
Elite Laboratories, Inc.
Northvale, NJ 07647
Made in USA
For more information call 1-888-852-6657
IN0552
Rev. 05/2024
The trademarks referenced herein are registered trademarks of its respective owner.
