FDA Label for Lisdexamfetamine Dimesylate

Warning: Abuse And Dependence

CNS stimulants, including lisdexamfetamine dimesylate capsules, other amphetamine-containing products, and methylphenidate, 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 [see Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)].

1 Indications And Usage

Lisdexamfetamine dimesylate capsules are indicated for the treatment of:

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

Limitations of Use:

• Pediatric patients with ADHD younger than 6 years of age experienced more long-term weight loss than patients 6 years and older [see Use in Specific Populations (8.4)].
• Lisdexamfetamine dimesylate capsules are 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 lisdexamfetamine dimesylate capsules for the treatment of obesity have not been established [see Warnings and Precautions (5.2)].

2.1        Pre-Treatment Screening

Prior to treating patients with CNS stimulants, including lisdexamfetamine dimesylate capsules, assess for the presence of cardiac disease (e.g., a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)].

To reduce the abuse of CNS stimulants including lisdexamfetamine dimesylate capsules, 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 lisdexamfetamine dimesylate capsules use [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].

2.2        General Instructions For Use

Take lisdexamfetamine dimesylate capsules by mouth in the morning with or without food; avoid afternoon doses because of the potential for insomnia. Lisdexamfetamine dimesylate capsules may be administered in one of the following ways:

Information for lisdexamfetamine dimesylate capsules:

• Swallow lisdexamfetamine dimesylate 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.

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

2.3        Dosage For Treatment Of Adhd

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

2.4        Dosage For Treatment Of Moderate To Severe Bed In Adults

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

2.5        Dosage In Patients With Renal Impairment

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

2.6        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 lisdexamfetamine dimesylate capsules dosage accordingly [see Drug Interactions (7.1)].

3 Dosage Forms And Strengths

Lisdexamfetamine dimesylate capsules:

• Capsules 10 mg: Opaque Pink Cap/Opaque Pink Body, Hard Gelatin Capsules, imprinted with black ink “10 mg” on the body and “M” in a box over “5111” on the cap
• Capsules 20 mg: Opaque Yellow Cap/Opaque Yellow Body, Hard Gelatin Capsules, imprinted with black ink “20 mg” on the body and “M” in a box over “5112” on the cap
• Capsules 30 mg: Opaque Orange Cap/Opaque White Body, Hard Gelatin Capsules, imprinted with black ink “30 mg” on the body and “M” in a box over “5113” on the cap
• Capsules 40 mg: Opaque Green Cap/Opaque White Body, Hard Gelatin Capsules, imprinted with black ink “40 mg” on the body and “M” in a box over “5114” on the cap
• Capsules 50 mg: Opaque Blue Cap/Opaque White Body, Hard Gelatin Capsules, imprinted with black ink “50 mg” on the body and “M” in a box over “5115” on the cap
• Capsules 60 mg: Opaque Blue Cap/Opaque Blue Body, Hard Gelatin Capsules, imprinted with black ink “60 mg” on the body and “M” in a box over “5116” on the cap
• Capsules 70 mg: Opaque Orange Cap/Opaque Blue Body, Hard Gelatin Capsules, imprinted with black ink “70 mg” on the body and “M” in a box over “5117” on the cap

4 Contraindications

Lisdexamfetamine dimesylate capsules are contraindicated in patients with:

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

5.1        Potential For Abuse And Dependence

CNS stimulants, including lisdexamfetamine dimesylate capsules, other amphetamine-containing products, and methylphenidate, 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 [see Drug Abuse and Dependence (9.2, 9.3)].

5.2        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 pediatric patients 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 lisdexamfetamine dimesylate capsules treatment.

5.3        Blood Pressure And Heart Rate Increases

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

5.4        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 patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing lisdexamfetamine dimesylate capsules. 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.

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

Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Lisdexamfetamine dimesylate capsules are not approved for use in pediatric patients below 6 years of age [see Use in Specific Populations (8.4)].

5.6        Peripheral Vasculopathy, Including Raynaud’S Phenomenon

Stimulants, including lisdexamfetamine dimesylate capsules, 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 postmarketing 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.

5.7        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 [see Drug Interactions (7.1)]. The co-administration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to the active metabolite of lisdexamfetamine dimesylate capsules (dextroamphetamine). In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6 [see Drug Interactions (7.1)].

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

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

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

6 Adverse Reactions

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

• Known hypersensitivity to amphetamine products or other ingredients of lisdexamfetamine dimesylate capsules [see Contraindications (4)]
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) and Drug Interactions (7.1)]
• Drug Dependence [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)]
• Serious Cardiovascular Reactions [see Warnings and Precautions (5.2)]
• Blood Pressure and Heart Rate Increases [see Warnings and Precautions (5.3)]
• Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
• Suppression of Growth [see Warnings and Precautions (5.5)]
• Peripheral Vasculopathy, including Raynaud’s phenomenon [see Warnings and Precautions (5.6)]
• Serotonin Syndrome [see Warnings and Precautions (5.7)]

6.1        Clinical Trials 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 controlled parallel-group clinical studies of lisdexamfetamine dimesylate capsules 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 capsules-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 capsules-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 capsules-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 Capsules-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 Capsules-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 capsules 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 Capsules and Greater than or Equal to 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 Pediatric Patients Ages 13 to 17 Years with ADHD Taking Lisdexamfetamine Dimesylate Capsules and Greater than or Equal to 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 Lisdexamfetamine Dimesylate Capsules and Greater than or Equal to 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 lisdexamfetamine dimesylate capsules and 0% on placebo; decreased libido was observed in 1.4% of subjects on lisdexamfetamine dimesylate capsules and 0% on placebo.

Weight Loss and Slowing Growth Rate in Pediatric Patients with ADHD
In a controlled trial of lisdexamfetamine dimesylate capsules 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 capsules, 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 capsules 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 capsules 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 capsules, 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 capsules, 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 capsules-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 capsules-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 Capsules-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 Capsules-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 capsules 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 Capsules and Greater than or Equal to Twice the Incidence in Patients Taking Placebo in 12-Week Clinical Trials (Study 11 and 12)

¹ Includes all preferred terms containing the word “insomnia.”

² Includes the preferred terms “heart rate increased” and “tachycardia.”

6.2        Postmarketing Experience

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

7.1        Drugs Having Clinically Important Interactions With Amphetamines

Table 5    Drugs having clinically important interactions with amphetamines.

7.2        Drugs Having No Clinically Important Interactions With Lisdexamfetamine Dimesylate Capsules

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

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

8.1        Pregnancy

Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and researchprograms/pregnancyregistry/adhdmedications/.

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 to 4% and 15 to 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.

8.2        Lactation

Risk Summary
Lisdexamfetamine is a prodrug 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.

8.4        Pediatric Use

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 capsules 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 capsules 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), 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.

8.5        Geriatric Use

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

8.6        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 [see Clinical Pharmacology (12.3)].

Lisdexamfetamine and d-amphetamine are not dialyzable.

9.1        Controlled Substance

Lisdexamfetamine dimesylate capsules contain lisdexamfetamine, a prodrug of amphetamine, a Schedule II controlled substance.

9.2        Abuse

CNS stimulants, including lisdexamfetamine dimesylate capsules, other amphetamine-containing products, and methylphenidate have a high potential for abuse. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Abuse is characterized by impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Both abuse and misuse may lead to addiction, and some individuals may develop addiction even when taking lisdexamfetamine dimesylate capsules as prescribed.

Signs and symptoms of amphetamine 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 [see Overdosage (10)].

To reduce the abuse of CNS stimulants, including lisdexamfetamine dimesylate capsules, 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 lisdexamfetamine dimesylate capsules use.

Studies of Lisdexamfetamine Dimesylate Capsules 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 capsules, 40 mg of immediate-release d-amphetamine sulphate (a controlled II substance), and 200 mg of diethylpropion hydrochloride (a controlled IV substance). Lisdexamfetamine dimesylate capsules 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 capsules 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.

9.3        Dependence

Physical Dependence
Lisdexamfetamine dimesylate capsules may produce physical dependence from continued therapy. Physical dependence is a state of adaptation manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include extreme fatigue and depression.

Tolerance
Lisdexamfetamine dimesylate capsules may produce tolerance from continued therapy. Tolerance is a state of adaptation in which exposure to a specific dose of a drug results in a reduction of the drug’s desired and/or undesired effects over time.

10 Overdosage

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 lisdexamfetamine dimesylate capsules. 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.

11 Description

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

Chemical Structure - lisdexamfetamine dimesylate 1

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

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).

Inactive ingredients: silicified microcrystalline cellulose, silicon dioxide, croscarmellose sodium, and magnesium stearate. The capsule shells contain gelatin, sodium lauryl sulfate, water, titanium dioxide, and one or more of the following: FD&C Red No. 3, FD&C Yellow No. 6, FD&C Blue No. 1, Ferric Oxide Yellow, shellac glaze, and Black Iron Oxide.

12.1      Mechanism Of Action

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

12.2      Pharmacodynamics

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.

12.3      Pharmacokinetics

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

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, T_max of lisdexamfetamine and dextroamphetamine was reached at approximately 1 hour and 3.5 hours post-dose, respectively. Weight/Dose normalized AUC and C_max 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 C_max of dextroamphetamine in healthy adults after single-dose oral administration of 70 mg of lisdexamfetamine dimesylate capsules. Food prolongs T_max 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 - lisdexamfetamine dimesylate 2

*Figure 1 shows the geometric mean ratios and the 90% confidence limits for C_max and AUC of d-amphetamine. Comparison for gender uses males as the reference. Comparison for age uses 55 to 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

13.1      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.

13.2      Animal Toxicology And/Or Pharmacology

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

14.1      Attention Deficit Hyperactivity Disorder (Adhd)

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 capsules or placebo once daily in the morning for a total of four weeks of treatment. All patients receiving lisdexamfetamine dimesylate capsules 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 to 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 capsules 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 capsules (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 capsules 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 capsules (30 mg, 50 mg, 70 mg), patients were randomly assigned to continue their optimized dose of lisdexamfetamine dimesylate capsules 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 capsules 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 capsules (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 capsules 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 capsules 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 capsules (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 capsules 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 capsules 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 capsules 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 capsules (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 capsules 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 capsules or placebo for a total of four weeks of treatment. All patients receiving lisdexamfetamine dimesylate capsules 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 capsules 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 capsules 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 capsules (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 capsules (optimized dose) followed by placebo, each for one week, or 2) placebo followed by lisdexamfetamine dimesylate capsules, 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 capsules 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 capsules 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 capsules (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 capsules 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

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.

* Difference (drug minus placebo) in least-squares mean change from baseline.

^† Doses statistically significantly superior to placebo.

^‡ Pre-dose SKAMP-DS was not collected.

^§ 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.

^¶ Pre-dose SKAMP-DS (Study 3) or PERMP (Study 8) total score, averaged over both periods.

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)

Figure 4 - lisdexamfetamine dimesylate 5

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)

14.2      Binge Eating Disorder (Bed)

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

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

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

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

Table 7    Summary of Primary Efficacy Results in BED

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.

* Difference (drug minus placebo) in least-squares mean change from baseline.

^† Doses statistically significantly superior to placebo.

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

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

Figure 8 - lisdexamfetamine dimesylate 9

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

16.1      How Supplied

Lisdexamfetamine Dimesylate Capsules:

• Lisdexamfetamine Dimesylate Capsules 10 mg: Opaque Pink Cap/Opaque Pink Body, Hard Gelatin Capsules, imprinted with black ink “10 mg” on the body and “M” in a box over “5111” on the cap
  
  Bottles of 100.................................................. NDC 0406-5111-01
  
• Lisdexamfetamine Dimesylate Capsules 20 mg: Opaque Yellow Cap/Opaque Yellow Body, Hard Gelatin Capsules, imprinted with black ink “20 mg” on the body and “M” in a box over “5112” on the cap
  
  Bottles of 100.................................................. NDC 0406-5112-01
• Lisdexamfetamine Dimesylate Capsules 30 mg: Opaque Orange Cap/Opaque White Body, Hard Gelatin Capsules, imprinted with black ink “30 mg” on the body and “M” in a box over “5113” on the cap

  Bottles of 100.................................................. NDC 0406-5113-01

• Lisdexamfetamine Dimesylate Capsules 40 mg: Opaque Green Cap/Opaque White Body, Hard Gelatin Capsules, imprinted with black ink “40 mg” on the body and “M” in a box over “5114” on the cap

  Bottles of 100.................................................. NDC 0406-5114-01

• Lisdexamfetamine Dimesylate Capsules 50 mg: Opaque Blue Cap/Opaque White Body, Hard Gelatin Capsules, imprinted with black ink “50 mg” on the body and “M” in a box over “5115” on the cap

  Bottles of 100.................................................. NDC 0406-5115-01

• Lisdexamfetamine Dimesylate Capsules 60 mg: Opaque Blue Cap/Opaque Blue Body, Hard Gelatin Capsules, imprinted with black ink “60 mg” on the body and “M” in a box over “5116” on the cap

  Bottles of 100.................................................. NDC 0406-5116-01

• Lisdexamfetamine Dimesylate Capsules 70 mg: Opaque Orange Cap/Opaque Blue Body, Hard Gelatin Capsules, imprinted with black ink “70 mg” on the body and “M” in a box over “5117” on the cap
  
  Bottles of 100.................................................. NDC 0406-5117-01

16.2      Storage And Handling

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

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

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

17 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 lisdexamfetamine dimesylate capsules are a controlled substance and it can be abused and lead to dependence and not to give lisdexamfetamine dimesylate capsules to anyone else [see Drug Abuse and Dependence (9.1, 9.2, and 9.3)]. Advise patients to store lisdexamfetamine dimesylate capsules in a safe place, preferably locked, to prevent abuse. Advise patients to dispose of remaining, unused, or expired lisdexamfetamine dimesylate capsules 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 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)].

Hypertension and Tachycardia
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 Risks
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)].

Suppression of Growth
Advise patients that lisdexamfetamine dimesylate capsules may cause slowing of growth including weight loss [see Warnings and Precautions (5.5)].

Impairment in Ability to Operate Machinery or Vehicles
Advise patients that lisdexamfetamine dimesylate capsules may impair their ability to engage in potentially dangerous activities such as operating machinery or vehicles. Instruct patients to find out how lisdexamfetamine dimesylate capsules will affect them before engaging in potentially dangerous activities [see Adverse Reactions (6.1, 6.2)].

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)].

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

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

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 for:
SpecGx LLC
Webster Groves, MO 63119 USA

For more information call 1-800-778-7898

ADDERALL XR is a registered trademark of its respective owner.

Mallinckrodt, the “M” brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company.

© 2022 Mallinckrodt.

Mallinckrodt™
Pharmaceuticals

Rev 02/2022                                                                                          

An electronic copy of this medication guide can be obtained from www.mallinckrodt.com/Medguide/MG20L03.pdf or by calling 1-800-778-7898 for alternate delivery options.

Principal Display Panel - 10 Mg Capsules

NDC 0406-5111-01

100 Capsules

Lisdexamfetamine Dimesylate
Capsules

CII

10 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Rx only

Mallinckrodt^™

L00L02
Rev 05/2021

PRINCIPAL DISPLAY PANEL - 10 mg Capsules - lisdexamfetamine dimesylate 10

Principal Display Panel - 20 Mg Capsules

NDC 0406-5112-01

100 Capsules

Lisdexamfetamine Dimesylate
Capsules

CII

20 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Rx only

Mallinckrodt^™

L00L03
Rev 05/2021

PRINCIPAL DISPLAY PANEL - 20 mg Capsules - lisdexamfetamine dimesylate 11

Principal Display Panel - 30 Mg Capsules

NDC 0406-5113-01

100 Capsules

Lisdexamfetamine Dimesylate
Capsules

CII

30 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Rx only

Mallinckrodt^™

L00L04
Rev 07/2018

PRINCIPAL DISPLAY PANEL - 30 mg Capsules - lisdexamfetamine dimesylate 12

Principal Display Panel - 40 Mg Capsules

NDC 0406-5114-01

100 Capsules

Lisdexamfetamine Dimesylate
Capsules

CII

40 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Rx only

Mallinckrodt™

L00L05
Rev 07/2018

PRINCIPAL DISPLAY PANEL - 40 mg Capsules - lisdexamfetamine dimesylate 13

Principal Display Panel - 50 Mg Capsules

NDC 0406-5115-01

100 Capsules

Lisdexamfetamine Dimesylate
Capsules

CII

50 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Rx only

Mallinckrodt^™

L00L06
Rev 07/2018

PRINCIPAL DISPLAY PANEL - 50 mg Capsules - lisdexamfetamine dimesylate 14

Principal Display Panel - 60 Mg Capsules

NDC 0406-5116-01

100 Capsules

Lisdexamfetamine Dimesylate
Capsules

CII

60 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Rx only

Mallinckrodt^™

L00L07
Rev 07/2018

PRINCIPAL DISPLAY PANEL - 60 mg Capsules - lisdexamfetamine dimesylate 15

Principal Display Panel - 70 Mg Capsules

NDC 0406-5117-01

100 Capsules

Lisdexamfetamine Dimesylate
Capsules

CII

70 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Rx only

Mallinckrodt^™

L00L08
Rev 07/2018

PRINCIPAL DISPLAY PANEL - 70 mg Capsules - lisdexamfetamine dimesylate 16