Lisdexamfetamine Dimesylate - Lisdexamfetamine Dimesylate capsule Prescribing Information
Clinical Effects of Overdose
Overdose of CNS stimulants is characterized by the following sympathomimetic effects:
- Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop.
- CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur.
- Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop.
Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of lisdexamfetamine dimesylate should be considered when treating patients with overdose. Lisdexamfetamine and d-amphetamine are not dialyzable. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
Lisdexamfetamine dimesylate has a high potential for abuse and misuse. The use of lisdexamfetamine dimesylate exposes individuals
to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction.
Lisdexamfetamine dimesylate can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence
(9.2)]. Misuse and abuse of CNS stimulants, including lisdexamfetamine dimesylate, can result in overdose and death [see
Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
Before prescribing lisdexamfetamine dimesylate, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and
their families about these risks and proper disposal of any unused drug. Advise patients to store lisdexamfetamine dimesylate in a safe
place, preferably locked, and instruct patients to not give lisdexamfetamine dimesylate to anyone else. Throughout lisdexamfetamine
dimesylate treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of
abuse, misuse, and addiction.
Lisdexamfetamine dimesylate has a high potential for abuse and misuse which can lead to the development of a substance use
disorder, including addiction [see Warnings and Precautions (5.1)]. Lisdexamfetamine dimesylate can be diverted for non-medical use
into illicit channels or distribution.
Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a
strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a
higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.
Misuse and abuse of lisdexamfetamine, a prodrug of amphetamine, may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including lisdexamfetamine dimesylate, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
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.
- Boxed Warning 10/2023
- Dosage and Administration 10/2023
2.1 Pre-treatment ScreeningPrior to treating patients with lisdexamfetamine dimesylate, assess:
- for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and
physical exam) [see Warnings and Precautions (5.2)].
- the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating lisdexamfetamine dimesylate [see Warnings and Precautions (5.8)].
- Warnings and Precautions (,
5.1 Abuse, Misuse, and AddictionLisdexamfetamine dimesylate has a high potential for abuse and misuse. The use of lisdexamfetamine dimesylate exposes individuals
to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction.
Lisdexamfetamine dimesylate can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence
(9.2)]. Misuse and abuse of CNS stimulants, including lisdexamfetamine dimesylate, can result in overdose and death [see
Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
Before prescribing lisdexamfetamine dimesylate, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and
their families about these risks and proper disposal of any unused drug. Advise patients to store lisdexamfetamine dimesylate in a safe
place, preferably locked, and instruct patients to not give lisdexamfetamine dimesylate to anyone else. Throughout lisdexamfetamine
dimesylate treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of
abuse, misuse, and addiction.
,5.2 Risks to Patients with Serious Cardiac DiseaseSudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage.
Avoid lisdexamfetamine dimesylate use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.
,5.3 Increased Blood Pressure and Heart RateCNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Some patients may have larger increases.
Monitor all lisdexamfetamine dimesylate-treated patients for potential tachycardia and hypertension.
,5.4 Psychiatric Adverse ReactionsExacerbation of Pre-existing PsychosisCNS 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 DisorderCNS stimulants may induce a manic or mixed episode. Prior to initiating lisdexamfetamine dimesylate 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 SymptomsCNS 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.
,5.5 Long-Term Suppression of Growth in Pediatric PatientsCNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.
In a 4-week, placebo-controlled trial of lisdexamfetamine dimesylate in pediatric patients ages 6 to 12 years old with ADHD, there was a dose-related decrease in weight in the lisdexamfetamine dimesylate groups compared to weight gain in the placebo group. Additionally, in studies of another stimulant, there was slowing of the increase in height [see Adverse Reactions (6.1)].
Closely monitor growth (weight and height) in lisdexamfetamine dimesylate-treated pediatric patients.Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. Lisdexamfetamine dimesylate is 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 PhenomenonCNS stimulants, including lisdexamfetamine dimesylate, used to treat ADHD are associated with peripheral vasculopathy, including
Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration
and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing
reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms
generally improved after dosage reduction or discontinuation of the CNS stimulant.
Careful observation for digital changes is necessary during lisdexamfetamine dimesylate treatment. Further clinical evaluation (e.g.,
rheumatology referral) may be appropriate for lisdexamfetamine dimesylate–treated patients who develop signs or symptoms of
peripheral vasculopathy.
) 10/20235.8 Motor and Verbal Tics, and Worsening of Tourette’s SyndromeCNS stimulants, including amphetamine, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions (6.2)].
Before initiating lisdexamfetamine dimesylate, assess the family history and clinically evaluate patients for tics or
Tourette’s syndrome. Regularly monitor lisdexamfetamine dimesylate-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.
Lisdexamfetamine dimesylate capsules and lisdexamfetamine dimesylate chewable tablets 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 Attention Deficit Hyperactivity Disorder (ADHD)PediatricPatients Ages 6 to 12 Years with ADHDA 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 ADHDA 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 ADHDA 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 ADHDMaintenance 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 ADHDA 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 ADHDA 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 in Pediatric Patients (Ages 6 to 17) and Adults with ADHD
Study Number (Age range)Primary EndpointTreatment GroupMean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo-subtracted Differencea(95% CI)Study 1
(6 – 12 years)
ADHD-RS-IV
Lisdexamfetamine Dimesylate (30 mg/day)*
43.2 (6.7)
-21.8 (1.6)
-15.6 (-19.9, -11.2)
Lisdexamfetamine Dimesylate (50 mg/day)*
43.3 (6.7)
-23.4 (1.6)
-17.2 (-21.5, -12.9)
Lisdexamfetamine Dimesylate (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 (30, 50 or 70 mg/day)*
--b
0.8 (0.1)d
-0.9 (-1.1, -0.7)
Placebo
--b
1.7 (0.1)d
--
Study 3
(6 – 12 years)
Average
SKAMP-DS
Lisdexamfetamine Dimesylate (30, 50 or 70 mg/day)*
0.9 (1.0)c
0.7 (0.1)d
-0.7 (-0.9, -0.6)
Placebo
0.7 (0.9)c
1.4 (0.1)d
--
Study 4
(13 – 17 years)
ADHD-RS-IV
Lisdexamfetamine Dimesylate (30 mg/day)*
38.3 (6.7)
-18.3 (1.2)
-5.5 (-9.0, -2.0)
Lisdexamfetamine Dimesylate (50 mg/day)*
37.3 (6.3)
-21.1 (1.3)
-8.3 (-11.8, -4.8)
Lisdexamfetamine Dimesylate (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 (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 (30 mg/day)*
40.5 (6.2)
-16.2 (1.1)
-8.0 (-11.5, -4.6)
Lisdexamfetamine Dimesylate (50 mg/day)*
40.8 (7.3)
-17.4 (1.0)
-9.2 (-12.6, -5.7)
Lisdexamfetamine Dimesylate (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 (30, 50 or 70 mg/day)*
260.1 (86.2)c
312.9 (8.6)d
23.4 (15.6, 31.2)
Placebo
261.4 (75.0)c
289.5 (8.6)d
--
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
aDifference (drug minus placebo) in least-squares mean change from baseline.
bPre-dose SKAMP-DS was not collected.
cPre-dose SKAMP-DS (Study 3) or PERMP (Study 8) total score, averaged over both periods.
dLS 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.
* Doses statistically significantly superior to placebo.
- 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)
figure 4 figure 5 figure 6 figure 7 - Moderate to severe binge eating disorder (BED) in adults [see Clinical Studies (.)]
14.2 Binge Eating Disorder (BED)A phase 2 study evaluated the efficacy of lisdexamfetamine dimesylate 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 30 mg/day was not statistically different from placebo on the primary endpoint. The 50 and 70 mg/day doses were statistically superior to placebo on the primary endpoint.
The efficacy of lisdexamfetamine dimesylate in the treatment of BED was demonstrated in two 12-week randomized, double-blind, multi-center, parallel-group, placebo-controlled, dose-optimization studies (Study 11 and Study 12) in adults aged 18-55 years (Study 11: N=374, Study 12: N=350) with moderate to severe BED. A diagnosis of BED was confirmed using DSM-IV criteria for BED. Severity of BED was determined based on having at least 3 binge days per week for 2 weeks prior to the baseline visit and on having a Clinical Global Impression Severity (CGI-S) score of ≥4 at the baseline visit. For both studies, a binge day was defined as a day with at least 1 binge episode, as determined from the subject’s daily binge diary.
Both 12-week studies consisted of a 4-week dose-optimization period and an 8-week dose-maintenance period. During dose-optimization, subjects assigned to lisdexamfetamine dimesylate 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 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 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 BEDStudyNumberTreatment GroupPrimary Efficacy Measure: Binge Days per Week at Week 12Mean Baseline Score (SD)LS Mean Change from Baseline (SE)Placebo-subtractedDifferencea(95% CI)Study 11
Lisdexamfetamine Dimesylate (50 or 70 mg/day)*
4.79 (1.27)
-3.87 (0.12)
-1.35 (-1.70, -1.01)
Placebo
4.60 (1.21)
-2.51 (0.13)
--
Study 12
Lisdexamfetamine Dimesylate (50 or 70 mg/day)*
4.66 (1.27)
-3.92 (0.14)
-1.66 (-2.04, -1.28)
Placebo
4.82 (1.42)
-2.26 (0.14)
--
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
aDifference (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 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 in the preceding 12-week open-label treatment phase were randomized to continuation of lisdexamfetamine dimesylate 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 during the 26-week double-blind randomized-withdrawal phase was demonstrated with lisdexamfetamine dimesylate being superior over placebo as measured by time to relapse.
- Figure 8 Kaplan-Meier Estimated Proportions of Subjects with Relapse in Adults with BED (Study 13)
Examination of population subgroups based on age (there were no patients over 65), gender, and race did not reveal any clear evidence of differential responsiveness in the treatment of BED.
figure 8
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 Pediatric UseADHDSafety and effectiveness of lisdexamfetamine dimesylate have been established in pediatric patients with ADHD ages 6 to 17 years
[see Dosage and Administration , Adverse Reactions , Clinical Pharmacology , and Clinical Studies ].Safety and effectiveness of lisdexamfetamine dimesylate 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.
BEDSafety and effectiveness of lisdexamfetamine dimesylate have not been established in pediatric patients with BED less than 18 years of age.
Growth SuppressionGrowth should be monitored during treatment with stimulants, including lisdexamfetamine dimesylate, and pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted
[see Warnings and PrecautionsandAdverse Reactions ].Juvenile Animal DataStudies 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/m2basis 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/m2basis for a child). This effect partially or fully reversed during a four- week drug-free recovery period.
- Lisdexamfetamine dimesylate is not indicated or recommended for weight loss. Use of other sympathomimetic drugs for weight loss has been associated with serious cardiovascular adverse events. The safety and effectiveness of lisdexamfetamine dimesylate for the treatment of obesity have not been established [see Warnings and Precautions (.)]
5.2 Risks to Patients with Serious Cardiac DiseaseSudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage.
Avoid lisdexamfetamine dimesylate use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.
Indicated Population | Initial Dose | Titration Schedule | Recommended Dose | Maximum Dose |
ADHD (Adults and pediatric patients 6 years and older) | 30 mg every morning | 10 mg or 20 mg weekly | 30 mg to 70 mg per day | 70 mg per day |
BED (Adults) | 30 mg every morning | 20 mg weekly | 50 mg to 70 mg per day | 70 mg per day |
- Prior to treatment, assess for presence of cardiac disease ( )
2.4 Dosage for Treatment of Moderate to Severe BED in AdultsThe 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 ]. Discontinue lisdexamfetamine dimesylate if binge eating does not improve. - Severe renal impairment: Maximum dose is 50 mg/day ( )
2.5 Dosage in Patients with Renal ImpairmentIn 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 ]. - End stage renal disease (ESRD): Maximum dose is 30 mg/day ( )
2.5 Dosage in Patients with Renal ImpairmentIn 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 ].
- Capsules 10 mg: Pink opaque cap/pink opaque body (imprinted with 'RM46' on cap and '10 mg' on body).
- Capsules 20 mg: Off white opaque cap /off white opaque body (imprinted with 'RM47' on cap and '20 mg' on body).
- Capsules 30 mg: Orange opaque cap/white opaque body (imprinted with 'RM48' on cap and '30 mg' on body).
- Capsules 40 mg: Dark green opaque cap/white opaque body (imprinted with 'RM49' on cap and '40 mg' on body).
- Capsules 50 mg: Blue opaque cap/white opaque body (imprinted with 'RM50' on cap and '50 mg' on body).
- Capsules 60 mg: Aqua blue opaque cap/aqua blue opaque body (imprinted with 'RM51' on cap and '60 mg' on body).
- Capsules 70 mg: Blue opaque cap/orange opaque body (imprinted with 'RM52' on cap and '70 mg' on body).
- Chewable tablets 10 mg: White to off-white round shaped tablet debossed with ‘10’ on one side and ‘S83’ on the other side
- Chewable tablets 20 mg: White to off-white hexagonal shaped tablet debossed with ‘20’ on one side and ‘S84’ on the other side
- Chewable tablets 30 mg: White to off-white arc triangular shaped tablet debossed with ‘30’ on one side and ‘S85’ on the other side
- Chewable tablets 40 mg: White to off-white capsule shaped tablet debossed with ‘40’ on one side and ‘S86’ on the other side
- Chewable tablets 50 mg: White to off-white arc square shaped tablet debossed with ‘50’ on one side and ‘S87’ on the other side
- Chewable tablets 60 mg: White to off-white arc diamond shaped tablet debossed with ‘60’ on one side and ‘S88’ on the other side
- Pregnancy: May cause fetal harm ()
8.1 PregnancyPregnancy Exposure RegistryThere 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/adhd-medications/.
Risk SummaryThe limited available data from published literature and postmarketing reports on use of lisdexamfetamine dimesylate 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 ConsiderationsFetal/Neonatal Adverse ReactionsAmphetamines, such as lisdexamfetamine dimesylate, 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.
DataAnimal DataLisdexamfetamine 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/m2body 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.
- Lactation:Breastfeeding not recommended ()
8.2 LactationRisk SummaryLisdexamfetamine 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.