Lisdexamfetamine Dimesylate Capsule
FDA Label NDC 0527-4663

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)].

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)].

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:

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)].

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.

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

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

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)].

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)].

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.

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.

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 capsule are not approved for use in pediatric patients below 6 years of age [see Use in Specific Populations (8.4)].

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 post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Serotonin syndrome, 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.

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)]

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.

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.

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)].

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.

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.

Lisdexamfetamine Dimesylate Capsules contain lisdexamfetamine, a prodrug of amphetamine, a Schedule II controlled substance.

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.

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.

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

Chemical Structure (Lisdexamfetamine Dimesylate Capsules 1)

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

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.

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

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

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.

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 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 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 18-55 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.

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 Proportions of Subjects with Relapse in Adults with BED (Study 13)

Figure 8 (Lisdexamfetamine Dimesylate Capsules 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.

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

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

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

NDC 0527-4661-37

Lisdexamfetamine Dimesylate Capsules

CII

10 mg

Pharmacist: Dispense the accompanying Medication Guide to each patient. 

Print Medication Guides at:

www.lannett.com/med-guide/lisdexamfetamine

Rx Only

100 Capsules

Lannett

10 mg (Lisdexamfetamine Dimesylate Capsules 10)

NDC 0527-4662-37

Lisdexamfetamine Dimesylate Capsules

CII

20 mg

Pharmacist: Dispense the accompanying Medication Guide to each patient. 

Print Medication Guides at:

www.lannett.com/med-guide/lisdexamfetamine

Rx Only

100 Capsules

Lannett

20 mg (Lisdexamfetamine Dimesylate Capsules 11)

NDC 0527-4663-37

Lisdexamfetamine Dimesylate Capsules

CII

30 mg

Pharmacist: Dispense the accompanying Medication Guide to each patient. 

Print Medication Guides at:

www.lannett.com/med-guide/lisdexamfetamine

Rx Only

100 Capsules

Lannett

30 mg (Lisdexamfetamine Dimesylate Capsules 12)

NDC 0527-4664-37

Lisdexamfetamine Dimesylate Capsules

CII

40 mg

Pharmacist: Dispense the accompanying Medication Guide to each patient. 

Print Medication Guides at:

www.lannett.com/med-guide/lisdexamfetamine

Rx Only

100 Capsules

Lannett

40 mg (Lisdexamfetamine Dimesylate Capsules 13)

NDC 0527-4665-37

Lisdexamfetamine Dimesylate Capsules

CII

50 mg

Pharmacist: Dispense the accompanying Medication Guide to each patient. 

Print Medication Guides at:

www.lannett.com/med-guide/lisdexamfetamine

Rx Only

100 Capsules

Lannett

50 mg (Lisdexamfetamine Dimesylate Capsules 14)

NDC 0527-4666-37

Lisdexamfetamine Dimesylate Capsules

CII

60 mg

Pharmacist: Dispense the accompanying Medication Guide to each patient. 

Print Medication Guides at:

www.lannett.com/med-guide/lisdexamfetamine

Rx Only

100 Capsules

Lannett

60 mg (Lisdexamfetamine Dimesylate Capsules 15)

NDC 0527-4667-37

Lisdexamfetamine Dimesylate Capsules

CII

70 mg

Pharmacist: Dispense the accompanying Medication Guide to each patient. 

Print Medication Guides at:

www.lannett.com/med-guide/lisdexamfetamine

Rx Only

100 Capsules

Lannett

70 mg (Lisdexamfetamine Dimesylate Capsules 16)