AHFS Class:

• Amphetamines 28:20.04

Generic Name(s):

• Lisdexamfetamine Dimesylate

Chemical Name:

• (2S)-2,6-diamino- N -[(1 S )-1-methyl-2-phenylethly] hexanamide dimethanesulfonate

Molecular Formula:

• C₁₅H₂₅N₃O • (CH₄O₃S)₂

Prodrug of dextroamphetamine; noncatechol, sympathomimetic amine with CNS-stimulating activity.1,8,28

Attention-Deficit/Hyperactivity Disorder

Lisdexamfetamine dimesylate is used as an adjunct to psychological, educational, social, and other remedial measures in the treatment of attention-deficit/hyperactivity disorder (ADHD) (hyperkinetic disorder, hyperkinetic syndrome of childhood, minimal brain dysfunction).1,3,28 Safety and efficacy for this indication have been established in controlled clinical trials in children and adolescents 6 years of age or older and in adults.1,2,3,4,29,30,44,45,46,48

Safety and efficacy of lisdexamfetamine dimesylate in the treatment of ADHD in children and adolescents 6 years of age or older have been evaluated in 5 short-term studies (3 in children 6-12 years of age, 1 in adolescents 13-17 years of age, and 1 in children and adolescents 6-17 years of age) and 1 randomized withdrawal study.48 Safety and efficacy of lisdexamfetamine dimesylate in adults with ADHD were evaluated in 2 short-term studies and 1 randomized withdrawal study.48

In a short-term, randomized, double-blind, placebo-controlled parallel-group study in children 6-12 years of age with ADHD, improvement in symptom scores, as measured using the ADHD Rating Scale version IV (ADHD-RS-IV), the revised Conners' Parent Rating Scale (CPRS-R), and the Clinical Global Impression of Improvement (CGI-I) scale, from baseline to study end (4 weeks) was greater in children receiving lisdexamfetamine dimesylate titrated to a fixed, final dosage of 30, 50, or 70 mg daily than in those receiving placebo.1,2,3,30,48 Mean changes in symptom scores generally were similar for all 3 lisdexamfetamine dosage levels; however, changes in ADHD-RS-IV scores were numerically greater with the 70-mg dose than with the 30- and 50-mg doses.1,2 Symptom control in patients receiving the drug was maintained throughout the day up to 6 p.m.1,2,3

In addition, 2 short-term, double-blind, placebo-controlled, crossover studies were conducted in children 6-12 years of age in an analog classroom environment using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) deportment score (a measure of deportment problems leading to classroom disruptions) as the primary measure of efficacy.3,4,29,30,48 Both studies utilized a 3- or 4-week open-label, dose-optimization period followed by randomization to 1 week each of double-blind treatment with lisdexamfetamine dimesylate or placebo.48 One of the studies used an active comparator (extended-release mixed amphetamine salts [Adderall XR^®] 10-30 mg daily) during dose-optimization and double-blind periods.3,4,29,30,48 In both studies, patients had substantially greater improvement in SKAMP deportment scores on day 7 of each treatment period while receiving lisdexamfetamine compared with placebo.3,4,29,30,48 This effect was observed at various intervals from 1.5-13 hours after dosing.48

In a randomized, double-blind, controlled study in children and adolescents 6-17 years of age with ADHD, improvement in the ADHD-RS-IV score from baseline to study end (7 weeks) was greater in patients receiving lisdexamfetamine dimesylate (given as a flexible dosage of 30-70 mg daily during the first 4 weeks and as a fixed dosage from weeks 5-7) than in those receiving placebo.44,48

Safety and efficacy of lisdexamfetamine in adolescents and adults with ADHD were evaluated in 2 similarly designed, double-blind, randomized, placebo-controlled studies of 4 weeks' duration in 314 adolescents 13-17 years of age and 420 adults 18-55 years of age who met DSM-IV-TR criteria for ADHD.27,47,48 In these parallel-group studies, patients were randomized to receive 30, 50, or 70 mg of lisdexamfetamine dimesylate daily or placebo.1,27,47,48 All patients receiving lisdexamfetamine initially received 30 mg daily for the first week, with subsequent dosage titrations occurring in 20-mg increments at weekly intervals for those randomized to receive 50 or 70 mg of the drug daily.1 The primary measure of efficacy in both studies was the ADHD Rating Scale (ADHD-RS) score.1,27,47,48 At study end point (4 weeks), patients randomized to receive lisdexamfetamine demonstrated significant improvements in ADHD symptoms compared with placebo recipients.1,47,48 Significant improvements in ADHD symptoms were evident within the first week of treatment in all lisdexamfetamine groups.27,47 In the adult study, patients randomized to receive lisdexamfetamine dimesylate 70 mg daily showed a greater reduction in ADHD-RS total score at weeks 3 and 4 compared with patients receiving lisdexamfetamine dimesylate 30 mg daily.27

In a crossover study in adults 18-55 years of age conducted in a simulated workplace environment, patients entered a 4-week, open-label, dose-optimization period with lisdexamfetamine dimesylate initiated at 30 mg and titrated up to a maximum of 70 mg daily followed by randomization to receive 1 week each of treatment with lisdexamfetamine or placebo.46,48 The primary measure of efficacy was the Permanent Product Measure of Performance (PERMP) total score (a skill-adjusted math test that measures attention in ADHD) assessed on day 7 of each treatment period at various intervals from 2-14 hours after dosing.46,48 Patients had substantially greater improvement in PERMP total scores after the treatment period with lisdexamfetamine compared with placebo.46,48

Efficacy of lisdexamfetamine dimesylate for maintenance therapy for ADHD was evaluated in 2 placebo-controlled, randomized withdrawal studies in children and adolescents 6-17 years of age and in adults 18-55 years of age with ADHD.45,48 In the pediatric study, patients who had demonstrated a clinical response to lisdexamfetamine during a 26-week, open-label, dose-optimization period were randomized to continue their lisdexamfetamine dosage or receive placebo during the 6-week, double-blind study period.45,48 In the adult study, patients who had received at least 6 months of lisdexamfetamine therapy and who maintained treatment response during a 3-week, open-label treatment period were randomized to continue their lisdexamfetamine dosage or receive placebo during the 6-week, double-blind study period.48 Treatment failure was defined as at least a 50% increase in ADHD-RS total score and at least a 2-point increase as measured using the Clinical Global Impression of Severity (CGI-S) scale; in both studies, substantially fewer patients receiving lisdexamfetamine (15.8 and 9% of pediatric and adult patients, respectively) experienced treatment failure than those receiving placebo (67.5 and 75% of pediatric and adult patients, respectively).45,48

For further information on the management of ADHD, including the use of stimulants such as amphetamines, see Uses: Attention-Deficit/Hyperactivity Disorder in the Amphetamines General Statement 28:20.04, and also in Methylphenidate 28:20.32.

Binge-Eating Disorder

Lisdexamfetamine dimesylate is used for the treatment of moderate to severe binge-eating disorder in adults.40,48 In controlled studies, treatment with lisdexamfetamine reduced the mean number of binge days per week compared with placebo.40,48

Lisdexamfetamine dimesylate should not be used for weight loss; use of other sympathomimetic drugs for weight loss has been associated with serious adverse cardiovascular events.48 Efficacy and safety of the drug for treatment of obesity have not been established.48

According to DSM-5 criteria, binge-eating disorder is characterized by recurrent episodes of binge eating (i.e., excessive food consumption during a discrete period of time, accompanied by a sense of lack of control) causing marked distress and occurring, on average, at least once per week for 3 months.39 Individuals with binge-eating disorder experience at least 3 of the following: eating much more rapidly than normal, eating until feeling uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of feeling embarrassed by how much one is eating, or feeling disgusted with onself, depressed, or very guilty afterward.39 Unlike bulimia nervosa, binge-eating disorder is not associated with recurrent and inappropriate compensatory behavior (e.g., purging, excessive exercise).39 DSM-5 describes binge-eating disorder as mild, moderate, severe, or extreme if the patient experiences 1-3, 4-7, 8-13, or 14 or more binge-eating episodes per week, respectively.39

The efficacy of lisdexamfetamine dimesylate for the treatment of binge-eating disorder has been established in 2 randomized, double-blind, placebo-controlled studies of 12-weeks' duration in adults 18-55 years of age with moderate to severe binge-eating disorder (DSM-IV criteria).40,48 Because DSM-IV criteria did not define severity of disease, severity of binge-eating disorder in these studies was determined by the investigators; moderate to severe disorder was defined as having at least 3 binge days per week for 2 consecutive weeks prior to baseline and a baseline CGI-S score of 4 or greater.40,48 Patients were randomized to receive placebo or lisdexamfetamine; lisdexamfetamine dimesylate was initiated at 30 mg daily and increased to 50 mg daily after 1 week, with increases to 70 mg daily as tolerated and clinically indicated.40,48 In both studies, lisdexamfetamine was more effective than placebo in reducing the mean number of binge days per week from baseline to week 12.40,48 From a mean of 4.6-4.82 binge days per week at baseline, lisdexamfetamine-treated patients experienced an average of 1.35-1.66 fewer binge days per week by week 12 than those receiving placebo.40,48

General

Patients should be assessed for the presence of cardiac disease prior to initiation of lisdexamfetamine therapy.48 (See Sudden Death and Serious Cardiovascular Events under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

In addition, the potential for abuse of CNS stimulants should be assessed prior to initiation of lisdexamfetamine therapy.48 (See Abuse Potential under Warnings/Precautions: Warnings, in Cautions.) After prescribing amphetamine therapy, prescription records should be carefully maintained, and patients should receive education regarding abuse of stimulants and be monitored for signs of abuse and overdose.48 The need for continued therapy with lisdexamfetamine should be reevaluated.48

Administration

Oral Administration

Administer lisdexamfetamine dimesylate capsules or chewable tablets once daily in the morning without regard to meals.1,48 Because of potential for insomnia, avoid administering in the afternoon.1,28,30,48

Capsules may be swallowed whole or may be opened and the entire contents mixed with water, orange juice, or yogurt until completely dispersed; resulting mixture should be administered immediately and not stored for use at a later time.1,48

Do not subdivide capsule contents; do not administer a dose less than the entire contents of one capsule or one chewable tablet.1,48

Chewable tablets should be chewed thoroughly before swallowing.48

Lisdexamfetamine capsules can be substituted for chewable tablets on a mg-per-mg basis.48

Dosage

Available as lisdexamfetamine dimesylate; dosage expressed in terms of the salt.1,48

Pediatric Patients

Attention-Deficit/Hyperactivity Disorder

Children 6 years of age or older: Initially, 30 mg once daily; dosage may be adjusted in 10- or 20-mg increments at weekly intervals up to a maximum dosage of 70 mg daily.1,28,30,48

If the initial 30-mg daily dosage is not tolerated, dosage can be decreased to 20 mg daily.27

Adults

Attention-Deficit/Hyperactivity Disorder

Initially, 30 mg once daily; dosage may be adjusted in 10- or 20-mg increments at weekly intervals up to a maximum dosage of 70 mg daily.1,28,48

If the initial 30-mg daily dosage is not tolerated, dosage can be decreased to 20 mg daily.27

Binge-Eating Disorder

Initially, 30 mg once daily.48 Dosage should be adjusted in 20-mg increments at weekly intervals to a target dosage of 50-70 mg daily.48 Dosages of 50 and 70 mg daily were effective in controlled trials.48 The maximum recommended dosage is 70 mg once daily.48

Lisdexamfetamine therapy should be discontinued if binge eating does not improve.48

Special Populations

In patients with severe renal impairment (glomerular filtration rate [GFR] 15 to less than 30 mL/minute per 1.73 m²), the maximum dosage of lisdexamfetamine dimesylate is 50 mg daily.48 In patients with end-stage renal disease (GFR less than 15 mL/minute per 1.73 m²), the maximum recommended dosage is 30 mg daily.48

Contraindications

Known hypersensitivity to amphetamines or any ingredient in the formulation of lisdexamfetamine dimesylate.48 Anaphylactic reactions, hypersensitivity, Stevens-Johnson syndrome, angioedema, and urticaria have been reported during postmarketing surveillance of lisdexamfetamine.48

Concurrent or recent (i.e., within 14 days) therapy with a monoamine oxidase (MAO) inhibitor, including linezolid or IV methylene blue, since hypertensive crisis could result.1,48 (See Drug Interactions: MAO Inhibitors.)

Warnings/Precautions

Warnings

Abuse Potential

CNS stimulants (e.g., amphetamines, methylphenidate) have a high potential for abuse and dependence.1,48 The risk of abuse should be assessed prior to initiation of lisdexamfetamine and patients should be monitored for signs of abuse and dependence during therapy.48

The possibility that family members may abuse the patient's medication should be considered.5

Other Warnings and Precautions

Sudden Death and Serious Cardiovascular Events

Sudden unexplained death, stroke, and myocardial infarction (MI) have been reported in adults with attention-deficit/hyperactivity disorder (ADHD) receiving usual dosages of stimulants; sudden death also has been reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of the drugs.1,9 A small number of cases of sudden unexplained death also has been reported in children without structural cardiac abnormalities receiving amphetamine combinations; however, confounding factors were present in some of these incidents.9 Postmarketing experience with lisdexamfetamine includes reports of cardiomyopathy and chest pain.48

Results of one retrospective, case-control epidemiologic study showed a possible association between use of stimulant medications (amphetamine, dextroamphetamine, methamphetamine, methylphenidate, or their derivatives) and sudden unexplained death in healthy children and adolescents.31,32,33 (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.) Because of postmarketing reports and the results of this and other epidemiologic studies, FDA collaborated with the Agency for Healthcare Research and Quality (AHRQ) to sponsor 3 large, related, retrospective cohort studies using data from several health care claims databases to evaluate possible associations between ADHD drug use (stimulants, atomoxetine, and pemoline [no longer commercially available in the US]) and the following serious cardiovascular events: MI, stroke, and sudden cardiac death in children and young adults 2-24 years of a MI and sudden cardiac death in adults 25-64 years of a and stroke and the composite end point of stroke, MI, and sudden cardiac death in the same group of adults.35,36,37,38 None of the 3 studies showed an association between serious cardiovascular events and current use of ADHD drugs, as compared with nonuse or as compared with former or remote use, although small increases in cardiovascular risk could not be excluded.35,36,37,38 The study in children and young adults included data for approximately 1.2 million patients and approximately 2.6 million patient-years of follow-up, including approximately 370,000 patient-years of current ADHD drug use, and found only 7 serious cardiovascular events (4 strokes, 3 sudden deaths) in current users of the drugs.35,38 The analyses in adults included data for approximately 440,000 patients, including approximately 150,000 current users of ADHD drugs; for the composite outcome of stroke, MI, and sudden cardiac death, there were approximately 107,000 patient-years of ADHD drug exposure and 234 such cardiovascular events in current users.36,37

A thorough medical history review (including evaluation for family history of sudden death or ventricular arrhythmia) and physical examination should be performed in all children, adolescents, and adults being considered for stimulant therapy, including lisdexamfetamine; if initial findings suggest presence of cardiac disease, further cardiac evaluation (e.g., ECG, echocardiogram) should be performed.1,5,6,31,48

Use of CNS stimulants should be avoided in patients with known structural cardiac abnormalities, cardiomyopathy, serious arrhythmias, coronary artery disease, or other serious cardiac conditions.1,6,8,9,48

Patients who develop exertional chest pain, unexplained syncope, arrhythmias, or other manifestations suggestive of cardiac disease during stimulant therapy should undergo prompt cardiac evaluation.1,28,48

For further information on screening for cardiac conditions, selecting appropriate candidates for stimulant therapy, and monitoring for treatment-emergent cardiac conditions, see Cardiovascular Precautions under Cautions: Precautions and Contraindications, in the Amphetamines General Statement 28:20.04.

Effects on Blood Pressure and Heart Rate

Possible modest increases in average blood pressure (i.e., by about 2-4 mm Hg) and heart rate (i.e., by about 3-6 beats/minute); larger increases may occur.1,28 All patients should be monitored for potential hypertension and tachycardia.1,48

Exacerbation or Precipitation of Psychotic Symptoms

May exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorder.1,5

Psychotic symptoms (e.g., hallucinations, delusional thinking) may occur with usual dosages in children and adolescents without prior history of psychotic illness.1,6 If psychotic symptoms occur, consider causal relationship to stimulants, and discontinue therapy as appropriate.1,6

Precipitation of Manic Symptoms

May precipitate mixed or manic episodes in patients with bipolar disorder.1,48 Prior to initiating therapy, patients should be screened for risk factors for developing a manic episode; screening should include a detailed psychiatric history (e.g., comorbid depressive symptoms or history of depressive symptoms; family history of suicide, bipolar disorder, or depression).1,48

Manic symptoms may occur with usual dosages in children and adolescents without prior history of mania.1 If manic symptoms occur, consider causal relationship to stimulants, and discontinue therapy as appropriate.1

Other Nervous System Effects

Amphetamines may impair the ability to engage in potentially hazardous activities (e.g., operating machinery or vehicles).1 Postmarketing experience with lisdexamfetamine includes reports of dyskinesia, tics, depression, dermatillomania, aggression, and seizures.48

Growth Suppression

Long-term (i.e., exceeding 12 months) administration is expected to cause at least a temporary suppression of normal weight and/or height patterns in some children and adolescents.1,6 Dose-related weight loss has been reported in children and adolescents during 4 weeks of therapy with lisdexamfetamine.1,48

Manufacturer recommends monitoring growth during treatment; patients not growing or gaining weight as expected may require temporary discontinuance of treatment.1,6,28,48 However, the American Academy of Pediatrics states that studies of stimulants in children found little or no decrease in expected height, with any decrease in growth early in treatment being compensated for later on.7

Peripheral Vascular Effects

Stimulants, including lisdexamfetamine, are associated with peripheral vascular disorders, such as Raynaud's phenomenon.48 Manifestations usually are intermittent and mild, but ulceration of the digits and/or breakdown of soft tissue may occur rarely.48 Peripheral vascular disorders, including Raynaud's phenomenon, have been reported during postmarketing experience in patients in all age groups receiving stimulants at therapeutic dosages and at various times throughout the treatment course.48 Manifestations generally improve following dosage reduction or drug discontinuance.48 Careful observation for digital changes is warranted during therapy with stimulants, and further clinical evaluation (e.g., referral to a rheumatologist) may be appropriate for certain patients.48 (See Advice to Patients.)

Serotonin Syndrome

Potentially life-threatening serotonin syndrome may occur when amphetamines are used concomitantly with other drugs that affect serotonergic neurotransmission, including MAO inhibitors, selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, 5-hydroxytryptamine (5-HT) type 1 receptor agonists (“triptans”), buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort (Hypericum perforatum) .48 Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular aberrations (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea).48

Serotonin syndrome also may occur when lisdexamfetamine and inhibitors of cytochrome P-450 [CYP] isoenzyme 2D6 are used concomitantly.48 Amphetamines and amphetamine derivatives are known to be metabolized to some degree by CYP2D6 and may show mild inhibition of CYP2D6 metabolism.48 The potential for a pharmacokinetic interaction exists, since such concomitant administration may increase the exposure of dextroamphetamine, the active metabolite of lisdexamfetamine, and thereby increase the risk of serotonin syndrome.48 In such clinical situations, alternative therapy should be considered with a non-serotonergic drug or a drug that does not inhibit CYP2D6.48 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Concomitant therapy with lisdexamfetamine and other serotonergic drugs or CYP2D6 inhibitors should only be used if the potential benefit justifies the risk.48 Concomitant use of lisdexamfetamine and MAO inhibitors is contraindicated.48 (See Cautions: Contraindications.) If symptoms of serotonin syndrome occur, therapy with lisdexamfetamine and any other concomitant serotonergic agents should be discontinued immediately and supportive therapy initiated.48 (See Drug Interactions: Serotonergic Drugs.)

Initiation of lisdexamfetamine therapy at lower dosages should be considered, if clinically warranted.48 Patients should be monitored for the emergence of serotonin syndrome during initiation of therapy or when dosage is increased.48 (See Advice to Patients.)

Visual Effects

Visual disturbances have been reported with stimulants.48 Postmarketing experience with lisdexamfetamine includes reports of mydriasis, diplopia, difficulty with visual accommodation, and blurred vision.48

Hepatic Effects

Postmarketing experience with lisdexamfetamine includes reports of eosinophilic hepatitis.48,49

GI Effects

Postmarketing experience with lisdexamfetamine includes reports of dysgeusia, bruxism, and constipation.48

Musculoskeletal Effects

Postmarketing experience with lisdexamfetamine includes reports of rhabdomyolysis.48

Alopecia

Postmarketing experience with lisdexamfetamine includes reports of alopecia.48

Endocrine Effects

Postmarketing experience with lisdexamfetamine includes reports of changes in libido and frequent or prolonged erections.48

Specific Populations

Pregnancy

May cause fetal harm.25,48 Data are limited regarding use of lisdexamfetamine dimesylate in pregnant women.48 Amphetamines may stimulate uterine contractions in pregnant women increasing the risk of premature delivery.48 Infants born to amphetamine-dependent women have increased risk of prematurity and low birth weight; such infants should be monitored for withdrawal symptoms (e.g., feeding difficulties, irritability, agitation, excessive drowsiness).25,48

In animals, lisdexamfetamine dimesylate had no effects on embryofetal morphology or survival when administered orally to rats and rabbits throughout the period of organogenesis.48 Prenatal and postnatal studies were not conducted specifically with lisdexamfetamine dimesylate.48 However, administration of amphetamine to pregnant rats during gestation and lactation resulted in decreased pup survival and body weight that correlated with developmental delays at clinically relevant dosages of amphetamine.48

Lactation

Lisdexamfetamine (a prodrug of dextroamphetamine) is distributed into milk based on limited data with amphetamine.25,48 There are no reports of adverse effects on nursing infants.25,48 However, large dosages of dextroamphetamine may interfere with milk production, especially in women whose lactation is not well established.48 Because of the potential for serious adverse reactions to lisdexamfetamine in nursing infants, the manufacturer does not recommend breast-feeding during therapy.48

Pediatric Use

Safety and efficacy of lisdexamfetamine for management of ADHD have not been established in children younger than 6 years of age.48

Safety and efficacy of lisdexamfetamine for binge-eating disorder have not been established in pediatric patients younger than 18 years of age.48

Psychotic (e.g., hallucinations, delusional thinking) or manic symptoms have been reported in children and adolescents receiving stimulants for management of ADHD.1,48 (See Exacerbation or Precipitation of Psychotic Symptoms and also see Precipitation of Manic Symptoms under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Sudden death has been reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of stimulants.1,48 Sudden unexplained death also was reported in a small number of children without structural cardiac abnormalities receiving amphetamine combinations.9 Results of one retrospective, case-control epidemiologic study suggested a possible association between use of stimulant medications and sudden unexplained death in healthy children and adolescents.31,32,33 A more recent retrospective study in children and adolescents did not show an association between serious cardiovascular events and current use of drugs to treat ADHD compared with nonuse or former use, although small increases in cardiovascular risk could not be excluded.35,38 (See Sudden Death and Serious Cardiovascular Events under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Long-term administration is expected to cause at least a temporary suppression of normal weight and/or height patterns in some children and adolescents.1 (See Growth Suppression under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Geriatric Use

Clinical studies of lisdexamfetamine dimesylate did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults.48 While other reported clinical experience has not revealed differences in response between geriatric and younger adults, dosage selection in geriatric patients should generally start at the lower end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in such patients.48

Hepatic Impairment

Not specifically studied in hepatic impairment.27

Renal Impairment

Reduced clearance and increased exposure of dextroamphetamine have been observed in patients with severe renal impairment or end-stage renal disease compared with individuals with normal renal function.48 Dosage of lisdexamfetamine dimesylate should not exceed 50 mg daily in patients with severe renal impairment or 30 mg daily in patients with end-stage renal disease.1,48 (See Dosage and Administration: Special Populations.)

Dialysis does not substantially affect the clearance of dextroamphetamine.48

Common Adverse Effects

Adverse effects occurring in 5% or more of children, adolescents, or adults receiving lisdexamfetamine for ADHD and at a frequency at least twice that reported with placebo include anorexia, anxiety, decreased appetite, decreased weight, diarrhea, dizziness, dry mouth, irritability, insomnia, nausea, upper abdominal pain, and vomiting.48

Adverse effects occurring in 5% or more of adults receiving lisdexamfetamine for binge-eating disorder and at a frequency at least twice that reported with placebo include dry mouth, insomnia, decreased appetite, increased heart rate, constipation, jittery feeling, and anxiety.48

In one study, lisdexamfetamine did not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2D6, or 3A, and may have minimally inhibited CYP2C19.41

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

The prodrug lisdexamfetamine dimesylate is not metabolized by CYP isoenzymes before its conversion to dextroamphetamine; therefore, pharmacokinetic interactions are unlikely with drugs that inhibit or induce CYP isoenzymes.48 In one study, no clinically important changes in the pharmacokinetics of caffeine, dextromethorphan, or midazolam (substrates of CYP1A2, 2D6, and 3A, respectively) occurred when the drugs were administered concomitantly with lisdexamfetamine dimesylate (single 70-mg dose); minimal inhibition of CYP2C19 substrate metabolism was observed.41 The manufacturer states that lisdexamfetamine is unlikely to affect the pharmacokinetics of drugs metabolized by CYP isoenzymes 1A2 (e.g., duloxetine, melatonin, theophylline), 2D6 (e.g., atomoxetine, desipramine, venlafaxine), 2C19 (e.g., clobazam, lansoprazole, omeprazole), or 3A4 (e.g., midazolam, pimozide, simvastatin).48

Pharmacokinetic interaction (increased exposure of dextroamphetamine) may occur when lisdexamfetamine is used concomitantly with inhibitors of CYP2D6 (e.g., fluoxetine, paroxetine, quinidine, ritonavir) and may increase the risk of serotonin syndrome.48 (See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Urinary Acidifying Agents

Increased urinary excretion and decreased serum concentrations and efficacy of amphetamines may occur with concomitant use of urinary acidifying agents (ammonium chloride, ascorbic acid, methenamine salts, sodium acid phosphate, cranberry juice).1,8,48 Lisdexamfetamine dosage should be increased based on clinical response during such concomitant therapy.48

Urinary Alkalinizing Agents

Decreased urinary excretion and increased serum concentrations of amphetamines resulting in potentiation of action may occur with concomitant use of alkalinizing agents (carbonic anhydrase inhibitors, sodium bicarbonate, some thiazides).1,8,48 Concomitant use of lisdexamfetamine with urinary alkalinizing agents should be avoided.48

5-HT1 Receptor Agonists (“Triptans”)

Pharmacologic interaction (potentially life-threatening serotonin syndrome) may occur if lisdexamfetamine is used concomitantly with 5-hydroxytryptamine type 1 (5-HT₁) receptor agonists (“triptans”).48 Lisdexamfetamine and triptans should be used concomitantly only if the potential benefit justifies the risk.48 If concomitant use is clinically warranted, the patient should be observed carefully, particularly during treatment initiation or when dosage is increased.48 (See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Guanfacine

No clinically important pharmacokinetic interactions were observed when guanfacine and lisdexamfetamine were used concomitantly.43 Dosage adjustment of either drug is not necessary.48

MAO Inhibitors

Concomitant use of monoamine oxidase (MAO) inhibitors and CNS stimulants can result in potentially life-threatening hypertensive crisis.1,48 Amphetamines are contraindicated in patients who are currently receiving or have recently (within 14 days) received an MAO inhibitor.1,48 (See Cautions: Contraindications.)

Selective Serotonin-reuptake Inhibitors and Selective Serotonin- and Norepinephrine-reuptake Inhibitors

Potential pharmacologic interaction (potentially life-threatening serotonin syndrome) may occur when lisdexamfetamine is used concomitantly with selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs).48 Lisdexamfetamine and SSRIs or SNRIs should be used concomitantly only if the potential benefit justifies the risk.48 (See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Serotonergic Drugs

Potential pharmacologic interaction (potentially life-threatening serotonin syndrome) may occur with drugs affecting serotonergic neurotransmission, including buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort (Hypericum perforatum) .48 Lower dosages of lisdexamfetamine should be used during initiation of such concomitant therapy, and patients should be monitored for signs and symptoms of serotonin syndrome, especially when therapy is initiated or dosage is increased.48 If serotonin syndrome occurs, concomitant use of lisdexamfetamine and the serotonergic drug should be discontinued.48 (See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Tricyclic Antidepressants

Enhanced activity of tricyclic antidepressants or sympathomimetic agents; desipramine or protriptyline may cause striking and sustained increases in the concentration of dextroamphetamine in the brain; cardiovascular effects can be potentiated.48 Patients receiving concomitant therapy with lisdexamfetamine and tricyclic antidepressants should be monitored frequently.48 Dosage of lisdexamfetamine should be adjusted or alternative therapy should be used based on clinical response.48

Potential pharmacologic interaction (potentially life-threatening serotonin syndrome) may occur when lisdexamfetamine is used concomitantly with tricyclic antidepressants.48 Lisdexamfetamine and tricyclic antidepressants should be used concomitantly only if the potential benefit justifies the risk.48 (See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Omeprazole

Concomitant use of omeprazole and lisdexamfetamine is not expected to have a clinically important effect on the pharmacokinetics of omeprazole.41,48 Dosage adjustment of either drug is not necessary.48

Venlafaxine

No clinically important pharmacokinetic interactions were observed when venlafaxine and lisdexamfetamine were used concomitantly; additive effects on blood pressure and heart rate have been reported.42,48 Dosage adjustment of either drug is not necessary.48 Monitoring of blood pressure and heart rate is recommended during concomitant therapy.42

Pharmacokinetics

Absorption

Bioavailability

Lisdexamfetamine (a prodrug of dextroamphetamine) is rapidly absorbed from the GI tract.1,28 Peak plasma concentrations of lisdexamfetamine occur in approximately 1 hour; concentrations are low and transient; nonquantifiable by 8 hours after administration.1 Peak plasma concentrations of dextroamphetamine occur in approximately 3.5-3.7 hours.1,3,30

Onset

Occurs within 2 hours after oral administration.3

Duration

Approximately 10-12 hours.1,8,27

Food

Food (high-fat meal or yogurt) delays time to peak plasma concentration of dextroamphetamine by about 1 hour; however, administration with a high-fat meal, yogurt, or orange juice does not affect magnitude of peak plasma concentration or AUC of dextroamphetamine.1,48

Distribution

Extent

Amphetamines readily cross the blood-brain barrier and are distributed into most body tissues.26

Amphetamines are distributed into milk in concentrations 3-7 times maternal blood concentrations.21,25

Elimination

Metabolism

Lisdexamfetamine (a prodrug of dextroamphetamine) is converted to l -lysine and dextroamphetamine by hydrolytic activity of erythrocytes, which have a high capacity for metabolism of lisdexamfetamine.1,48

Lisdexamfetamine is not metabolized by CYP isoenzymes.1

Elimination Route

Excreted principally in urine.1 Approximately 96% of a 70-mg radiolabeled oral dose of lisdexamfetamine was recovered in urine; parent drug accounted for about 2% of the recovered radioactivity.1

Changes in urinary pH may alter excretion of amphetamines.1

Half-life

Lisdexamfetamine: less than 1 hour;1,8 dextroamphetamine: 9.4-13 hours.3,8,30

Description

Lisdexamfetamine, a prodrug of dextroamphetamine, is a CNS stimulant.1,3,28 Lisdexamfetamine is inactive until hydrolyzed in vivo to l -lysine, a naturally occurring essential amino acid, and dextroamphetamine, which is responsible for the drug's activity.1,2,3,28 For information on the pharmacology of amphetamines, see Pharmacology in the Amphetamines General Statement 28:20.04.

Lisdexamfetamine is rapidly absorbed from the GI tract;1,3,28 following oral administration, the onset of action occurs within 2 hours.3 Conversion of lisdexamfetamine to l -lysine and dextroamphetamine occurs mainly via hydrolytic activity of erythrocytes, which have a high capacity for this metabolism.1,48 Lisdexamfetamine is not metabolized by the cytochrome P-450 (CYP) enzyme system, and the ability of dextroamphetamine to inhibit this enzyme pathway has not been fully elucidated.1,3 The plasma half-lives of lisdexamfetamine and dextroamphetamine are less than 1 hour and 9.4-9.7 hours, respectively.1,3 Approximately 96% of a radiolabeled dose of lisdexamfetamine is excreted in urine, with the parent drug accounting for only about 2% of the recovered radioactivity.1,3

Advice to Patients

Importance of providing patient or caregiver with a copy of the manufacturer's patient information (medication guide); discuss and answer questions about its contents as needed.1 Importance of advising patient or caregiver to read and understand contents of medication guide before initiating therapy and each time the prescription is refilled.1

Importance of informing patients that lisdexamfetamine is a controlled substance that can be abused and can lead to dependence.48 Advise patients on proper storage and disposal of controlled substances.48

Importance of taking the drug in the morning to minimize insomnia.1

Risk of serious cardiovascular events (e.g., sudden death, myocardial infarction [MI], stroke, hypertension).48 Importance of patients immediately informing a clinician if they develop exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease.48

Risk of increased blood pressure and heart rate; importance of advising patients to monitor blood pressure and heart rate during therapy.48

Risk of psychiatric effects (e.g., psychosis, mania), even in patients without a history of such effects.48

Risk of weight loss or decreased growth rate; importance of monitoring height and weight of pediatric patients during therapy.48

Appetite suppression may occur.1,5 Giving the morning dose with a meal and providing a high-caloric drink or snack late in the evening when the stimulant effects have subsided may be helpful.5

Importance of instructing patients about the potential for amphetamines to impair their ability to perform potentially hazardous activities, such as driving or operating heavy machinery.1

Potential risk of peripheral vascular disorders, including Raynaud's phenomenon, and the associated signs and symptoms (e.g., numbness, coolness, pain, or changes in color [from pale to blue to red] in fingers or toes).48 Advise patients to report any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes and to immediately inform clinician if any signs of unexplained wounds appear on fingers or toes; further clinical evaluation may be appropriate.48

Potential risk of serotonin syndrome with concomitant use of lisdexamfetamine and other serotonergic agents (e.g., buspirone, fentanyl, lithium, selective serotonin-reuptake inhibitors [SSRIs], selective serotonin- and norepinephrine-reuptake inhibitors [SNRIs], tramadol, tricyclic antidepressants, 5-hydroxytryptamine type 1 [5-HT₁] receptor agonists [triptans], tryptophan, and St. John's wort [Hypericum perforatum] ) or drugs that impair metabolism of serotonin (e.g., MAO inhibitors), both those used to treat psychiatric disorders and others, such as the anti-infective agent linezolid.48 Importance of immediately contacting clinician if signs and/or symptoms of serotonin syndrome develop.48

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary supplements, and herbal products, as well as any concomitant illnesses/conditions (e.g., hypertension, cardiovascular disease, psychiatric disorders).1,48

Importance of women informing clinicians if they are or plan to become pregnant.1

Importance of advising women to avoid breast-feeding during therapy.48

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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