2.1 Pre-treatment Screening

Prior to treating patients with EVEKEO ODT, 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)].

Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically re-evaluate the need for EVEKEO ODT use [see Warnings and Precautions (5.1), and Drug Abuse and Dependence (9)].

2.2 Dosage Information

Administer EVEKEO ODT orally in the morning with or without food or liquid.

The recommended starting dosage for pediatric patients 6 to 17 years of age is 5 mg once or twice daily. If necessary, administer an additional dose after 4 to 6 hours. Titrate the dosage in increments of 5 mg at weekly intervals depending on response and tolerability.

Only in rare cases will it be necessary to exceed a total of 40 mg daily.

Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy.

Amphetamine should be administered at the lowest effective dosage and dosage should be individually adjusted.

2.3 Administration Instructions

Instruct the patient or caregiver on the following administration instructions:

• Do not remove the tablet from the blister pack until just prior to dosing. Do not store the tablet for future use.
• Use dry hands to open the blister.
• Remove the tablet by pushing it through the back of the foil-lined blister pack.
• As soon as the blister is opened, remove the tablet and place the tablet on the patient's tongue.
• Place the whole tablet on the tongue and allow it to disintegrate without chewing or crushing.
• The tablet will disintegrate in saliva so that it can be swallowed. No liquid is needed to take the tablet. The tablet can be actively moved around between the tongue and the roof of the mouth until it disintegrates.

2.4 Switching from Other Amphetamine Products

Switching from EVEKEO to EVEKEO ODT can be done on a milligram-per-milligram basis.

When switching from other amphetamine products, discontinue treatment and titrate with EVEKEO ODT using the titration schedule above. Do not substitute for other amphetamine products on a milligram-per-milligram basis because of different amphetamine salt compositions and differing pharmacokinetic profiles [see Description (11), Clinical Pharmacology (12.3)].

2.5 Dosage Modifications Due to Drug Interactions

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

5.1 Potential for Abuse and Dependence

CNS stimulants, including EVEKEO ODT, other amphetamine-containing products, and methylphenidate, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy [see Drug Abuse and Dependence (9.2, 9.3)].

5.2 Serious Cardiovascular Reactions

Sudden death, stroke, and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during EVEKEO ODT treatment.

5.3 Blood Pressure and Heart Rate Increases

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

5.4 Psychiatric Adverse Reactions

5.5 Long-Term Suppression of Growth

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including EVEKEO ODT.

Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted [see Use in Specific Populations (8.4)].

5.6 Seizures

There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, discontinue EVEKEO ODT.

5.7 Peripheral Vasculopathy, including Raynaud's Phenomenon

Stimulants, including EVEKEO ODT, used to treat ADHD 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 ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

5.8 Serotonin Syndrome

Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as 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 EVEKEO ODT. 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 EVEKEO ODT with MAOI drugs is contraindicated [see Contraindications (4)].

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

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Study 1 was conducted with EVEKEO tablets (i.e., not the ODT formulation) in children ages 6 to 12 years who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) criteria for ADHD. This study began with an 8-week, open-label, dose-optimization phase followed by a 2-week double-blind, placebo-controlled, randomized, crossover phase. Adverse reactions reported in > 5% of patients (N=105; doses of 10 to 40 mg/day) during the open-label phase included: decreased appetite (28%), infections (22%), abdominal pain (15%), irritability (14%), headache (13%), nausea (6%), vomiting (6%), affect lability (includes mood swings; 9%), tachycardia (9%), insomnia (10%), fatigue (10%),and dry mouth (6%). During the open-label phase, six patients discontinued due to adverse reactions: irritability (n=3), affect lability (n=1), initial insomnia (n=1), and rash (n=1).

Table 1 lists the adverse reactions reported during the double-blind, cross-over phase. No patient discontinued the study for an adverse reaction during the double-blind crossover phase. Because of the trial design (an initial 8-week, open-label, active treatment phase), the adverse reaction rates described in the double-blind phase are lower than expected in clinical practice.

6.2 Postmarketing Experience

The following adverse reactions have been associated during post approval use of amphetamines. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular: Palpitations, tachycardia, elevation of blood pressure, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use.

Central Nervous System: Psychotic episodes at recommended doses, overstimulation, irritability, restlessness, dizziness, insomnia, euphoria, mood swings, aggression, anger, logorrhea, dermatillomania, dyskinesia, dysphoria, tremor, fatigue, headache, exacerbation of motor and phonic tics and Tourette's syndrome

Gastrointestinal: Dry mouth, unpleasant taste, constipation, nausea, intestinal ischemia, other gastrointestinal disturbances, anorexia, and weight loss.

Allergic: Urticaria, rash, hypersensitivity reactions, including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis have been reported.

Endocrine: Impotence, changes in libido, and frequent or prolonged erections.

Skin: Alopecia.

Vascular Disorders: Raynaud's phenomenon.

Musculoskeletal: Rhabdomyolysis.

7.1 Drugs Having Clinically Important Interactions with Amphetamines

7.2 Drug-Laboratory Test Interactions

Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of EVEKEO ODT have been established in pediatric patients 6 years and older. Use of EVEKEO ODT is based on one adequate and well-controlled study with another immediate-release amphetamine sulfate product (EVEKEO) in pediatric patients 6 to 12 years [see Clinical Studies (14)], along with dosing and safety information for other amphetamine products.

Safety and efficacy in pediatric patients below the age of 6 years have not been established.

8.5 Geriatric Use

EVEKEO ODT has not been studied in patients over the age of 65 years.

9.1 Controlled Substance

EVEKEO ODT contains amphetamine, a Schedule II controlled substance.

9.2 Abuse

CNS stimulants including EVEKEO ODT, other amphetamine-containing products, and methylphenidates 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 a 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 EVEKEO ODT 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 amphetamine may use unapproved routes of administration which can result in overdose and death [see Overdosage (10)].

To reduce the abuse of CNS stimulants, including EVEKEO ODT, 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 EVEKEO ODT use.

9.3 Dependence

12.1 Mechanism of Action

Amphetamines are non-catecholamine sympathomimetic amines with central nervous system (CNS) stimulant activity. The mode of therapeutic action in ADHD is not known.

12.2 Pharmacodynamics

Amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

EVEKEO ODT is a 1:1 racemic mixture of d- and l-amphetamine. The l-isomer is more potent than the d-isomer in cardiovascular activity while the d-isomer is more potent than the l-isomer in causing CNS excitatory effects.

12.3 Pharmacokinetics

Amphetamine demonstrates linear pharmacokinetics over the dose range of 5 to 40 mg.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

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

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C -30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Store EVEKEO ODT blister packages in the provided plastic sleeve.

Disposal

Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired EVEKEO ODT at authorized collection sites such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix EVEKEO ODT with an undesirable, nontoxic substance to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and discard EVEKEO ODT in the household trash.

Controlled Substance Status/Potential for Abuse, Misuse, and Dependence

Advise patients and their caregivers that EVEKEO ODT is a federally controlled substance because it can be abused or lead to dependence. Advise patients to store EVEKEO ODT in a safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired EVEKEO ODT by a medicine take-back program if available [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.2)].

Dosage and Administration Instructions

Provide the following instructions on administration to the patient:

• The tablet should remain in the blister pack until the patient is ready to take it.
• The patient or caregiver should use dry hands to open the blister.
• Remove the tablet by pushing it through the back of the foil-lined blister packaging.
• As soon as the blister is opened, place the tablet on the patient's tongue.
• The whole tablet should be placed on the tongue and allowed to disintegrate without chewing or crushing.
• The tablet will disintegrate in saliva so that it can be swallowed.

Serious Cardiovascular Risks

Advise patients, caregivers, and family members that there is a potential serious cardiovascular risk (including sudden death, myocardial infarction, stroke, and hypertension) with EVEKEO ODT. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2)].

Blood Pressure and Heart Rate Increases

Instruct patients and their caregivers that EVEKEO ODT can cause elevations of their blood pressure and pulse rate and that patients should be monitored for such effects [see Warnings and Precautions (5.3)].

Psychiatric Risks

Advise patients and their caregivers that EVEKEO ODT, at recommended doses, may cause psychotic symptoms or mania even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)].

Long-Term Suppression of Growth

Advise patients, family members, and caregivers that EVEKEO ODT may cause slowing of growth including weight loss [see Warnings and Precautions (5.5)].

Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, including Raynaud's Phenomenon]

Instruct patients and their caregivers beginning treatment with EVEKEO ODT about the risk of peripheral vasculopathy, including Raynaud's phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking EVEKEO ODT. Further clinical evaluation (e.g. rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.7)].

Serotonin Syndrome

Caution patients and their caregivers about the risk of serotonin syndrome with concomitant use of EVEKEO ODT and other serotonergic drugs including SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others such as linezolid [see Contraindications (4), Warnings and Precautions (5.8) and Drug Interactions (7.1)]. Advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.

Concomitant Medications

Advise patients and their caregivers to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs because there is a potential for interactions [see Drug Interactions (7.1)].

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EVEKEO ODT during pregnancy [see Use in Specific Populations (8.1)].

Pregnancy

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

Lactation

Advise patients not to breastfeed if they are taking EVEKEO ODT [see Use in Specific Populations (8.2)].