Evekeo ODT Dailymed

Warning: Abuse, Misuse, And Addiction

EVEKEO ODT has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including EVEKEO ODT, 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 EVEKEO ODT, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout EVEKEO ODT treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1)and Drug Abuse and Dependence (9.2)].


WARNING: ABUSE, MISUSE, AND ADDICTION

See full prescribing information for complete boxed warning.

EVEKEO ODT has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including EVEKEO ODT, can result in overdose and death ( 5.1, 9.2, 10):

• Before prescribing EVEKEO ODT, assess each patient's risk for abuse, misuse, and addiction.
• Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug.
• Throughout treatment, reassess each patient's risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

• Administer in the morning with or without food or liquid. ( 2.2)
• Recommended starting dosage 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. ( 2.2)
• Only in rare cases will it be necessary to exceed a total of 40 mg daily. ( 2.2)
• Place the whole tablet on tongue and allow to disintegrate in saliva, so that it can be swallowed. ( 2.3)
• Do not substitute for other amphetamine products on a milligram-per-milligram basis because of different amphetamine salt compositions and differing pharmacokinetic profiles. ( 2.4 )

2.1 Pretreatment 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)].
• the family history and clinically evaluate patients for motor or verbal tics or Tourette's syndrome before initiating EVEKEO ODT [see Warnings and Precautions (5.9)].

2.2 Recommended Dosage

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.

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 buler pack until just prior to dosing. Do not store the tablet for future use.
• Use dry hands to open the buler.
• Remove the tablet by pushing it through the back of the foil-lined buler pack.
• As soon as the buler 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)] .

3 Dosage Forms And Strengths

EVEKEO ODT (amphetamine sulfate) orally disintegrating tablets are supplied as follows:

• 5 mg: white to off-white, round, flat-faced radius-edged tablet with "5" on one side and "EVI" on the other.
• 10 mg: white to off-white, round, flat-faced radius-edged tablet with "10" on one side and "EVI" on the other.
• 15 mg: white to off-white, round, flat-faced radius-edged tablet with "15" on one side and "EVI" on the other.
• 20 mg: white to off-white, round, flat-faced radius-edged tablet with "20" on one side and "EVI" on the other.

Orally disintegrating tablets: 5 mg, 10 mg, 15 mg, and 20 mg. ( 3)

4 Contraindications

EVEKEO ODT is contraindicated in patients:

• With known hypersensitivity to amphetamine, or other components of EVEKEO ODT. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products [see Adverse Reactions (6.2)] .
• Receiving concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis [see Warnings and Precautions (5.8), Drug Interactions (7.1)].

• Known hypersensitivity to amphetamine products or other ingredients in EVEKEO ODT. ( 4)
• Use of monoamine oxidase inhibitor (MAOI) or within 14 days of the last MAOI dose. ( 4)

5 Warnings And Precautions

• Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. ( 5.2)
• Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. ( 5.3)
• Psychiatric Adverse Reactions: Prior to initiating EVEKEO ODT, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing EVEKEO ODT. ( 5.4)
• Long-term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. ( 5.5)
• Seizures: May lower the convulsive threshold. If a seizure occurs, discontinue EVEKEO ODT .( 5.6)
• Peripheral Vasculopathy, including Raynaud's Phenomenon: Careful observation for digital changes is necessary during EVEKEO ODT treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. ( 5.7)
• Serotonin Syndrome: Increased risk when co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue EVEKEO ODT and initiate supportive treatment. ( 5.8)
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome:Before initiating EVEKEO ODT, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette's syndrome. Discontinue treatment if clinically appropriate. ( 5.9)

5.1 Abuse, Misuse, and Addiction

EVEKEO ODT has a high potential for abuse and misuse. The use of EVEKEO ODT exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. EVEKEO ODT 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 EVEKEO ODT, 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 EVEKEO ODT, 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 EVEKEO ODT in a safe place, preferably locked, and instruct patients to not give EVEKEO ODT to anyone else. Throughout EVEKEO ODT 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 Disease

Sudden 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 EVEKEO ODT 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 Rate

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). Some patients may have larger increases.

Monitor all EVEKEO ODT-treated patients for potential tachycardia and hypertension.

5.4 Psychiatric Adverse Reactions

Exacerbation of Pre-Existing Psychosis

CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.

Induction of a Manic Episode in Patients with Bipolar Disease

CNS stimulants may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating EVEKEO ODT treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or has a history of depressive symptoms or a family history of suicide, bipolar disorder, and depression).

New Psychotic or Manic Symptoms

CNS stimulants, at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without 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 EVEKEO ODT.

5.5 Long-Term Suppression of Growth in Pediatric Patients

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

Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

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

CNS 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, 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 dosage 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 EVEKEO ODT treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for EVEKEO ODT-treated patients who develop signs or symptoms of peripheral vasculopathy.

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.

5.9 Motor and Verbal Tics, and Worsening of Tourette's Syndrome

CNS stimulants, including amphetamine sulfate, 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 EVEKEO ODT, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor EVEKEO ODT-treated patients for the emergence or worsening of tics or Tourette's syndrome, and discontinue treatment if clinically appropriate.

6 Adverse Reactions

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

• Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)]
• Hypersensitivity to amphetamine, or other components of EVEKEO ODT [see Contraindications (4)]
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4)and Drug Interactions (7.1)]
• Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)]
• Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)]
• Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
• Seizures [see Warnings and Precautions (5.6)]
• Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.5)]
• Peripheral Vasculopathy, including Raynaud's Phenomenon [see Warnings and Precautions (5.7)]
• Serotonin Syndrome [see Warnings and Precautions (5.8)]
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome [see Warnings and Precautions (5.9)]

Most common adverse reactions (incidence ≥4% and at a rate at least twice placebo) in pediatric patients are: decreased appetite and insomnia. ( 6)

To report SUSPECTED ADVERSE REACTIONS, contact Arbor Pharmaceuticals, LLC at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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, 4 ^thedition, 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 uls 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.

Table 1: Adverse Reactions Reported in ≥ 2%, and > Placebo, of EVEKEO-Treated Pediatric Patients (6 to 12 Years) During the Double-Blind Cross-Over Weeks. Drug exposures and placebo exposures from cross-over were combined for analysis.

System Organ Class   Preferred Term	EVEKEO (n= 97)	Placebo (n= 97)
Subjects with at least one adverse event	22%	14%
Metabolism and Nutrition Disorders
  Decreased appetite	4%	0%
Gastrointestinal Disorders
  Abdominal pain	3%	0%
Psychiatric Disorders
  Affect Lability Includes mood swings.	3%	0%
  Insomnia	4%	0%
Injury, poisoning and procedural complications
  Injury	3%	2%

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 verbal 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.