Pharmacodynamics

Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Amphetamines are thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

Pharmacokinetics

Adderall® tablets contain d-amphetamine and l-amphetamine salts in the ratio of 3:1. Following administration of a single dose 10 or 30 mg of Adderall® to healthy volunteers under fasted conditions, peak plasma concentrations occurred approximately 3 hours post-dose for both d-amphetamine and l-amphetamine. The mean elimination half-life (t1/2) for d-amphetamine was shorter than the t1/2 of the l-isomer (9.77 to 11 hours vs. 11.5 to 13.8 hours). The PK parameters (Cmax, AUC0-inf) of d-and l-amphetamine increased approximately three-fold from 10 mg to 30 mg indicating dose-proportional pharmacokinetics.

The effect of food on the bioavailability of Adderall® has not been studied.

Attention Deficit Hyperactivity Disorder (ADHD)

A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV®) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go;” excessive talking; blurting answers; can't wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met.

Abuse, Misuse, and Addiction

Adderall® has a high potential for abuse and misuse. The use of Adderall® exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Adderall® can be diverted for non-medical use into illicit channels or distribution [see DRUG ABUSE AND DEPENDENCE: Abuse]. Misuse and abuse of CNS stimulants, including Adderall®, can result in overdose and death [see OVERDOSAGE], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing Adderall® 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 amphetamine sulfate in a safe place, preferably locked, and instruct patients to not give Adderall® to anyone else. Throughout Adderall® treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

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 stimulant treatment at the recommended ADHD dosages.

Avoid Adderall® use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

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 Adderall®-treated patients for potential tachycardia and hypertension.

Psychiatric Adverse Reactions

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 Adderall®-treated pediatric patients treated with CNS stimulants.

Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see PRECAUTIONS, PEDIATRIC USE].

Seizures

There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizure, 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, the drug should be discontinued.

Peripheral Vasculopathy, Including Raynaud’s Phenomenon

Stimulants, including Adderall®, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing 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 Adderall® treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for Adderall®-treated patients who develop signs or symptoms of peripheral vasculopathy.

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 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]. The coadministration with cytochrome P450 (CYP2D6) inhibitors increase the risk with increased exposure to Adderall®. In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6 [see DRUG INTERACTIONS].

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 Adderall® with MAOI drugs is contraindicated [see CONTRAINDICATIONS].

Discontinue treatment with Adderall® and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Adderall® with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate Adderall® 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.

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. Before initiating Adderall®, 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 with Adderall®, and discontinue treatment if clinically appropriate.

Information for Patients

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

Drug Interactions

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.

Carcinogenesis/Mutagenesis and Impairment of Fertility

No evidence of carcinogenicity was found in studies in which d,l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats. These doses are approximately 2.4, 1.5, and 0.8 times, respectively, the maximum recommended human dose of 30 mg/day [child] on a mg/m2 body surface area basis.

Amphetamine, in the enantiomer ratio present in Adderall® (immediate-release)(d- to l- ratio of 3:1), was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli component of the Ames test in vitro. d, l-Amphetamine (1:1 enantiomer ratio) has been reported to produce a positive response in the mouse bone marrow micronucleus test, an equivocal response in the Ames test, and negative responses in the in vitro sister chromatid exchange and chromosomal aberration assays.

Amphetamine, in the enantiomer ratio present in Adderall® (immediate-release)(d- to l- ratio of 3:1), did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day (approximately 5 times the maximum recommended human dose of 30 mg/day on a mg/m2 body surface area basis).

Pregnancy

Usage in Nursing Mothers

Amphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing.

Pediatric Use

Long-term effects of amphetamines in children have not been well established. Amphetamines are not recommended for use in children under 3 years of age with Attention Deficit Hyperactivity Disorder described under INDICATIONS AND USAGE.

Geriatric Use

Adderall® has not been studied in the geriatric population.

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, restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, motor and verbal tics, aggression, anger, logorrhea, dermatillomania.

Eye Disorders

Vision blurred, mydriasis.

Gastrointestinal

Dryness of the mouth, unpleasant taste, diarrhea, constipation, intestinal ischemia, and other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects.

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, frequent or prolonged erections.

Skin

Alopecia.

Musculoskeletal

Rhabdomyolysis.

To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Controlled Substance

Adderall® contains amphetamine, a Schedule II controlled substance.

Abuse

Adderall® has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction [see WARNINGS and PRECAUTIONS]. Adderall® can be diverted for non-medical use into illicit channels or distribution.

Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of amphetamines may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including Adderall®, can result in overdose and death [see OVERDOSAGE], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Dependence

Physical Dependence

Adderall® may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including Adderall® include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance

Adderall® may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Clinical Effects of Overdose

Overdose of CNS stimulants is characterized by the following sympathomimetic effects:

• Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop.
• CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur.
• Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop.

Overdose Management

Consider the possibility of multiple drug ingestion. D-amphetamine is not dialyzable. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

Attention Deficit Hyperactivity Disorder

Not recommended for children under 3 years of age. In children from 3 to 5 years of age, start with 2.5 mg daily; daily dosage may be raised in increments of 2.5 mg at weekly intervals until optimal response is obtained.

In children 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.

Prior to treating patients with Adderall®, 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].
• the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating Adderall® [see WARNINGS].

Narcolepsy

Usual dose 5 mg to 60 mg per day in divided doses, depending on the individual patient response.

Narcolepsy seldom occurs in children under 12 years of age; however, when it does, dextroamphetamine sulfate may be used. The suggested initial dose for patients aged 6 to 12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.