DEXTROAMPHETAMINE SACCHARATE

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.

Mixed Salts of a Single Entity Amphetamine Product contain d-amphetamine and l-amphetamine salts in the ratio of 3:1. Following administration of a single dose 10 or 30 mg of Mixed Salts of a Single Entity Amphetamine Product 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 (t_½) for d-amphetamine was shorter than the t_½ of the l-isomer (9.77 to 11 hours vs. 11.5 to 13.8 hours). The PK parameters (C_max, AUC_0-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 Mixed Salts of a Single Entity Amphetamine Product has not been studied. 

Metabolism and Excretion

Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain α or β carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxy-amphetamine are both active and each is subsequently oxidized to form 4-hydroxy-norephedrine.
Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid. Although the enzymes involved in amphetamine metabolism have not been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy-amphetamine. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility.

Amphetamine is known to inhibit monoamine oxidase, whereas the ability of amphetamine and its metabolites to inhibit various P450 isozymes and other enzymes has not been adequately elucidated. In vitro experiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites. However, due to the probability of auto-inhibition and the lack of information on the concentration of these metabolites relative to in vivo concentrations, no predications regarding the potential for amphetamine or its metabolites to inhibit the metabolism of other drugs by CYP isozymes in vivo can be made.

With normal urine pHs approximately half of an administered dose of amphetamine is recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30% to 40% of the dose is recoverable in urine as amphetamine itself. Since amphetamine has a pKa of 9.9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pHs result in less ionization and reduced renal elimination, and acidic pHs and high flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion. Urinary recovery of amphetamine has been reported to range from 1% to 75%, depending on urinary pH, with the remaining fraction of the dose hepatically metabolized. Consequently, both hepatic and renal dysfunction have the potential to inhibit the elimination of amphetamine and result in prolonged exposures. In addition, drugs that affect urinary pH are known to alter the elimination of amphetamine, and any decrease in amphetamine’s metabolism that might occur due to drug interactions or genetic polymorphisms is more likely to be clinically significant when renal elimination is decreased (see   PRECAUTIONS).

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.

Mixed Salts of a Single Entity Amphetamine Product has a high potential for abuse and misuse. The use of Mixed Salts of a Single Entity Amphetamine Product exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Mixed Salts of a Single Entity Amphetamine Product 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 Mixed Salts of a Single Entity Amphetamine Product, 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 Mixed Salts of a Single Entity Amphetamine Product, 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 Mixed Salts of a Single Entity Amphetamine Product to anyone else. Throughout Mixed Salts of a Single Entity Amphetamine Product treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

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 Mixed Salts of a Single Entity Amphetamine Product use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

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 Mixed Salts of a Single Entity Amphetamine Product-treated patients for potential tachycardia and hypertension.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in Mixed Salts of a Single Entity Amphetamine Product-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).

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.

Stimulants, including Mixed Salts of a Single Entity Amphetamine Product, 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 dosages 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 Mixed Salts of a Single Entity Amphetamine Product treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for Mixed Salts of a Single Entity Amphetamine Product-treated patients who develop signs or symptoms of peripheral vasculopathy.

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 Mixed Salts of a Single Entity Amphetamine Product. 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 Mixed Salts of a Single Entity Amphetamine Product with MAOI drugs is contraindicated (see CONTRAINDICATIONS).

Discontinue treatment with Mixed Salts of a Single Entity Amphetamine Product and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Mixed Salts of a Single Entity Amphetamine Product with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate Mixed Salts of a Single Entity Amphetamine Product 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.

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. Assess the family history and clinically evaluate patients for tics or Tourette’s syndrome before initiating Mixed Salts of a Single Entity Amphetamine Product. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome with Mixed Salts of a Single Entity Amphetamine Product, and discontinue treatment if clinically appropriate.

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

Abuse, Misuse, and Addiction

Educate patients and their families about the risks of abuse, misuse, and addiction of Mixed Salts of a Single Entity Amphetamine Product, which can lead to overdose and death, and proper disposal of any unused drug (see WARNINGS,  DRUG ABUSE AND DEPENDENCE,  OVERDOSAGE). Advise patients to store Mixed Salts of a Single Entity Amphetamine Product in a safe place, preferably locked, and instruct patients to not give Mixed Salts of a Single Entity Amphetamine Product to anyone else.

Risks to Patients with Serious Cardiac Disease

Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with Mixed Salts of a Single Entity Amphetamine Product use. 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).

Increased Blood Pressure and Heart Rate

Advise patients that Mixed Salts of a Single Entity Amphetamine Product can elevate blood pressure and heart rate (see WARNINGS).

Psychiatric Adverse Reactions

Advise patients that Mixed Salts of a Single Entity Amphetamine Product, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania (see WARNINGS).

Long-Term Suppression of Growth in Pediatric Patients

Advise patients that Mixed Salts of a Single Entity Amphetamine Product may cause slowing of growth including weight loss (see WARNINGS).

Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon]

• Instruct patients beginning treatment with Mixed Salts of a Single Entity Amphetamine Product 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 color 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 Mixed Salts of a Single Entity Amphetamine Product.

Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with concomitant use of Mixed Salts of a Single Entity Amphetamine Product 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,  WARNINGS ,  and DRUG INTERACTIONS). Advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.

Motor and Verbal Tics, and Worsening of Tourette’s Syndrome

• Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with Mixed Salts of a Single Entity Amphetamine Product. Instruct the patients to notify their healthcare provider if emergence or worsening of tics or Tourette’s syndrome occurs (see WARNINGS).

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

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 Mixed Salts of a Single Entity Amphetamine Product (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 Mixed Salts of a Single Entity Amphetamine Product (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).

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

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.

Mixed Salts of a Single Entity Amphetamine Product have not been studied in the geriatric population.

Mixed Salts of a Single Entity Amphetamine Product 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). Mixed Salts of a Single Entity Amphetamine Product 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 healthcare 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 Mixed Salts of a Single Entity Amphetamine Product, 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.

Physical Dependence

Mixed Salts of a Single Entity Amphetamine Product 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 Mixed Salts of a Single Entity Amphetamine Product include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance

Mixed Salts of a Single Entity Amphetamine Product 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).

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.

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

Prior to treating patients with Mixed Salts of a Single Entity Amphetamine Product 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 Mixed Salts of a Single Entity Amphetamine Product (see WARNINGS).

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.