Dextroamphetamine Sulfate Extended-Release Capsules

Each dextroamphetamine sulfate extended-release capsule is so prepared that an initial dose is released promptly and the remaining medication is released gradually over a prolonged period.

Each capsule, with white opaque cap and white opaque body, contains dextroamphetamine sulfate USP. The 5 mg capsule is imprinted with an ® on the cap and is imprinted 8960 5 mg on the body in black. The 10 mg capsule is imprinted with an ® on the cap and is imprinted 8961 10 mg on the body in blue. The 15 mg capsule is imprinted with an ® on the cap and is imprinted 8962 15 mg on the body in pink. Inactive ingredients consist of sugar spheres, titanium dioxide, gelatin, shellac glaze-45%, SD-45 alcohol, iron oxide black, propylene glycol, FD&C Blue #2/Indigo Carmine Lake, FD&C Red #40/Allura Red AC Lake, FD&C Blue #1/Brilliant Blue FCF Lake, D&C Yellow #10 Lake, SD3A alcohol, shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, strong ammonia solution, FD&C Blue #2 Aluminum Lake, D&C Red #7 Calcium Lake, hydroxypropyl methylcellulose/hypromellose, macrogol/polyethylene glycol, purified water, ethylcellulose, ammonium hydroxide 28%, medium chain triglycerides, oleic acid.

Pharmacokinetics

The pharmacokinetics of the tablet and sustained-release capsule were compared in 12 healthy subjects.  The extent of bioavailability of the sustained-release capsule was similar compared to the immediate-release tablet.  Following administration of three 5 mg tablets, average maximal dextroamphetamine plasma concentrations (Cmax) of 36.6 ng/mL were achieved at approximately 3 hours.

Following administration of one 15 mg sustained-release capsule, maximal dextroamphetamine plasma concentrations were obtained approximately 8 hours after dosing.  The average Cmax was 23.5 ng/mL.  The average plasma T1/2 was similar for both the tablet and sustained-release capsule and was approximately 12 hours. In 12 healthy subjects, the rate and extent of dextroamphetamine absorption were similar following administration of the sustained-release capsule formulation in the fed (58 g to 75 g fat) and fasted state.

Serious Cardiovascular Events

Sudden Death in Patients with Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems

Children and Adolescents

Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems.  Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug.



Adults

Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems.  Adults with such abnormalities should also generally not be treated with stimulant drugs (see CONTRAINDICATIONS).

Hypertension and Other Cardiovascular Conditions

Stimulant medications cause a modest increase in average blood pressure (about 2 mmHg to 4 mmHg) and average heart rate (about 3 bpm to 6 bpm), and individuals may have larger increases.  While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure.  Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia (see CONTRAINDICATIONS).

Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications

Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.

Psychiatric Adverse Events

Pre-Existing Psychosis

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



Bipolar Illness

Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients.  Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.



Emergence of New Psychotic or Manic Symptoms

Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses.  If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate.  In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients.



Aggression

 Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD.  Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of, or worsening of, aggressive behavior or hostility.

Long-Term Suppression of Growth

Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children older than 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 

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, the drug should be discontinued.

Peripheral Vasculopathy, Including Raynaud’s Phenomenon

Stimulants, including dextroamphetamine sulfate extended-release capsules, 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 postmarketing 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.

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). Amphetamines and amphetamine derivatives are known to be metabolized, to some degree, by cytochrome P450 2D6 (CYP2D6) and display minor inhibition of CYP2D6 metabolism (see CLINICAL PHARMACOLOGY). The potential for a pharmacokinetic interaction exists with the co-administration of CYP2D6 inhibitors which may increase the risk with increased exposure to dextroamphetamine sulfate extended-release capsules. 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 dextroamphetamine sulfate extended-release capsules with MAOI drugs is contraindicated (see CONTRAINDICATIONS).

Discontinue treatment with dextroamphetamine sulfate extended-release capsules and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of dextroamphetamine sulfate extended-release capsules with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate dextroamphetamine sulfate extended-release capsules 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.

Visual Disturbance

Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.

General

The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage.

Information for Patients

Amphetamines may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or vehicles; the patient should therefore be cautioned accordingly.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with dextroamphetamine and should counsel them in its appropriate use. A patient Medication Guide is available for dextroamphetamine sulfate extended-release capsules. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon]

• Instruct patients beginning treatment with dextroamphetamine sulfate extended-release capsules 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 dextroamphetamine sulfate extended-release capsules.
• Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Drug Interactions

Acidifying Agents

Lower blood levels and efficacy of amphetamines. Increase dose based on clinical response. Examples of acidifying agents include gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid) and urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts).

Adrenergic Blockers

Adrenergic blockers are inhibited by amphetamines.

Alkalinizing Agents

Increase blood levels and potentiate the action of amphetamine. Co-administration of dextroamphetamine sulfate extended-release capsules and gastrointestinal alkalinizing agents should be avoided. Examples of alkalinizing agents include gastrointestinal alkalinizing agents (e.g., sodium bicarbonate) and urinary alkalinizing agents (e.g., acetazolamide, some thiazides).

Tricyclic Antidepressants

May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. Monitor frequently and adjust or use alternative therapy based on clinical response. Examples of tricyclic antidepressants include desipramine, Protriptyline.

CYP2D6 Inhibitors

The concomitant use of dextroamphetamine sulfate extended-release capsules and CYP2D6 inhibitors may increase the exposure of dextroamphetamine sulfate extended-release capsules compared to the use of the drug alone and increase the risk of serotonin syndrome. Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during dextroamphetamine sulfate extended-release capsules initiation and after a dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine sulfate extended-release capsules and the CYP2D6 inhibitor (see WARNINGS, OVERDOSAGE). Examples of CYP2D6 Inhibitors include paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir.

Serotonergic Drugs

The concomitant use of dextroamphetamine sulfate extended-release capsules and serotonergic drugs increases the risk of serotonin syndrome. Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during dextroamphetamine sulfate extended-release capsules initiation or dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine sulfate extended-release capsules and the concomitant serotonergic drug(s) (see WARNINGS and PRECAUTIONS). Examples of serotonergic drugs include selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort.

MAO Inhibitors

Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure. Do not administer dextroamphetamine sulfate extended-release capsules concomitantly or within 14 days after discontinuing MAOI (see CONTRAINDICATIONS and WARNINGS). Examples of MAOIs include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue.

Proton Pump Inhibitors

Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone. Monitor patients for changes in clinical effect and adjust therapy based on clinical response. An example of a proton pump inhibitor is omeprazole.

Antihistamines

Amphetamines may counteract the sedative effect of antihistamines.

Antihypertensives

Amphetamines may antagonize the hypotensive effects of antihypertensives.

Chlorpromazine

Chlorpromazine blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning.

Ethosuximide

Amphetamines may delay intestinal absorption of ethosuximide.

Haloperidol

Haloperidol blocks dopamine and norepinephrine reuptake, thus inhibiting the central stimulant effects of amphetamines.

Lithium Carbonate

The stimulatory effects of amphetamines may be inhibited by lithium carbonate.

Meperidine

Amphetamines potentiate the analgesic effect of meperidine.

Methenamine Therapy

Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy.

Norepinephrine

Amphetamines enhance the adrenergic effect of norepinephrine.

Phenobarbital

Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action.

Phenytoin

Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action.

Propoxyphene

In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur.

Veratrum Alkaloids

Amphetamines inhibit the hypotensive effect of veratrum alkaloids.

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

Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of dextroamphetamine sulfate extended-release capsules have not been performed.

Pregnancy

Teratogenic Effects

Dextroamphetamine sulfate extended-release capsules have been shown to have embryotoxic and teratogenic effects when administered to A/Jax mice and C57BL mice in doses approximately 41 times the maximum human dose.  Embryotoxic effects were not seen in New Zealand white rabbits given the drug in doses 7 times the human dose nor in rats given 12.5 times the maximum human dose.  While there are no adequate and well-controlled studies in pregnant women, there has been one report of severe congenital bony deformity, tracheoesophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy.  Dextroamphetamine sulfate extended-release capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.



Nonteratogenic Effects

Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight.  Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude.

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 pediatric patients have not been well established.

Dextroamphetamine sulfate extended-release capsules are not recommended for use in pediatric patients younger than 6 years of age with Attention Deficit Disorder with Hyperactivity described under INDICATIONS AND USAGE.  



Clinical experience suggests that in psychotic children, administration of amphetamines may exacerbate symptoms of behavior disturbance and thought disorder.



Amphetamines have been reported to exacerbate motor and phonic tics and Tourette’s syndrome.  Therefore, clinical evaluation for tics and Tourette’s syndrome in children and their families should precede use of stimulant medications.



Data are inadequate to determine whether chronic administration of amphetamines may be associated with growth inhibition; therefore, growth should be monitored during treatment.



Drug treatment is not indicated in all cases of Attention Deficit Disorder with Hyperactivity and should be considered only in light of the complete history and evaluation of the child.  The decision to prescribe amphetamines should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his or her age.  Prescription should not depend solely on the presence of one or more of the behavioral characteristics.



When these symptoms are associated with acute stress reactions, treatment with amphetamines is usually not indicated.

TREATMENT

Consult with a Certified Poison Control Center for up-to-date guidance and advice.  Management of acute amphetamine intoxication is largely symptomatic and includes gastric lavage, administration of activated charcoal, administration of a cathartic, and sedation.  Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard.  Acidification of the urine increases amphetamine excretion, but is believed to increase risk of acute renal failure if myoglobinuria is present.  If acute, severe hypertension complicates amphetamine overdosage, administration of intravenous phentolamine (Bedford Laboratories) has been suggested.  However, a gradual drop in blood pressure will usually result when sufficient sedation has been achieved.



Chlorpromazine antagonizes the central stimulant effects of amphetamines and can be used to treat amphetamine intoxication.



Since much of the dextroamphetamine sulfate extended-release capsule medication is coated for gradual release, therapy directed at reversing the effects of the ingested drug and at supporting the patient should be continued for as long as overdosage symptoms remain. Saline cathartics are useful for hastening the evacuation of pellets that have not already released medication.