Amphetamine Sulfate

Noncatechol, sympathomimetic amine with CNS-stimulating activity.a b c

Contraindications

• Contraindicated in patients with hypersensitivity or idiosyncrasy to the sympathomimetic amines,a c d symptomatic cardiovascular disease,a c d hyperthyroidism,a c d moderate to severe hypertension,a c d glaucoma,a c d e or advanced arteriosclerosis;a c d within 14 days of MAO inhibitor therapy;a c d e and in agitated patients.a c d

• Although amphetamines generally should not be used in patients with a history of drug abuse,a c d e some experts state that this is not an absolute contraindication, provided the patient can be monitored more carefully than would otherwise be indicated.e

Warnings/Precautions

Warnings

Sudden unexplained death, stroke, and MI reported in adults with ADHD receiving usual dosages of stimulants; sudden death also reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of the drugs.a c g

Epidemiologic data suggest a possible association between use of stimulants and sudden unexplained death in healthy children and adolescents.h i j FDA unable to conclude that these data affect evaluation of overall risk and benefit of stimulants used to treat ADHD in children and adolescents.h FDA is conducting an ongoing safety review of amphetamines and other stimulants to evaluate possible link between use of these agents and sudden death in children.h i j Pediatric patients with ADHD and their parents should avoid discontinuing the child’s use of such stimulants before consulting a clinician.h

Thoroughly review medical history (including evaluation for family history of sudden death or ventricular arrhythmia) and perform physical examination in all children, adolescents, and adults being considered for stimulant therapy; if initial findings suggest presence of cardiac disease, perform further cardiac evaluation (e.g., ECG, echocardiogram).a c

In general, avoid use of CNS stimulants in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, CAD, or other serious cardiac conditions.a c g (See Contraindications under Cautions.)

Patients who develop exertional chest pain, unexplained syncope, or other manifestations suggestive of cardiac disease during stimulant therapy should undergo prompt cardiac evaluation.a c

Possible modest increases in average BP (i.e., by about 2–4 mm Hg) and heart rate (i.e., by about 3–6 bpm); larger increases may occur.a c Modest increases not expected to have short-term sequelae; however, monitor all patients for larger changes in BP and heart rate.a c

Caution advised in patients with underlying medical conditions that might be affected by increases in BP or heart rate (e.g., hypertension, heart failure, recent MI, ventricular arrhythmia).a c

May exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorder.a c

Psychotic symptoms (e.g., hallucinations, delusional thinking) may occur with usual dosages in children and adolescents without prior history of psychotic illness.a c If psychotic symptoms occur, consider causal relationship to stimulants, and discontinue therapy as appropriate.a c

May precipitate mixed or manic episodes in ADHD patients with comorbid bipolar disorder; use with caution in these patients.a c Prior to initiating therapy, carefully screen patients with ADHD and comorbid depressive symptoms to identify risk for bipolar disorder; screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, or depression).a c

Manic symptoms may occur with usual dosages in children and adolescents without prior history of mania.a c If manic symptoms occur, consider causal relationship to stimulants, and discontinue therapy as appropriate.a c

Aggressive behavior and hostility (frequently observed in children and adolescents with ADHD) reported in patients receiving drug therapy for ADHD.a c No systematic evidence that stimulants cause these adverse effects; however, monitor patients beginning treatment for ADHD for onset or worsening of aggressive behavior or hostility.a c

Long-term (i.e., >14 months) administration expected to cause at least a temporary suppression of normal weight and/or height patterns in some children and adolescents.a c Dose-related weight loss reported in adolescents during first 4 weeks of therapy with extended-release capsules.c

Manufacturers recommend monitoring growth during treatment; patients not growing or gaining weight as expected may require temporary discontinuance of treatment.a c However, AAP states that studies of stimulants in children found little or no decrease in expected height, with any decrease in growth early in treatment being compensated for later on.

Possible lowering of seizure threshold in patients with history of seizures, in those with prior EEG abnormalities but no history of seizures, and, very rarely, in those without history of seizures and with no prior evidence of EEG abnormalities.a c If seizures occur, discontinue therapy.a c

Visual disturbances (difficulty with accommodation, blurred vision) reported with stimulants.a c

General Precautions

Least amount of amphetamine feasible should be prescribed or dispensed at one time in order to minimize possible overdosage.a c

Amphetamines reported to exacerbate motor and phonic tics and Tourette’s syndrome.a c d However, a history of tics or their development during therapy is not an absolute contraindication to continued use.e Several controlled studies have not found stimulants to worsen or precipitate tics or Tourette’s syndrome.e Nevertheless, evaluate for presence of tics and Tourette’s syndrome in children and their families prior to initiating stimulant therapy.a c d

When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.

Specific Populations

Category C.a c f

Risk of prematurity, low birth weight, and withdrawal symptoms (e.g., dysphoria, lassitude, agitation) in infants born to dependent women.a c f

Distributed into milk.a c f Discontinue nursing or the drug.a c

Not recommended for ADHD in children <3 years of age.a c e

Aggressive behavior, hostility, and psychotic (e.g., hallucinations, delusional thinking) or manic symptoms reported in children and adolescents receiving stimulants for management of ADHD.a c (See Warnings under Cautions.)

Sudden death reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of stimulants.a c Epidemiologic data also suggest a possible association between use of stimulants and sudden death in healthy children and adolescents.h i j (See Sudden Death and Serious Cardiovascular Events under Cautions.)

Long-term administration expected to cause at least a temporary suppression of normal weight and/or height patterns in some children and adolescents.a c (See Growth Suppression under Cautions.)

Not studied in geriatric patients.a c

Possible inhibition of drug elimination, resulting in prolonged exposure.a c

Possible inhibition of drug elimination, resulting in prolonged exposure.a c

Common Adverse Effects

Palpitations,a c tachycardia,a c elevation of BP,a c overstimulation,a c restlessness,a c dizziness,a c insomnia,a c euphoria,a c dyskinesia,a c dysphoria,a c tremor,a c headache,a c dryness of mouth,a c taste aberration,a c diarrhea,a c constipation,a c abdominal bloating,a c impotence and changes in libido.a c

Isolated reports of cardiomyopathy associated with chronic amphetamine use.a b c

Anorexia and weight loss may occur as undesirable effects when amphetamines are used for other than the anorectic effect.a c

Absorption

Bioavailability

Plasma concentration-time profiles similar for single 20-mg extended-release dose versus two 10-mg immediate-release doses given 4 hours apart.c

Peak plasma concentration and AUC decrease with increasing body weight.c

Rapidly absorbed from the GI tract.PDH

Duration

Therapeutic effects persist for 4–24 hours.PDH

Food

Food does not affect the extent of absorption of the extended-release preparation (Adderall XR), but prolongs Tmax by 2.5 hours (for d-amphetamine) and 2.1 hours (for l-amphetamine).c Opening the capsule and sprinkling the contents on applesauce results in comparable absorption to the intact capsule taken in the fasted state.c

Plasma Concentrations

Tmax, immediate-release: About 3 hours.a c

Tmax, extended-release: About 7 hours.c

Therapeutic plasma concentrations are 5–10 mcg/dL.PDH

Distribution

Extent

Distributed widely throughout body, with high levels in the brain.PDH

Apparently crosses the placenta since withdrawal manifestations have occurred in neonates.a c f

Distributed into milk in concentrations 3–7 times maternal blood concentrations.f

Volume of distribution increases with increasing body weight.c

Elimination

Metabolism

Metabolized to several active metabolites.a c

Enzymes involved in metabolism not clearly defined; however, CYP2D6 is involved with formation of at least one metabolite.a c Because CYP2D6 is genetically polymorphic, potential variability in metabolism among patients exists.a c

Elimination Route

With normal urinary pH, excreted in urine as unchanged drug (approximately 30–40%) and metabolites (approximately 50%).a c Changes in urinary pH may alter excretion; urinary recovery of unchanged drug reported to range from 1–75%, depending on urinary pH.a c (See Specific Drugs and Laboratory Tests under Interactions.)

Clearance increases with increasing body weight.c On a mg/kg basis, however, children have higher clearance than adolescents or adults.c

Half-life

Children 6–12 years of age: 9 hours (for d-amphetamine) or 11 hours (for l-amphetamine).c

Adolescents 13–17 years of age: 11 hours (for d-amphetamine) or 13–14 hours (for l-amphetamine).c

Adults: 10 hours (for d-amphetamine) or 13 hours (for l-amphetamine).c

Elimination half-life increases with increasing body weight.c

• Amphetamines are sympathomimetic amines with CNS stimulant activity.a c d

• May block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneural space.a c d

• Pharmacologic actions of amphetamines are qualitatively similar to those of ephedrine and include CNS and respiratory stimulation and sympathomimetic activity including pressor response, mydriasis, bronchodilation, and contraction of the urinary bladder sphincter.d

• On a weight basis, dextroamphetamine has a stronger CNS action and a lesser activity on the peripheral nervous system than does the racemic amphetamine.d The CNS stimulating effect of dextroamphetamine is approximately twice that of amphetamine.d

• Mechanism of action on peripheral structures is thought to be a combination of release of norepinephrine from stores in adrenergic nerve terminals and a direct action on both alpha and beta receptor sites.d

• Mechanism of action involved in the central effect has not been determined.d The main sites of CNS action appear to be the cerebral cortex and possibly the reticular-activating system; stimulation by an amphetamine causes an increase in motor activity, mental alertness, diminished sense of fatigue, brighter spirits, and mild euphoria.d

• Theories of dysfunction in ADHD focus on the prefrontal cortex, which controls many executive functions (e.g., planning, impulse control).e Stimulants have putative effects on central dopamine and norepinephrine pathways that are crucial in frontal lobe function.e

• Produces an anorexigenic effect, leading to loss of weight.d No primary effect on appetite has been demonstrated in humans and it has been postulated that anorexigenic effects are secondary to increased sympathetic activity resulting from release of norepinephrine and dopamine. May also cause a loss of acuity of smell and taste, which may contribute to the anorexigenic effect of the drugs.d

Applies to amphetamine / dextroamphetamine: oral capsule extended release, oral tablet

Along with its needed effects, amphetamine / dextroamphetamine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking amphetamine / dextroamphetamine:

• Bladder pain
• bloody or cloudy urine
• difficult, burning, or painful urination
• fast, pounding, or irregular heartbeat or pulse
• frequent urge to urinate
• lower back or side pain

• Cold or flu-like symptoms
• cough or hoarseness
• fever or chills

• Blistering, peeling, or loosening of the skin
• chest pain or discomfort
• confusion
• dark-colored urine
• diarrhea
• difficulty breathing
• difficulty with speaking
• difficulty with swallowing
• dizziness
• double vision
• faintness
• headache
• inability to move the arms, legs, or facial muscles
• inability to speak
• itching, skin rash
• joint or muscle pain
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of bladder control
• muscle cramps or spasms
• muscle pain or stiffness
• muscle spasm or jerking of all extremities
• nausea
• pain or discomfort in the arms, jaw, back, or neck
• red skin lesions, often with a purple center
• red, irritated eyes
• seeing, hearing, or feeling things that are not there
• seizures
• slow speech
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• sudden loss of consciousness
• sweating
• swelling of the feet or lower legs
• tightness in the chest
• uncontrolled repeated movements (tics)
• uncontrolled vocal outbursts
• unusual tiredness or weakness
• vomiting

Some side effects of amphetamine / dextroamphetamine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Anxiety
• dry mouth
• lack or loss of strength
• stomach pain
• weight loss

• Constipation
• decreased interest in sexual intercourse
• false or unusual sense of well-being
• inability to have or keep an erection
• loss in sexual ability, desire, drive, or performance
• twitching, twisting, uncontrolled repetitive movements of the tongue, lips, face, arms, or legs

IR:
-Initial Dose: 5 mg orally 1 or 2 times a day
-Maintenance Dose: Daily dose may be raised in 5 mg increments at weekly intervals until optimal response is obtained.
-Maximum Dose: Only in rare cases will it be necessary to exceed 40 mg per day.

XR:
Patients starting treatment for the first time or switching from another medication:
-Initial Dose: 20 mg orally once a day

Comments:
-IR: The first dose should be given upon awakening; 1 to 2 additional doses should be given at intervals of 4 to 6 hours.
-Where possible, drug administration should be interrupted occasionally to determine if continued therapy is required.

Use: As part of a total treatment program for Attention Deficit Hyperactivity Disorder (ADHD).

US BOXED WARNING:
-Due to the high abuse potential, this drug should be prescribed/dispensed sparingly and particular attention should be paid to subjects possibly obtaining this drug for non-therapeutic use or distribution to others.
-Administering this drug for prolonged periods of time should be avoided as it may lead to drug dependence.
-Drug misuse may cause sudden death and serious cardiovascular adverse events.

Long-term effects of amphetamines in children have not been well established.
-For ADHD treatment, the IR formulation is not recommended in children younger than 3 years and the XR formulation is not recommended in children younger than 6 years.
-For narcolepsy treatment, the IR formulation is not recommended in children younger than 6 years; the XR formulation is not indicated to treat this condition in children.

Consult WARNINGS section for additional precautions.

US Controlled Substance: Schedule II

Administration Advice:
-Patients taking divided doses (e.g., 2 times a day) of the IR formulation may be switched to the XR formulation at the same total daily dose taken once a day.
-Regardless of indication, this drug should be administered at the lowest effective dose; dosage should be individualized according to patient needs and responses.
-Late evening doses should be avoided because of the potential for insomnia; afternoon doses also should be avoided if taking the XR formulation.
-This drug can be taken with or without food.
-XR capsules may be taken whole or capsule contents may be sprinkled on applesauce; the applesauce mixture should be consumed immediately without chewing.
-The dose of a single XR capsule should not be divided.

Storage Requirements:
-This drug should be stored between 20 to 25 degrees Celsius (68 to 77 Fahrenheit) and dispensed in a tight, light-resistant container.

General:
-Drug tablets contain d-amphetamine and l-amphetamine salts in a 3:1 ratio.
-Individual patient response to amphetamines varies widely: toxic symptoms can occur at doses as low as 2 mg but are rare with doses of less than 15 mg; 30 mg can produce severe reactions yet doses of 400 to 500 mg are not necessarily fatal.
-Overdosage: Management is largely symptomatic and may include gastric lavage, activated charcoal, a cathartic, and sedation; IV phentolamine has been suggested if acute severe hypertension occurs; chlorpromazine can antagonize the central stimulant effects; the prolonged release of mixed amphetamine salts in the XR formulation should be taken into consideration.

Monitoring:
-Cardiovascular: Blood pressure, heart rate, changes in fingers and toes
-General: Signs of abuse/dependence
-Musculoskeletal: Growth suppression
-Psychiatric: Aggressive behavior/hostility; psychotic and manic symptoms

Patient Advice:
-Avoid driving and other potentially dangerous activities such as operating machinery until you know how this drug affects you.
-Avoid drinking alcohol during treatment.
-Contact your healthcare provider if you experience any of the following on your fingers or toes during treatment: unexplained wounds, new numbness, pain, skin color change, or temperature sensitivity.
-If a take-back program or authorized collectors are not available, dispose of this drug by mixing it with an undesirable, nontoxic substance and place it in a sealed plastic bag in the household trash.
-You should not use this drug to combat fatigue or to replace rest.