ADDERALL XR® (mixed salts of a single-entity amphetamine product)

ADDERALL XR® (mixed salts of a single-entity amphetamine product)

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ADDERALL XR®

ADDERALL XR extended-release capsules contain mixed salts of a single-entity amphetamine, a CNS stimulant. ADDERALL XR contains equal amounts (by weight) of four salts: dextroamphetamine sulfate, amphetamine sulfate, dextroamphetamine saccharate and amphetamine (D,L)-aspartate monohydrate. This results in a 3.1:1 mixture of dextro- to levo- amphetamine base equivalent.

The 5 mg, 10 mg, 15 mg, 20 mg, 25 mg and 30 mg strength extended release capsules are for oral administration. Adderall XR contains two types of drug-containing beads (immediate-release and delayed release) which prolong the release of amphetamine compared to the ADDERALL (immediate-release) tablet formulation.

Indications and usage

ADDERALL XR, a CNS stimulant, is indicated for the treatment of attention deficit hyperactivity disorder (ADHD).

  • Children (ages 6-12): Efficacy was established in one 3-week outpatient, controlled trial and one analogue classroom, controlled trial in children with ADHD.
  • Adolescents (ages 13-17): Efficacy was established in one 4-week controlled trial in adolescents with ADHD.
  • Adults: Efficacy was established in one 4-week controlled trial in adults with ADHD

Mechanism of Action

Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in ADHD is not known.

Pharmacodynamics

Amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

Dosage and administration

  • Pediatric patients (ages 6-17): 10 mg once daily in the morning. Maximum dose for children 6-12 years of age is 30 mg once daily.
  • Adults: 20 mg once daily in the morning.
  • Pediatric patients (ages 6-17) with severe renal impairment: 5 mg once daily in the morning. Maximum dose for children 6- 12 years of age with severe renal impairment is 20 mg once daily.
  • Adults with severe renal impairment: 15 mg once daily in the morning.
  • Patients with ESRD: not recommended

Contraindications

  • Advanced arteriosclerosis
  • Symptomatic cardiovascular disease
  • Moderate to severe hypertension
  • Hyperthyroidism
  • Known hypersensitivity or idiosyncrasy to amphetamine
  • Glaucoma
  • Agitated states
  • History of drug abuse
  • During or within 14 days following the administration of monoamine oxidase inhibitors (MAOI)

Warnings and precautions

  • Serious Cardiovascular Reactions: Sudden death has been reported with usual doses of CNS stimulants in children and adolescents with structural cardiac abnormalities or other serious heart problems; sudden death, stroke, and myocardial infarction have been reported in adults taking CNS stimulants at usual doses. Stimulant drugs should not be used in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious heart problems.
  • Increase in Blood Pressure: Monitor blood pressure and pulse at appropriate intervals. Use with caution in patients for whom blood pressure increases may be problematic.
  • Psychiatric Adverse Events: Stimulants may cause treatment-emergent psychotic or manic symptoms in patients with no prior history, or exacerbation of symptoms in patients with pre-existing psychosis. Evaluate for bipolar disorder prior to stimulant use. Monitor for aggressive behavior.
  • Long-Term Suppression of Growth: Monitor height and weight at appropriate intervals.
  • Seizures: May lower the convulsive threshold. Discontinue in the presence of seizures.
  • Peripheral Vasculopathy, including Raynaud’s phenomenon: Stimulants used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Careful observation for digital changes is necessary during treatment with ADHD stimulants.
  • Serotonin Syndrome: Increased risk when co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue ADDERALL XR and initiate supportive treatment
  • Visual Disturbance: Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
  • Tics: May exacerbate tics. Evaluate for tics and Tourette’s syndrome prior to stimulant administration.

Adverse reactions

  • Children (ages 6 to 12): Most common adverse reactions (≥5% and with a higher incidence than on placebo) were loss of appetite, insomnia, abdominal pain, emotional lability, vomiting, nervousness, nausea, and fever.
  • Adolescents (ages 13 to 17): Most common adverse reactions (≥5% and with a higher incidence than on placebo) were loss of appetite, insomnia, abdominal pain, weight loss, and nervousness.
  • Adults: Most common adverse reactions ≥5% and with a higher incidence than on placebo were dry mouth, loss of appetite, insomnia, headache, weight loss, nausea, anxiety, agitation, dizziness, tachycardia, diarrhea, asthenia, and urinary tract infections

Drug interactions

Monoamine Oxidase Inhibitors (MAOIs): 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.

Examples: selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue.

Serotonergic Drugs: The concomitant use of ADDERALL XR and serotonergic drugs increases the risk of serotonin syndrome. Examples; selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort.

CYP2D6 Inhibitors : The concomitant use of ADDERALL XR and CYP2D6 inhibitors may increase the exposure of ADDERALL XR compared to the use of the drug alone and increase the risk of serotonin syndrome. Examples; paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir

Alkalinizing Agents: Increase blood levels and potentiate the action of amphetamine. Examples; Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid). Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts).

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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. Examples; desipramine, protriptyline

Proton Pump Inhibitors: Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone. Examples; Omeprazole

Use in specific populations

Pregnancy: Available data from published epidemiologic studies and postmarketing reports on use of prescription amphetamine in pregnant women have not identified a drug-associated risk of major birth defects and miscarriage. Adverse pregnancy outcomes, including premature delivery and low birth weight, have been seen in infants born to mothers taking amphetamines during pregnancy.

Amphetamines, such as ADDERALL XR, cause vasoconstriction and thereby may decrease placental perfusion. In addition, amphetamines can stimulate uterine contractions, increasing the risk of premature delivery. Infants born to mothers taking amphetamines during pregnancy have an increased risk of premature delivery and low birth weight.

Monitor infants born to mothers taking amphetamines for symptoms of withdrawal such as feeding difficulties, irritability, agitation, and excessive drowsiness.

Lactation: Based on limited case reports in published literature, amphetamine (d- or d, l-) is present in human milk, at relative infant doses of 2% to 13.8% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.9 and 7.5. There are no reports of adverse effects on the breastfed infant. Long-term neurodevelopmental effects on infants from amphetamine exposure are unknown. It is possible that large dosages of amphetamine might interfere with milk production, especially in women whose lactation is not well established. Because of the potential for serious adverse reactions in nursing infants, advise patients that breastfeeding is not recommended during treatment with ADDERALL XR.

Pediatric Use: ADDERALL XR is indicated for use in children 6 years of age and older. The safety and efficacy of ADDERALL XR in children under 6 years of age have not been studied. Long-term effects of amphetamines in children have not been well established.

Growth should be monitored during treatment with stimulants, including ADDERALL XR, and pediatric patients aged 6 to 17 years who are not growing or gaining weight as expected may need to have their treatment interrupted

Drug abuse and dependence

Controlled Substance: ADDERALL XR contains amphetamine, a Schedule II controlled substance.

Abuse: ADDERALL XR is a CNS stimulant that contains amphetamine, which has a high potential for abuse. Abuse is characterized by impaired control of drug use, compulsive use despite harm, and craving.

Signs and symptoms of amphetamine abuse may include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, suicidal or homicidal ideation have also been observed. Abusers of amphetamines may use other unapproved routes of administration which can result in overdose and death

To reduce the abuse of CNS stimulants, including ADDERALL XR, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and proper storage and disposal of CNS stimulants. Monitor for signs of abuse while on therapy and re-evaluate the need for ADDERALL XR use.

Dependence

Tolerance (a state of adaptation in which exposure to a specific dose of a drug results in a reduction of the drug’s desired and/or undesired effects over time, in such a way that a higher dose of the drug is required to produce the same effect that was once obtained at a lower dose) may occur during chronic therapy of CNS stimulants including ADDERALL XR.

Physical Dependence (which is manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants including ADDERALL XR. Withdrawal symptoms after abrupt cessation of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Overdosage

Manifestations of amphetamine overdose include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Serotonin syndrome has been reported with amphetamine use, including ADDERALL XR. Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma.

Storage

Store at room temperature, 20º C to 25º C (68º F to 77º F). Excursions permitted to 15-30º C (59-86ºF) [see USP CONTROLLED ROOM TEMPERATURE].

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