Dextroamphetamine Sulfate Er (dextroamphetamine sulfate)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Dextroamphetamine is the dextrorotatory isomer of amphetamine, a non-catecholamine, sympathomimetic amine with CNS-stimulating activity.
Dextroamphetamine sulfate is the dextrorotatory isomer of d,l-amphetamine sulfate, a non-catecholamine, sympathomimetic amine with CNS-stimulating activity. The pharmacologic action of amphetamines involved in the treatment of ADHD has not been fully elucidated; however, its actions are thought to be related to the blockade of norepinephrine and dopamine reuptake into presynaptic neurons and the increased release of norepinephrine and dopamine into the extraneuronal space. Other than CNS stimulant activity, peripheral actions of amphetamines include elevation of systolic and diastolic blood pressure, weak bronchodilation, and weak respiratory stimulation.
Commercially available dextroamphetamine products include single-entity products and fixed combination products that contain mixed amphetamine salts. Conventional (short-acting) formulations include dextroamphetamine sulfate tablets (Zenzedi(R)), dextroamphetamine sulfate oral solution (Procentra(R)), and conventional tablets containing mixed amphetamine salts (amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate; e.g., Adderall(R)). Sustained-release dextroamphetamine sulfate capsules (Dexedrine(R) Spansules(R)) are considered an intermediate-acting formulation.
A long-acting transdermal system formulation of dextroamphetamine (Xelstrym(R)) is also available. Two formulations of extended-release capsules containing mixed amphetamine salts are commercially available. One formulation of extended-release capsules containing mixed amphetamine salts (Mydayis(R)) contains 3 types of drug-releasing beads (1 type of immediate-release and 2 types of delayed-release beads), which allow for approximately one-third of the total to be delivered immediately, and the remaining two-thirds to be dissolved at pHs of 5.5 and 7.
The other formulation of extended-release capsules containing mixed amphetamine salts (Adderall(R) XR) delivers the medicine in equal amounts as an immediate release dose and as a sustained-release second dose. Extended-release tablets and oral suspension (Dyanavel(R) XR) containing amphetamine (complexed with sodium polystyrene sulfonate), amphetamine aspartate, and dextroamphetamine sulfate are also available.
Following oral administration of conventional dextroamphetamine sulfate tablets, peak plasma concentrations were attained after approximately 3 hours. Following oral administration of conventional tablets containing mixed amphetamine salts (Adderall(R)), peak plasma concentrations of d-amphetamine and l-amphetamine were attained at 3 hours. The pharmacokinetics of d-amphetamine and l-amphetamine are dose-proportional over the oral dosing range of 10-30 mg.
Effects persist for 4-6 hours after oral administration of conventional preparations of dextroamphetamine sulfate and mixed amphetamine salts (Adderall(R)). The effect of food on the pharmacokinetics of mixed amphetamine salts (Adderall(R)) has not been evaluated.
Following oral administration of sustained-release capsules containing dextroamphetamine sulfate (Dexedrine(R) Spansules(R)), peak plasma concentrations of dextroamphetamine occur after 8 hours.
Following oral administration of extended-release capsules containing mixed amphetamine salts (Adderall(R) XR), peak plasma concentrations are attained at 7 hours. The pharmacokinetics of Adderall XR(R) are dose proportional over the oral dosing range of 20-60 mg in adults and adolescents that weigh >75 kg, over 10-40 mg in adolescents that weigh <=75 kg, and over 5-30 mg in children 6-12 years of age. There is no expected accumulation of Adderall XR(R) at steady state when used in children.
Food does not affect the absorption of d- or l-amphetamine from Adderall XR(R), but administration with a high-fat meal prolongs the time to peak plasma concentrations for d-amphetamine from 5.2 hours to 7.7 hours, and for l-amphetamine from 5.6 hours to 8.3 hours. There is comparable absorption to the intact capsule in the fasting state when the contents are opened and sprinkled onto applesauce. A single 20 mg dose of extended-release capsules containing mixed amphetamine salts (Adderall XR(R)) provides comparable plasma concentrations of d-amphetamine and l-amphetamine to immediate-release mixed amphetamine salts (Adderall(R)) 10 mg twice daily administered 4 hours apart.
The duration of action of Adderall XR(R) is approximately 10-12 hours.
Following oral administration of extended-release capsules containing mixed amphetamine salts (Mydayis(R)) in adults and pediatric patients, peak plasma concentrations occurred at 8 hours for d- and l-amphetamine in adults, and at 7-10 hours in pediatric patients. The pharmacokinetics of Mydayis(R) are linear and dose proportional over the oral dosing range of 12.5-50 mg; steady state is achieved after 7-8 days of standard dosing. Mydayis(R) has a mean accumulation ratio of 1.6.
A single 37.5 mg dose of Mydayis(R) provides plasma exposure to d- and l-amphetamine comparable to that with a 25 mg dose of Adderall XR(R) followed by a 12.5 mg dose of immediate-release amphetamine 8 hours later. Following oral administration of extended-release capsules of mixed amphetamine salts (Mydayis(R)) in the fasting state, peak plasma concentrations of d-amphetamine are attained at 7 hours, and l-amphetamine at 7.5 hours. When administered with a high-fat meal, absorption is not affected, but peak plasma concentrations of d- and l-amphetamine are delayed to 12 hours.
There is comparable absorption to the intact capsule in the fasting state when the contents are opened and sprinkled onto applesauce. The duration of action of Mydayis(R) is estimated to be up to 16 hours. In vitro studies evaluating the effect of alcohol on the release of amphetamine indicate increased release of Mydayis(R) in the presence of 20% alcohol concentration, and more noticeably, at a 40% alcohol concentration.
Following oral administration of extended-release suspension (Dyanavel(R) XR) in adults, the median time to peak plasma concentrations was 4 hours for d-amphetamine and l-amphetamine. After oral administration of extended-release tablets (Dyanavel(R) XR) in adults, the median time to peak plasma concentrations was 5 hours for d-amphetamine and l-amphetamine. Under fasting conditions, chewing or swallowing the extended-release tablets does not significantly impact amphetamine exposure or time to peak plasma concentrations.
In pediatric patients 6-12 years of age under fasting conditions, the median time to peak plasma concentrations following oral administration of extended-release suspension (Dyanavel(R) XR) was 3.9 hours for d-amphetamine and 4.5 hours for l-amphetamine. The relative bioavailability of extended-release suspension (Dyanavel(R) XR) is 106% for d-amphetamine and 111% for l-amphetamine compared with an equal dosage of Adderall(R), and is 94% for both d- and l-amphetamine compared to Adderall XR(R). The relative bioavailability of an equivalent dosage of extended-release tablets compared to extended-release suspension is 105% for d-amphetamine and 106% for l-amphetamine.
Administration of the extended-release suspension with a high fat meal delays the time to peak plasma concentrations by 1 hour, increases maximum plasma concentrations by 2%, and decreases exposure to d- amphetamine by 5.7% and l-amphetamine by 7.4%. Following oral administration of the extended-release tablets with a high fat meal, maximum plasma concentrations are decreased by 3%; total exposure to d-amphetamine is decreased by 4%, and total exposure to l-amphetamine is decreased by 7.3%. The duration of action of Dyanavel(R) XR extended-release suspension and tablets is approximately 13 hours.
In vitro studies evaluating the effect of alcohol on the extended-release oral suspension showed that in the presence of 40% alcohol concentration, there was dose dumping potential. When extended-release oral tablets were evaluated, there was no alcohol-induced dumping in the presence of 40% alcohol. Dose dumping was also not observed in the presence of 5%, 10%, or 20% alcohol for the extended-release suspension or tablets.
Following a single application of the dextroamphetamine transdermal system (Xelstrym(R)), peak plasma concentrations occurred in 6-9 hours; peak plasma concentrations occurred in 6 hours following repeated application. Application of a heating pad shortens the median time to peak plasma concentrations by 2 hours and increases peak plasma concentrations and total exposure over 9 hours by 16% and 50%, respectively. Application of the transdermal system to various recommended sites (e.g., hip, upper arm, chest, upper back, or flank) does not alter dextroamphetamine pharmacokinetics.
Although some of the enzymes involved in metabolism have not been fully elucidated, cytochrome P-450 (CYP) isoenzyme 2D6 is known to be involved in the oxidation of 4-hydroxyamphetamine. Because CYP2D6 is polymorphic, there is a potential for variability in metabolism amongst patients. Amphetamine reportedly undergoes oxidation to form several metabolites, which include 4-hydroxyamphetamine, alpha-hydroxy-amphetamine, and norephedrine.
Norephedrine and 4-hydroxyamphetamine are active metabolites of amphetamine, which undergo subsequent oxidation to form 4-hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, and ultimately, benzoic acid and its glucuronide and glycine conjugate hippuric acid.
The elimination half-life of dextroamphetamine sulfate oral solution (ProCentra(R)) is 11.75 hours. The elimination half-life of conventional dextroamphetamine sulfate tablets (Zenzedi(R)) and sustained-release dextroamphetamine sulfate capsules (Dexedrine(R) Spansule(R)) is approximately 12 hours.
Following removal of the dextroamphetamine transdermal system (Xelstrym(R)) after 9 hours, the mean elimination half-life was approximately 6.4 hours in pediatric patients and 11.5 hours in adults.
Following oral administration of conventional mixed amphetamine salts (Adderall(R)), the mean elimination half-life ranges from 9.77-11 hours for d-amphetamine and from 11.5-13.8 hours for l-amphetamine.
Following oral administration of extended-release dextroamphetamine sulfate in fixed combination with other amphetamines (Mydayis(R)) in pediatric and adult patients, the mean elimination half-life of d-amphetamine ranges from 10-11 hours, and the mean elimination half-life of l-amphetamine ranges from 10-13 hours.
The mean elimination half-life of extended-release mixed amphetamine salts (Adderall(R) XR) is shorter for children than for adults. When adjusted for weight, amphetamine exposure is 30% less in children. The elimination half-life of d-amphetamine is 9 hours in children 6-12 years of age, 11 hours in adolescents 13-17 years of age, and 10 hours in adults.
For the l-amphetamine isomer, the elimination half-life is 11 hours in children 6-12 years of age, 13-14 hours in adolescents, and 13 hours in adults.
Following oral administration of extended-release amphetamine oral suspension (Dyanavel(R) XR), the mean elimination half-life was 12.4 hours for d-amphetamine and 15.1 hours for l-amphetamine. Following oral administration of extended-release amphetamine tablets (Dyanavel(R) XR), the mean elimination half-life was 13.5 hours for d-amphetamine and 17.3 hours for l-amphetamine. In pediatric patients 6-12 years of age, the mean elimination half-life of the extended-release oral suspension was 10.4 hours for d-amphetamine and 12.1 hours for l-amphetamine.
Amphetamine has a pKa of 9.9; therefore, urinary recovery of amphetamine is highly dependent on urine pH and flow rates. At normal urinary pHs, approximately 50% of an amphetamine dose is recovered in urine as derivatives of alpha-hydroxy-amphetamine, and another 30-40% in urine as unchanged amphetamine. Acidic urinary pH and high flow rates result in increased renal elimination that exceeds the clearance of glomerular filtration rates, while alkaline urinary pHs result in reduced ionization and renal elimination.
The urinary recovery of amphetamine ranges from 1-75%, which depends on urinary pH; the remainder of the dose undergoes hepatic metabolism. Both renal and hepatic impairment can inhibit the elimination of amphetamine and prolong exposure.
Dextroamphetamine is commercially available as dextroamphetamine, dextroamphetamine sulfate, and in mixed salt preparations containing either amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate or amphetamine, amphetamine aspartate, and dextroamphetamine sulfate.
Generic name: dextroamphetamine sulfate
Pronunciation: (DEX-troe-am-FET-a-meen)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Dextroamphetamine Sulfate Er
Indications
The following indications are listed for Dextroamphetamine Sulfate Er:
- Attention-Deficit Hyperactivity Disorder
- Narcolepsy Syndrome
Also known as: Add With Hyperactivity, Friedmann's Disease, Gelineau's Syndrome, Hypnolepsy, Narcolepsy, Paroxysmal Sleep.
Dosing
Dosage of dextroamphetamine sulfate for the treatment of attention deficit hyperactivity disorder (ADHD) should be individualized based on patient response and tolerance. The smallest dose required to produce the desired response should always be used.
The manufacturer states that the total daily dosage of immediate-release mixed amphetamine salts (Adderall(R)) is bioequivalent to the same total daily dosage of mixed amphetamine salts extended-release capsules (Adderall XR(R)) administered once daily.
Manufacturers state that Mydayis(R) should not be substituted with other amphetamine products on a milligram-per-milligram basis due to different amphetamine base compositions and pharmacokinetic profiles.
Substitution of Dyanavel(R) XR extended-release oral suspension for Dyanavel(R) XR extended-release oral tablets may occur on a milligram-per-milligram basis; however, other amphetamine products should not be substituted on a milligram-per-milligram basis due to different amphetamine base compositions and pharmacokinetic profiles.
Dosages of Dyanavel(R) XR are expressed as the amount of amphetamine base, and dosages of Xelstrym(R) are expressed as the amount of dextroamphetamine delivered over 9 hours; the dosages of other dextroamphetamine products are expressed in terms of the total amount of the salt(s).
Preparations containing dextroamphetamine sulfate are administered orally or transdermally.
The following dextroamphetamine formulations are commercially available in the US: immediate-release dextroamphetamine sulfate conventional tablets (e.g., Zenzedi(R)); immediate-release dextroamphetamine sulfate oral solution (e.g, ProCentra(R)); dextroamphetamine sulfate sustained-release capsules (e.g., Dexedrine(R) Spansule(R)); dextroamphetamine transdermal system (e.g., Xelstrym(R)); immediate-release conventional tablets containing mixed amphetamine salts (amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate; e.g., Adderall(R)); triphasic extended-release capsules containing mixed amphetamine salts (amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate; e.g., Mydayis(R)); biphasic extended-release capsules containing mixed amphetamine salts (amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate; e.g., Adderall XR(R)); extended-release tablets containing amphetamine, amphetamine aspartate, and dextroamphetamine sulfate (e.g., Dyanavel(R) XR); and extended-release oral suspension containing amphetamine, amphetamine aspartate, and dextroamphetamine sulfate (e.g., Dyanavel(R) XR).
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Amphetamines and amphetamine derivatives are metabolized to some extent by cytochrome P-450 (CYP) isoenzyme 2D6, and to a minor extent, inhibit CYP2D6 metabolism. In vitro, metabolites of amphetamine have also been shown to minimally inhibit CYP1A2 and CYP3A4. The effects of amphetamine or its metabolites in vivo on drug metabolism by CYP enzymes are not known. Amphetamine also inhibits monoamine oxidase (MAO).
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*Hypersensitivity to dextroamphetamine or other components of the formulation.
*Concomitant use of monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing an MAOI (including linezolid and IV methylene blue), because of the increased risk of hypertensive crisis.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in patients receiving conventional and sustained-release dextroamphetamine preparations include palpitations, tachycardia, blood pressure elevations, sudden death, myocardial infarction, reports of cardiomyopathy with chronic use, psychotic episodes (rare), overstimulation, restlessness, dizziness, insomnia, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, headache, motor and verbal tics, exacerbation of Tourette's syndrome, aggression, anger, logorrhea, dermatillomania, blurred vision, mydriasis, mouth dryness, unpleasant taste, diarrhea, constipation, intestinal ischemia, other gastrointestinal disturbances, anorexia, weight loss, urticaria, rash, angioedema, anaphylaxis, serious skin rashes (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis), impotence, libido changes, frequent or prolonged erections, alopecia, and rhabdomyolysis.
Common adverse effects reported in >=5% of patients and at least twice the rate of placebo in pediatric patients >=13 years of age receiving extended-release capsules containing mixed amphetamine salts (Mydayis(R)) include decreased appetite, insomnia, nausea, irritability, and weight loss; in studies in adults, the most common adverse effects were insomnia, decreased appetite, dry mouth, weight loss, tachycardia, and anxiety.
Common adverse effects reported in >=5% of patients and with an incidence higher than placebo in pediatric patients 6-12 years of age receiving extended-release amphetamine capsules containing mixed amphetamine salts (Adderall XR(R)) include loss of appetite, insomnia, abdominal pain, emotional lability, vomiting, nervousness, nausea, and fever. In pediatric patients 13-17 years of age, the most common adverse effects were loss of appetite, insomnia, abdominal pain, weight loss, and nervousness. In adults, the most common adverse effects were dry mouth, loss of appetite, insomnia, headache, weight loss, nausea, anxiety, agitation, dizziness, tachycardia, diarrhea, asthenia, and urinary tract infections.
The most common adverse effects reported in patients receiving amphetamine extended-release oral suspension or extended-release oral tablets (Dyanavel(R) XR) include dry mouth, anorexia, weight loss, abdominal pain, nausea, insomnia, restlessness, emotional lability, dizziness, and tachycardia.
The most common adverse reactions reported in >=2% of pediatric patients 6 to 17 years of age treated with dextroamphetamine transdermal system were decreased appetite, headache, insomnia, tic, abdominal pain, vomiting, nausea, irritability, increased blood pressure, and increased heart rate. The most common adverse reactions reported in >=5% of adults treated with lisdexamfetamine (Vyvanse(R)) in clinical studies (which were used to support efficacy of dextroamphetamine transdermal system) were decreased appetite, insomnia, dry mouth, diarrhea, nausea, and anxiety.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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Safety and efficacy of immediate-release dextroamphetamine tablets (Zenzedi(R)), immediate-release dextroamphetamine oral solution (ProCentra(R)), and immediate-release mixed amphetamine salts (Adderall(R)) have been established for ADHD in pediatric patients >=3 years of age. Safety and efficacy of these preparations have not been established in pediatric patients <3 years of age.
Safety and efficacy of dextroamphetamine sustained-release capsules (Dexedrine(R) Spansule(R)) have been established for ADHD in pediatric patients >=6 years of age. Use of the dextroamphetamine sustained-release capsule formulation is not recommended in children <6 years of age.
Safety and efficacy of amphetamine extended-release oral tablets and suspension (Dyanavel(R) XR) and the dextroamphetamine transdermal system (Xelstrym(R)) are established for ADHD in pediatric patients 6-17 years of age. Safety and efficacy of these preparations have not been established in children<6 years of age.
Safety and efficacy of extended-release capsules containing mixed amphetamine salts (Mydayis(R)) have been established for ADHD in pediatric patients 13-17 years of age. Safety and efficacy of extended-release capsules containing mixed amphetamine salts have not been established for ADHD in pediatric patients <=12 years of age. Although extended-release capsules containing mixed amphetamine salts have been studied in patients 6-12 years of age in 2 clinical studies, a safe and effective dosage has not been established in patients <=12 years of age.
Safety and efficacy of extended-release capsules containing mixed amphetamine salts (Adderall XR(R)) have been established for ADHD in pediatric patients >=6 years of age. Safety and efficacy of extended-release capsules containing mixed amphetamine salts have not been established for ADHD in pediatric patients <6 years of age.
Long-term effects of amphetamines are not well established in the pediatric patient population.
The National Pregnancy Registry for ADHD Medications monitors pregnancy outcomes in females exposed to ADHD medication during pregnancy. Clinicians are encouraged to register females who become pregnant while receiving amphetamines by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/research/pregnancyregistry/.
Available data from published studies and postmarketing reports have not identified a drug-associated risk of major birth defects and miscarriage in females exposed to amphetamine during pregnancy. Adverse pregnancy outcomes, including premature delivery and low birth weight, have been observed in infants of mothers taking amphetamines.
In embryofetal development studies in rats and rabbits, no effects on morphologic development were observed following oral administration of amphetamine during organogenesis. In a pre- and postnatal development study in rats, oral administration of amphetamine throughout pregnancy and lactation was associated with decreased pup weight, which correlated with delayed development, and with decreased pup survival. Adverse effects on pup reproductive performance were also observed. Animal developmental studies have also reported long-term neurochemical and behavioral effects.
Amphetamines can cause vasoconstriction and may decrease placental perfusion. Additionally, amphetamines can stimulate uterine contractions, increasing the risk of preterm delivery. Infants born to mothers receiving amphetamines during pregnancy are an increased risk of preterm delivery and low birth weight.
Infants born to mothers receiving amphetamines during pregnancy should be monitored for symptoms of withdrawal such as feeding difficulties, irritability, agitation, and excessive drowsiness.
Based on limited reports, amphetamine is present in human milk at a relative infant dose of 2-13.8% of the maternal weight-adjusted dosage and has a milk/plasma ratio between 1.9 and 7.5. There have been no reports of adverse effects from amphetamine exposure on the breast-fed infant. Long-term neurodevelopmental effects from amphetamine exposure through the breast milk are not known. There is the potential that large doses of amphetamine could interfere with milk production, particularly in mothers whose lactation has not been established. Because of the potential for serious adverse effects in breast-fed infants, breastfeeding is not recommended during amphetamine therapy.
Dextroamphetamine has not been studied in the geriatric patient population. Generally, dosage selection for geriatric patients should start at the lower end of the dosage range, reflecting the greater frequency of reduced hepatic, renal, or cardiac function and of concomitant diseases and medication therapy in geriatric patients.
Clinical studies of amphetamine did not include a sufficient number of patients >=65 years of age to assess differences in response compared to younger adults. Other reported clinical experience has not identified differences in response between geriatric patients and younger adults.
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Last reviewed · Source: First Databank (FDB) drug data
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