Evekeo Odt (amphetamine sulfate)

Amphetamine is a non-catecholamine, sympathomimetic amine with CNS-stimulating activity.

Amphetamine is a non-catecholamine, sympathomimetic amine with CNS-stimulating activity. The pharmacologic action of amphetamines 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 amphetamine include elevation of systolic and diastolic blood pressure, weak bronchodilation, and respiratory stimulation.

The l-amphetamine isomer exerts greater cardiovascular activity and less CNS excitatory effects compared to the d-amphetamine isomer. Racemic amphetamine is less effective as an appetite suppressant compared to dextroamphetamine.

Amphetamines are commonly known as ''anorectics'' or ''anorexigenics'' in the treatment of obesity, although it is not known if their weight loss effects are primarily due to appetite suppression or other CNS or metabolic effects that may occur. The magnitude of weight loss with amphetamine therapy is a fraction of a pound each week, with the greatest weight loss usually occurring in the first weeks of treatment and declining thereafter.

Commercially available amphetamine products include conventional tablets formulated for immediate release of the drug as well as extended-release capsules, tablets, oral suspension, and orally disintegrating tablets, which exert a longer duration of activity. Immediate-release formulations include amphetamine sulfate conventional tablets (Evekeo(R)) and conventional tablets containing mixed amphetamine salts (amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate; e.g., Adderall(R)). 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 immediate-release and 2 types of delayed-release beads), which allow for approximately one-third of the total drug 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 XR(R)) delivers the drug in equal amounts as an immediate release dose and as a sustained-release second dose. Extended-release amphetamine orally disintegrating tablets (Adzenys XR-ODT(R)) deliver half of the total amphetamine dose immediately, and the remainder as a sustained-release second dose.

Extended-release tablets and oral suspension (Dyanavel(R) XR) contain amphetamine (complexed with sodium polystyrene sulfonate), amphetamine aspartate, and dextroamphetamine sulfate.

While children eliminate amphetamine faster than adults, for a given dose of amphetamine, children have greater exposure to amphetamine based on an increased weight-based dosage compared to adults. After adjustment for differences in body weight, amphetamine exposure is 30% less in children than adults.

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. The effect of food on the pharmacokinetics of mixed amphetamine salts (Adderall(R)) has not been evaluated.

Effects persist for 4-6 hours after oral administration of immediate-release preparations of amphetamine; twice daily administration of Evekeo(R) has a duration of activity of 10 hours.

Following oral administration of extended-release capsules containing mixed amphetamine salts (Adderall XR(R)), 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 by 2.5 hours for d-amphetamine from 5.2 hours to 7.7 hours, and 2.7 hours 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 dose of extended-release capsules containing mixed amphetamine salts (Adderall XR(R)) 20 mg 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 occur 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 comparable plasma exposure to d- and l-amphetamine as 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 containing 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. In vitro studies evaluating the effect of alcohol on the release of amphetamine indicated that there is increased release of Mydayis(R) in the presence of 20% alcohol concentration, and more noticeably, at a 40% alcohol concentration. The duration of action of Mydayis(R) is estimated to be up to 16 hours.

Following administration of extended-release oral 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 was 3.9 hours for d-amphetamine and 4.5 hours for l-amphetamine. The relative bioavailability of extended-release suspension compared with an equal dosage of Adderall(R) is 106% for d-amphetamine and 111% for l-amphetamine, 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 l-amphetamine by 7.3%. The duration of action of the 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 oral administration of extended-release orally disintegrating tablets (Adzenys XR-ODT(R)) in adults under fasting conditions, peak plasma concentrations occurred after 5 hours. When administered following a high-fat meal, the time to peak plasma concentrations was 7 hours. Although food prolongs the time to peak plasma concentrations, these changes are not considered clinically significant.

A single 18.8-mg dose of extended-release orally disintegrating tablets provides comparable plasma concentrations of d- and l-amphetamine to a 30-mg dose of extended-release amphetamine mixed salts. In vitro studies evaluating the effect of alcohol on extended-release orally disintegrating tablets showed substantial release of amphetamine in the presence of 40% alcohol concentration, but not with 5%, 10%, or 20% concentrations.

Although some of the enzymes involved in amphetamine metabolism have not been fully elucidated, cytochrome P-450 (CYP) isoenzyme 2D6 is known to be involved in the oxidation of 4-hydroxy-amphetamine. 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-hydroxy-amphetamine, alpha-hydroxy-amphetamine, and norephedrine.

Norephedrine and 4-hydroxy-amphetamine 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.

Following oral administration of immediate-release mixed amphetamine salts (Adderall(R)), the mean elimination half-life of d-amphetamine ranges from 9.77-11 hours, and the mean elimination half-life of l-amphetamine ranges from 11.5-13.8 hours.

Following oral administration of extended-release mixed amphetamine salts (Mydayis(R)) in pediatric and adult patients, the mean elimination half-life of d-amphetamine ranges from 10-11 hours and l-amphetamine from 10-13 hours.

The mean elimination half-life of Adderall XR(R) is shorter for children than adults based on a mg/kg dosing weight. 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 oral suspension (Dyanavel(R) XR), the mean elimination half-life of d-amphetamine is 12.4 hours and l-amphetamine, 15.1 hours. Following oral administration of extended-release tablets (Dyanavel(R) XR), the mean elimination half-life of d-amphetamine is 13.5 hours and l-amphetamine, 17.3 hours. In pediatric patients 6-12 years of age, the mean elimination half-life of the extended-release oral suspension is 10.4 hours for d-amphetamine and 12.1 hours for l-amphetamine.

Following oral administration of extended-release orally disintegrating tablets (Adzenys XR-ODT(R)) in adults, the mean elimination half-life of d-amphetamine and l-amphetamine is 11 hours and 14 hours, respectively. In pediatric patients 6-12 years of age, the mean elimination half-life of d-amphetamine is 9-10 hours, and the mean elimination half-life of l-amphetamine is 10-11 hours.

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.

Amphetamine is commercially available as amphetamine, amphetamine 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: amphetamine sulfate

The following indications are listed for Evekeo Odt:

• Attention-Deficit Hyperactivity Disorder

Also known as: Add With Hyperactivity.

No ICD codes are available for this drug.