Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, and Amphetamine Sulfate (Page 8 of 10)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No evidence of carcinogenicity was found in studies in which d,l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats. These doses are approximately 2.4, 1.5, and 0.8 times, respectively, the maximum recommended human dose of 30 mg/day given to children, on a mg/m 2 basis.

Mutagenesis

Amphetamine, in the enantiomer ratio d- to l- ratio of 3:1, was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli component of the Ames test in vitro. d,l-Amphetamine (1:1 enantiomer ratio) has been reported to produce a positive response in the mouse bone marrow micronucleus test, an equivocal response in the Ames test, and negative responses in the in vitro sister chromatid exchange and chromosomal aberration assays.

Impairment of Fertility

Amphetamine, in the enantiomer ratio d- to l- ratio of 3:1, did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day (approximately 8 times the maximum recommended human dose of 20 mg/day given to adolescents, on a mg/m 2 basis).

13.2 Animal Toxicology and/or Pharmacology

Acute administration of high doses of amphetamine (d- or d,l-) has been shown to produce long-lasting neurotoxic effects, including irreversible nerve fiber damage, in rodents. The significance of these findings to humans is unknown.

14 CLINICAL STUDIES

Pediatric Patients
A double-blind, randomized, placebo-controlled, parallel-group study was conducted in children aged 6-12 (N=584) who met DSM-IV ® criteria for ADHD (either the combined type or the hyperactive- impulsive type). Patients were randomized to fixed-dose treatment groups receiving final doses of 10, 20, or 30 mg of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules or placebo once daily in the morning for three weeks. Significant improvements in patient behavior, based upon teacher ratings of attention and hyperactivity, were observed for all dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules doses compared to patients who received placebo, for all three weeks, including the first week of treatment, when all dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules subjects were receiving a dose of 10 mg/day. Patients who received dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules showed behavioral improvements in both morning and afternoon assessments compared to patients on placebo.
In a classroom analogue study, patients (N=51) receiving fixed doses of 10 mg, 20 mg or 30 mg dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules demonstrated statistically significant improvements in teacher-rated behavior and performance measures, compared to patients treated with placebo.

A double-blind, randomized, multi-center, parallel-group, placebo-controlled study was conducted in adolescents aged 13-17 (N=327) who met DSM-IV ® criteria for ADHD. The primary cohort of patients (n=287, weighing ≤ 75kg/165lbs) was randomized to fixed-dose treatment groups and received four weeks of treatment. Patients were randomized to receive final doses of 10 mg, 20 mg, 30 mg, and 40 mg dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules or placebo once daily in the morning. Patients randomized to doses greater than 10 mg were titrated to their final doses by 10 mg each week. The secondary cohort consisted of 40 subjects weighing >75kg/165lbs who were randomized to fixed-dose treatment groups receiving final doses of 50 mg and 60 mg dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules or placebo once daily in the morning for 4 weeks. The primary efficacy variable was the Attention Deficit Hyperactivity Disorder-Rating Scale IV (ADHD-RS-IV) total score for the primary cohort. The ADHD-RS-IV is an 18-item scale that measures the core symptoms of ADHD. Improvements in the primary cohort were statistically significantly greater in all four primary cohort active treatment groups (dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules 10 mg, 20 mg, 30 mg, and 40 mg) compared with the placebo group. There was not adequate evidence that doses greater than 20 mg/day conferred additional benefit.

Adult Patients
A double-blind, randomized, placebo-controlled, parallel-group study was conducted in adults (N=255) who met DSM-IV ® criteria for ADHD. Patients were randomized to fixed-dose treatment groups receiving final doses of 20, 40, or 60 mg of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules or placebo once daily in the morning for four weeks. Significant improvements, measured with the Attention Deficit Hyperactivity Disorder-Rating Scale (ADHD-RS), an 18-item scale that measures the core symptoms of ADHD, were observed at endpoint for all dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules doses compared to patients who received placebo for all four weeks. There was not adequate evidence that doses greater than 20 mg/day conferred additional benefit.

16 HOW SUPPLIED/STORAGE AND HANDLING

Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules 5 mg: capsule with white opaque body and lime green cap (imprinted 5 mg on body and ELI-510 on cap with black ink). Capsules filled with orange pellets, bottles of 100, NDC 51407-548-01


Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules 10 mg: capsules with blue body and blue cap (imprinted 10 mg on body and ELI-511 on cap with black ink). Capsules filled with orange pellets, bottles of 100, NDC 51407-549-01


Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules 15 mg: capsule with white opaque body and green cap (imprinted 15 mg on body and ELI-512 on cap with black ink). Capsules filled with orange pellets, bottles of 100, NDC 51407-550-01


Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules 20 mg: capsule with white opaque body and light pink cap (imprinted 20 mg on body and ELI-513 on cap with black ink). Capsules filled with orange pellets, bottles of 100, NDC 51407-551-01


Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules 25 mg: capsules with pink body and pink cap (imprinted 25 mg on body and ELI-514 on cap with black ink). Capsules filled with orange pellets, bottles of 100, NDC 51407-552-01


Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules 30 mg: capsules with white opaque body and dark pink cap (imprinted 30 mg on body and ELI-515 on cap with black ink). Capsules filled with orange pellets, bottles of 100, NDC 51407-553-01

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure, as required.

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

Disposal

Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules at authorized collection sites such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules with an undesirable, nontoxic substance to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and discard dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules in the household trash.

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