Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate, and Amphetamine Sulfate (Page 3 of 9)

5.8 Visual Disturbance

Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.

5.9 Tics

Amphetamines have been reported to exacerbate motor and phonic tics and Tourette’s syndrome. Therefore, clinical evaluation for tics and Tourette’s syndrome in patients and their families should precede use of stimulant medications.

5.10 Prescribing and Dispensing

The least amount of amphetamine feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage. MAS-ER Capsules should be used with caution in patients who use other sympathomimetic drugs.

6 ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.1 Clinical Trials Experience

The premarketing development program for MAS-ER Capsules included exposures in a total of 1315 participants in clinical trials (635 pediatric patients, 350 adolescent patients, 248 adult patients, and 82 healthy adult subjects). Of these, 635 patients (ages 6 to 12) were evaluated in two controlled clinical studies, one open-label clinical study, and two single-dose clinical pharmacology studies (N= 40). Safety data on all patients are included in the discussion that follows. Adverse reactions were assessed by collecting adverse reactions, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.

Adverse reactions during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a smaller number of standardized event categories. In the tables and listings that follow, COSTART terminology has been used to classify reported adverse reactions.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed.

Adverse Reactions Leading to Discontinuation of Treatment

In two placebo-controlled studies of up to 5 weeks duration among children with ADHD, 2.4% (10/425) of MAS-ER Capsules-treated patients discontinued due to adverse reactions (including 3 patients with loss of appetite, one of whom also reported insomnia) compared to 2.7% (7/259) receiving placebo.

The most frequent adverse reactions leading to discontinuation of MAS-ER Capsules in controlled and uncontrolled, multiple-dose clinical trials of children (N=595) were anorexia (loss of appetite) (2.9%), insomnia (1.5%), weight loss (1.2%), emotional lability (1%), and depression (0.7%). Over half of these patients were exposed to MAS-ER Capsules for 12 months or more.

In a separate placebo-controlled 4-week study in adolescents with ADHD, five patients (2.1%) discontinued treatment due to adverse events among MAS-ER Capsules-treated patients (N=233) compared to none who received placebo (N=54). The most frequent adverse event leading to discontinuation and considered to be drug-related (i.e. leading to discontinuation in at least 1% of MAS-ER Capsules-treated patients and at a rate at least twice that of placebo) was insomnia (1.3%, n=3).

In one placebo-controlled 4-week study among adults with ADHD with doses 20 mg to 60 mg, 23 patients (12.0%) discontinued treatment due to adverse events among MAS-ER Capsules-treated patients (N=191) compared to one patient (1.6%) who received placebo (N=64). The most frequent adverse events leading to discontinuation and considered to be drug-related (i.e. leading to discontinuation in at least 1% of MAS-ER Capsules-treated patients and at a rate at least twice that of placebo) were insomnia (5.2%, n=10), anxiety (2.1%, n=4), nervousness (1.6%, n=3), dry mouth (1.6%, n=3), anorexia (1.6%, n=3), tachycardia (1.6%, n=3), headache (1.6%, n=3), and asthenia (1.0%, n=2).

Adverse Reactions Occurring in Controlled Trials

Adverse reactions reported in a 3-week clinical trial of children and a 4-week clinical trial in adolescents and adults, respectively, treated with MAS-ER Capsules or placebo are presented in the tables below.

Table 1 Adverse Reactions Reported by 2% or More of Children (6-12 Years Old) Receiving MAS-ER Capsules with Higher Incidence Than on Placebo in a 584-Patient Clinical Study
Body System Preferred Term MAS-ER Capsules (n=374) Placebo (n=210)
General Abdominal Pain (stomachache) 14% 10%
Fever 5% 2%
Infection 4% 2%
Accidental Injury 3% 2%
Asthenia (fatigue) 2% 0%
Digestive System Loss of Appetite 22% 2%
Vomiting 7% 4%
Nausea 5% 3%
Dyspepsia 2% 1%
Nervous System Insomnia 17% 2%
Emotional Lability 9% 2%
Nervousness 6% 2%
Dizziness 2% 0%
Metabolic/Nutritional Weight Loss 4% 0%
Table 2 Adverse Reactions Reported by 5% or More of Adolescents (13-17 Years Old) Weighing ≤ 75 kg/165 lbs Receiving MAS-ER Capsules with Higher Incidence Than Placebo in a 287 Patient Clinical Forced Weekly-Dose Titration Study *
Body System Preferred Term MAS-ER Capsules (n=233) Placebo (n=54)
Note: The following reactions did not meet the criterion for inclusion in Table 2 but were reported by 2% to 4% of adolescent patients receiving MAS-ER Capsules with a higher incidence than patients receiving placebo in this study: accidental injury, asthenia (fatigue), dry mouth, dyspepsia, emotional lability, nausea, somnolence, and vomiting.
*
Included doses up to 40 mg
Dose-related adverse reactions
Appears the same due to rounding
General Abdominal Pain (stomachache) 11% 2%
Digestive System Loss of Appetite 36% 2%
Nervous System Insomnia 12% 4%
Nervousness 6% 6%
Metabolic/Nutritional Weight Loss 9% 0%
Table 3 Adverse Reactions Reported by 5% or More of Adults Receiving MAS-ER Capsules with Higher Incidence Than on Placebo in a 255 Patient Clinical Forced Weekly-Dose Titration Study *
Body System Preferred Term MAS-ER Capsules (n=191) Placebo (n=64)
Note: The following reactions did not meet the criterion for inclusion in Table 3 but were reported by 2% to 4% of adult patients receiving MAS-ER Capsules with a higher incidence than patients receiving placebo in this study: infection, photosensitivity reaction, constipation, tooth disorder (e.g., teeth clenching, tooth infection), emotional lability, libido decreased, somnolence, speech disorder (e.g., stuttering, excessive speech), palpitation, twitching, dyspnea, sweating, dysmenorrhea, and impotence.
*
Included doses up to 60 mg.
Appears the same due to rounding
General Headache 26% 13%
Asthenia 6% 5%
Digestive System Dry Mouth 35% 5%
Loss of Appetite 33% 3%
Nausea 8% 3%
Diarrhea 6% 0%
Nervous System Insomnia 27% 13%
Agitation 8% 5%
Anxiety 8% 5%
Dizziness 7% 0%
Nervousness 13% 13%
Cardiovascular System Tachycardia 6% 3%
Metabolic/Nutritional Weight Loss 10% 0%
Urogenital System Urinary Tract Infection 5% 0%

Hypertension [see Warnings and Precautions (5.2)]

In a controlled 4-week outpatient clinical study of adolescents with ADHD, isolated systolic blood pressure elevations ≥15 mmHg were observed in 7/64 (11%) placebo-treated patients and 7/100 (7%) patients receiving MAS-ER Capsules 10 or 20 mg. Isolated elevations in diastolic blood pressure ≥ 8 mmHg were observed in 16/64 (25%) placebo-treated patients and 22/100 (22%) MAS-ER Capsules-treated patients. Similar results were observed at higher doses.

In a single-dose pharmacokinetic study in 23 adolescents with ADHD, isolated increases in systolic blood pressure (above the upper 95% CI for age, gender, and stature) were observed in 2/17 (12%) and 8/23 (35%), subjects administered 10 mg and 20 mg MAS-ER Capsules, respectively. Higher single doses were associated with a greater increase in systolic blood pressure. All increases were transient, appeared maximal at 2 to 4 hours post dose and not associated with symptoms.

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