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

5.4 Long-Term Suppression of Growth

Monitor growth in children during treatment with stimulants. Patients who are not growing or gaining weight as expected may need to have their treatment interrupted.

Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development.

In a controlled trial of Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release in adolescents, mean weight change from baseline within the initial 4 weeks of therapy was –1.1 lbs. and –2.8 lbs., respectively, for patients receiving 10 mg and 20 mg Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release. Higher doses were associated with greater weight loss within the initial 4 weeks of treatment. Chronic use of amphetamines can be expected to cause a similar suppression of growth.

5.5 Seizures

There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in the absence of seizures, and very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release should be discontinued.

5.6 Peripheral Vasculopathy,including Raynaud’s Phenomenon

Stimulants,includingDextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release,usedto treatADHDareassociatedwithperipheralvasculopathy,includingRaynaud’sphenomenon. Signsandsymptomsareusuallyintermittentand mild;however,veryraresequelaeincludedigitalulcerationand/orsofttissuebreakdown. Effectsofperipheralvasculopathy,includingRaynaud’sphenomenon,wereobservedinpost-marketingreportsatdifferenttimesandat therapeuticdosesinallagegroupsthroughoutthecourseoftreatment.Signsandsymptomsgenerallyimproveafterreduction indoseor discontinuationofdrug.Carefulobservation fordigitalchangesisnecessaryduringtreatmentwithADHDstimulants.Furtherclinicalevaluation (e.g.,rheumatologyreferral) may beappropriateforcertainpatients.

5.7 Serotonin Syndrome

Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as MAOIs, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort [see DRUG INTERACTIONS (7.1)]. Amphetamines and amphetamine derivatives are known to be metabolized, to some degree, by cytochrome P450 2D6 (CYP2D6) and display minor inhibition of CYP2D6 metabolism [see CLINICAL PHARMACOLOGY (12.3)]. The potential for a pharmacokinetic interaction exists with the co-administration of CYP2D6 inhibitors which may increase the risk with increased exposure to Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release. In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6 [see DRUG INTERACTIONS (7.1)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).Concomitant use of Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release with MAOI drugs is contraindicated [see CONTRAINDICATIONS (4)].

Discontinue treatment with Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment. Concomitant use of Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release with other serotonergic drugs or CYP2D6 inhibitors should be used only if the potential benefit justifies the potential risk. If clinically warranted, consider initiating Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release with lower doses, monitoring patients for the emergence of serotonin syndrome during drug initiation or titration, and informing patients of the increased risk for serotonin syndrome.

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. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release 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 Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release 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 Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release-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 Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release 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 Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release 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 Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release-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 Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release-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 Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release-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 Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release-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 Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release or placebo are presented in the tables below.

Table 1 Adverse Reactions Reported by 2% or More of Children (6 to 12 Years Old) Receiving Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, Amphetamine Sulfate Extended-Release with Higher Incidence Than on Placebo in a 584-Patient Clinical Study

Body System

Preferred Term

Amphetamine Salts

(n=374)

Placebo

(n=210)

General

Abdominal Pain (stomachache)

Fever

Infection

Accidental Injury

Asthenia (fatigue)

14%

5%

4%

3%

2%

10%

2%

2%

2%

0%

Digestive System

Loss of Appetite

Vomiting

Nausea

Dyspepsia

22%

7%

5%

2%

2%

4%

3%

1%

Nervous System

Insomnia

Emotional Lability

Nervousness

Dizziness

17%

9%

6%

2%

2%

2%

2%

0%a

Metabolic/Nutritional

Weight Loss

4%

0%

Table 2 Adverse Reactions Reported by 5% or More of Adolescents (13 to 17 Years Old) Weighing75 kg/165 lbs Receiving Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, Amphetamine Sulfate Extended-Release with Higher Incidence Than Placebo in a 287 Patient Clinical Forced Weekly-Dose Titration Study*

Body System

Preferred Term

Amphetamine Salts

(n=233)

Placebo

(n=54)

General

Abdominal Pain (stomachache)

11%

2%

Digestive System

Loss of Appetite b

36%

2%

Nervous System

Insomnia b

Nervousness

12%

6%

4%

6%a

Metabolic/Nutritional

Weight Loss b

9%

0%

*Included doses up to 40 mg

a Appears the same due to rounding

b Dose-related adverse reactions

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 Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release with a higher incidence than patients receiving placebo in this study: accidental injury, asthenia (fatigue), dry mouth, dyspepsia, emotional lability, nausea, somnolence, and vomiting.

Table 3 Adverse Reactions Reported by 5% or More of Adults Receiving Dextroamphetamine Saccharate, Amphetamine Aspartate Monohydrate, Dextroamphetamine Sulfate, Amphetamine Sulfate Extended-Release with Higher Incidence Than on Placebo in a 255 Patient Clinical Forced Weekly-Dose Titration Study*

Body System

Preferred Term

Amphetamine Salts

(n=191)

Placebo

(n=64)

General

Headache

Asthenia

26%

6%

13%

5%

Digestive System

Dry Mouth

Loss of Appetite

Nausea

Diarrhea

35%

33%

8%

6%

5%

3%

3%

0%

Nervous System

Insomnia

Agitation

Anxiety

Dizziness

Nervousness

27%

8%

8%

7%

13%

13%

5%

5%

0%

13% a

Cardiovascular System

Tachycardia

6%

3%

Metabolic/Nutritional

Weight Loss

10%

0%

Urogenital System

Urinary Tract Infection

5%

0%

*Included doses up to 60 mg.

a Appears the same due to rounding

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 Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release 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.

Hypertension [see WARNINGS AND PRECAUTIONS (5.3)]

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 Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release 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%) Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release-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 Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate extended-release, 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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