Vyvanse: Indications, Dosage, Precautions, Adverse Effects
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Vyvanse - Product Information

Manufacture: Shire, Inc.
Country: Canada
Condition: ADHD (Attention Deficit Hyperactivity Disorder), Binge Eating Disorder
Class: CNS stimulants
Form: Capsules
Ingredients: lisdexamfetamine dimesylate, croscarmellose sodium, magnesium stearate and microcrystalline cellulose. The capsule shells contain edible ink, gelatin, titanium dioxide (E171), and one or more of the following: FD and C Yellow #6 (E133), FD and C Blue #1 (E110), FD and C Red #3 (E127), FDA/E172 Black Iron Oxide, FDA/E172 Yellow Iron Oxide

lisdexamfetamine dimesylate Capsules

Summary Product Information

Route of Administration Dosage Form / Strength Nonmedicinal Ingredients
oral capsule
10mg, 20mg, 30mg, 40mg, 50mg, 60mg
croscarmellose sodium, magnesium stearate, microcrystalline cellulose and capsule shells which contain edible ink, gelatin, titanium dioxide (E171), and one or more of the following: FD and C Yellow #6 (E110), FD and C Blue #1 (E133), FD and C Red #3 (E127), FDA/E172 Black Iron Oxide, FDA/E172 Yellow Iron Oxide.

Indications and Clinical Use

VYVANSE (lisdexamfetamine dimesylate capsules) is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).

A diagnosis of ADHD (DSM-IV-TR) implies the presence of hyperactive-impulsive and/or inattentive symptoms that cause impairment and were present before the age of 7 years. The symptoms must be persistent, must be more severe than is typically observed in individuals at a comparable level of development, must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work), and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least six months: lack of attention to details/careless mistakes, lack of sustained attention, poor listener, failure to follow through on tasks, poor organization, avoids tasks requiring sustained mental effort, loses things, easily distracted, forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least six months (or adult equivalent symptoms): fidgeting/squirming, leaving seat, inappropriate running/climbing, difficulty with quiet activities, “on the go”, excessive talking, blurting answers, can′t wait turn, intrusive. For a Combined Type diagnosis, both inattentive and hyperactive-impulsive criteria must be met.

Special Diagnostic Considerations

The specific etiology of ADHD is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but also of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV characteristics.

Need for Comprehensive Treatment Program

VYVANSE is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational/vocational, social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Drug treatment is not intended for use in a patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational/vocational placement is essential in patients with this diagnosis and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe drug treatment will depend upon the physician's assessment of the chronicity and severity of the patient′s symptoms and on the level of functional impairment.

Long-term Use

The physician who elects to use VYVANSE for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see Dosage and Administration).

The efficacy of VYVANSE has been evaluated separately in both children and adolescents for up to four weeks, and in adults for up to ten weeks. In a separate controlled trial of a combined population of children and adolescents, the efficacy of VYVANSE has been evaluated for up to seven weeks.

Geriatrics

VYVANSE has not been systematically studied in, and is therefore not indicated for use in, the geriatric population (>65 years of age) (see Action and Clinical Pharmacology, Pharmacokinetics).

Pediatrics (<6 years of age)

Amphetamines should not be used in children under six years, since safety and efficacy in this age group have not been established.

Contraindications

  • Advanced arteriosclerosis
  • Symptomatic cardiovascular disease
  • Moderate to severe hypertension
  • Hyperthyroidism
  • Known hypersensitivity or idiosyncrasy to the sympathomimetic amines
  • Allergy to amphetamines or to components of VYVANSE or its container
  • Glaucoma
  • Agitated states
  • Patients with a history of drug abuse
  • During or within 14 days following the administration of monoamine oxidase inhibitors (hypertensive crises may result) (see Drug Interactions).

Warnings and Precautions

Serious Warnings and Precautions

Amphetamines have a potential for abuse, misuse, dependence, or diversion for nontherapeutic uses that physicians should consider when prescribing this product (see Cardiovascular, Misuse and Serious Cardiovascular Adverse Events, and Dependence Liability sections below).

General

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

Cardiovascular

Misuse and Serious Cardiovascular Adverse Events

The misuse of amphetamines may cause serious cardiovascular adverse events and sudden death.

Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems

Children and Adolescents

Sudden death has been reported with sympathomimetic drugs used for ADHD treatment at therapeutic doses in children/adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, sympathomimetic drugs generally should not be used in children/adolescents with known serious structural cardiac abnormalities or other serious cardiac problems (e.g., cardiomyopathy, serious heart rhythm abnormalities), that may place them at increased vulnerability to the sympathomimetic effects of ADHD drugs (see Contraindications).

Adults

Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs (see Contraindications).

Hypertension and Other Cardiovascular Conditions

Sympathomimetic medications cause a modest increase in average blood pressure (about 2-4mmHg) and average heart rate (about 3-6bpm) and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia (see Contraindications and Drug Interactions). Blood pressure and pulse should be monitored at appropriate intervals in patients taking VYVANSE, especially patients with hypertension.

Assessing Cardiovascular Status in Patients Being Treated with Sympathomimetic Medications

Theoretically there exists a pharmacological potential for all ADHD drugs to increase the risk of sudden/cardiac death. Although confirmation of an incremental risk for adverse cardiac events arising from treatment with ADHD medications is lacking, prescribers should consider this potential risk.

All drugs with sympathomimetic effects prescribed in the management of ADHD should be used with caution in patients who: a) are involved in strenuous exercise or activities b) use other sympathomimetic drugs or c) have a family history of sudden/cardiac death. Patients who are being considered for treatment with sympathomimetic medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.

Suppression of Growth

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients (see Adverse Reactions). Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including VYVANSE. Patients who are not growing or gaining weight as expected may need to have their treatment interrupted.

Children and Adolescents in VYVANSE Clinical Trials

In a 4-week controlled trial of lisdexamfetamine in children ages 6 to 12 years, mean weight loss from baseline to endpoint was -0.9, -1.9, and -2.5lbs, respectively, for patients assigned to receive 30mg, 50mg, and 70mg of lisdexamfetamine, compared to a 1.0lb weight gain for patients receiving placebo. Higher doses were associated with greater weight loss with four weeks of treatment. Careful follow-up for weight in children ages 6 to 12 years who received lisdexamfetamine over 12 months suggests that consistently medicated children (i.e., treatment for seven days per week throughout the year) have a slowing in growth rate measured by body weight as demonstrated by an age- and sex-normalized mean change from baseline in percentile of -13.4 over one year (average percentiles at baseline and 12 months were 60.9 and 47.2, respectively).

In a 4-week controlled trial of VYVANSE in adolescents aged 13 to 17 years, mean weight change from baseline to endpoint was -2.7, -4.3, and -4.8lbs, respectively, for patients assigned to receive 30mg, 50mg, and 70mg of VYVANSE, compared to a 2.0lb weight gain for patients receiving placebo. Careful follow-up for weight in adolescents aged 13 to 17 years who received lisdexamfetamine over 12 months suggests that consistently medicated adolescents (i.e., treatment for 7 days per week throughout the year) have a slowing in growth rate measured by body weight as demonstrated by an age- and sex-normalized mean change from baseline in percentile of -6.5 over 1 year. The average percentile at baseline (n=265) and 12 months (n=156), were 66.0 and 61.5, respectively.

Stimulant Use in Adolescents and Children

Published data for other stimulants report that in children aged 7 to 10 years there is a temporary slowing in growth rate without evidence of growth rebound during this period of development. In a controlled trial of amphetamine (d- to l-enantiomer ratio of 3:1) in adolescents, mean weight change from baseline within the initial four weeks of therapy was –1.1lbs and –2.8lbs, respectively, for patients receiving 10mg and 20mg of amphetamine (d- to l-enantiomer ratio of 3:1). Higher doses were associated with greater weight loss within the initial four weeks of treatment. Published data are inadequate to determine whether the chronic use of amphetamines in children may be causally associated with suppression of growth.

Dependence Liability

Amphetamines have been extensively abused. Tolerance, extreme psychological dependence, and severe social disability have occurred. There are reports of patients who have increased the dosage to levels many times higher than recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Careful supervision is therefore recommended during drug withdrawal. Manifestations of chronic intoxication with amphetamines may include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia.

In a human abuse liability study, when equivalent oral doses of 100mg lisdexamfetamine dimesylate and 40mg immediate-release d-amphetamine sulfate were administered to individuals with a history of drug abuse, lisdexamfetamine dimesylate 100mg produced subjective responses on a scale of "Drug Liking Effects" (primary endpoint) that were significantly less than d-amphetamine immediate-release 40mg. However, oral administration of 150mg lisdexamfetamine dimesylate produced increases in positive subjective responses on this scale that were statistically indistinguishable from the positive subjective responses produced by 40mg of oral immediate-release d-amphetamine and 200mg of diethylpropion.

Intravenous administration of 50mg lisdexamfetamine dimesylate to individuals with a history of drug abuse produced positive subjective responses on scales measuring "Drug Liking", "Euphoria", "Amphetamine Effects", and "Benzedrine Effects" that were not significantly different from placebo. Administration of a dose of 20mg of intravenous d-amphetamine produced significant positive subjective responses on these scales.

Psychiatric

Pre-existing Psychosis

Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.

Screening Patients for Bipolar Disorder

Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Emergence of New Psychotic or Manic Symptoms

Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children/adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients.

Aggression

Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the post-marketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment of ADHD should be monitored for the appearance of, or worsening of, aggressive behavior or hostility.

Suicidal Behavior and Ideation

There have been post-marketing reports of suicide-related events in patients treated with ADHD drugs, including cases of ideation, attempts, and very rarely, completed suicide. The mechanism of this risk is not known. ADHD and its related co-morbidities may be associated with increased risk of suicidal ideation and/or behavior. Therefore, it is recommended for patients treated with ADHD drugs that caregivers and physicians monitor for signs of suicide-related behavior, including at dose initiation/optimization and drug discontinuation. Patients should be encouraged to report any distressing thoughts or feelings at any time to their healthcare professional. Patients with emergent suicidal ideation and behavior should be evaluated immediately. The physician should initiate appropriate treatment of the underlying psychiatric condition and consider a possible change in the ADHD treatment regimen.

Neurologic

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 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, the drug should be discontinued.

Tics

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

Ophthalmologic

Difficulties with accommodation and blurring of vision have been reported with stimulant treatment (see Contraindications).

Vascular

Peripheral Vasculopathy, Including Raynaud′s Phenomenon

Stimulants used to treat ADHD, such as VYVANSE, are associated with peripheral vasculopathy, including Raynaud′s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud′s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Special Populations

Pregnant Women

The effects of VYVANSE on labour and delivery in humans are unknown.

There are no adequate and well-controlled studies in pregnant women. There has been one report of severe congenital bony deformity, tracheoesophageal fistula, and anal atresia (VATER association) in a baby born to a woman who took d-amphetamine sulfate with lovastatin during the first trimester of pregnancy.

A number of studies in rodents indicate that prenatal or early postnatal exposure to amphetamine (d- or d,l-) at doses similar to those used clinically can result in long-term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function.

Non-teratogenic Effects

Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude.

VYVANSE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Women

Amphetamines are excreted in human milk. Long-term neurodevelopmental effects on infants from amphetamine exposure are unknown. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatrics (<6 years of age)

Amphetamines are not recommended for use in children under 6 years of age. Long-term effects of amphetamines in children have not been well established (see Warnings and Precautions, Suppression of Growth).

Renal Impairment

Due to reduced clearance in patients with severe renal insufficiency (GFR 15 to <30 mL/min/1.73 m2), the maximum dose should not exceed 50mg/day. Further dosage reduction should be considered in patients undergoing dialysis (see Dosage and Administration; Action and Clinical Pharmacology, Special Populations and Conditions).

Lisdexamfetamine and d-amphetamine are not dialyzable.

Effects on Ability to Operate Machinery or Vehicles

Patients should find out how VYVANSE will affect them before engaging in activities such as operating machinery or vehicles, as VYVANSE may impair the ability to engage in these activities.

Adverse Reactions

Adverse Drug Reaction Overview

The pre-marketing development program for VYVANSE included exposures in a total of 992 participants in clinical trials (345 pediatric patients aged 6 to 12 years, 233 adolescent patients aged 13 to 17 years, 358 adult patients and 56 healthy adult subjects). Of these, 345 pediatric patients (aged 6 to 12 years) were evaluated in two controlled clinical studies (one parallel-group and one crossover), one open-label extension study, and one single-dose clinical pharmacology study, 233 adolescent (aged 13 to 17 years) patients were evaluated in one controlled clinical study, and 358 adult patients were evaluated in one controlled clinical study and one open-label extension study.

The information included in this section is based on data from the 4-week parallel-group controlled clinical trials in children, adolescent and adult patients with ADHD. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.

Adverse events 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 events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and listings that follow, MedDRA terminology has been used to classify reported adverse events.

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

Adverse drug reactions (ADRs) observed with VYVANSE treatment mainly reflect side effects commonly associated with amphetamine use. In clinical trials, approximately a third of pediatric, adolescent and adult subjects treated with VYVANSE reported decreased appetite and insomnia. Other very common adverse drug reactions include dry mouth, headache and upper abdominal pain. Stimulant side effects generally occur early in treatment and tend to decrease over time.

Adverse Events Associated with Discontinuation of Treatment

Nine percent (20/218) of VYVANSE-treated children aged 6 to 12 years discontinued due to adverse events compared to 1% (1/72) who received placebo. The most frequent adverse events leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of VYVANSE-treated patients and at a rate at least twice that of placebo) were ECG voltage criteria for ventricular hypertrophy, tic, vomiting, psychomotor hyperactivity, decreased appetite, insomnia, and rash (2/218 each; 1%).

In the controlled adolescent (aged 13 to 17 years) trial, 4% (10/233) of VYVANSE-treated patients discontinued due to adverse reactions compared to 1% (1/77) who received placebo. The most frequent adverse events leading to discontinuation in at least 1% of VYVANSE-treated patients and considered to be drug-related were irritability (3/233; 1%), decreased appetite, and insomnia (2/233 each; 1%).

In the controlled adult trial, 6% (21/358) of VYVANSE-treated patients discontinued due to adverse events compared to 2% (1/62) who received placebo. The most frequent adverse events leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of VYVANSE-treated patients and at a rate at least twice that of placebo) were insomnia (8/358; 2%), tachycardia (3/358; 1%), irritability (2/358; 1%), hypertension (4/358; 1%), headache (2/358; 1%), anxiety (2/358; 1%), and dyspnea (3/358; 1%).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adverse reactions reported in the controlled trials in children (aged 6 to 12 years), adolescents (aged 13 to 17 years) and adult patients treated with VYVANSE (incidence of 1% or greater) and greater than that observed in placebo-treated patients are presented in Table 1 to Table 3.

The children clinical trial was a Phase 3, randomized, multi-center, double-blind, parallel-group, placebo-controlled study in 290 children aged 6 to 12 years with ADHD. Adverse drug reactions with the highest subject incidence rates (≥5.0%) in VYVANSE treatment groups combined were decreased appetite, insomnia, upper abdominal pain, headache, irritability, weight decreased, vomiting, nausea and dizziness. All of these adverse drug reactions are typical side effects of amphetamine products. 54.1% of these adverse drug reactions occurred within the first week of treatment with VYVANSE, when all of the active-treated subjects received VYVANSE 30mg.

Three hundred and fourteen (314) adolescent subjects (aged 13 to 17 years) with ADHD were enrolled in a Phase 3, randomized, double-blind, multi-center, placebo-controlled, parallel-group, forced-dose titration, safety and efficacy study of VYVANSE. The most common ADRs (≥5.0%) reported with VYVANSE treatment reflected side effects commonly associated with amphetamine use. These included decreased appetite, headache, insomnia, weight decreased and irritability; there was no apparent dose effect for these events among VYVANSE treatment groups. Most ADRs tended to occur early during the course of treatment and their incidence generally decreased over time despite the forced-dose titration schedule of the study.

Four hundred and twenty (420) adult subjects with ADHD were enrolled in a Phase 3, randomized, double-blind, multi-center, placebo-controlled, parallel-group, forced-dose titration, safety and efficacy study of VYVANSE. The most common ADRs (≥5.0%) reported with VYVANSE treatment reflected side effects commonly associated with amphetamine use. These included decreased appetite, dry mouth, headache, insomnia, nausea, diarrhea, anxiety, anorexia and initial insomnia; there was no apparent dose effect for these events among VYVANSE treatment groups. Most ADRs tended to occur early during the course of treatment and their incidence generally decreased over time despite the forced-dose titration schedule of the study.

Small increases in heart rate were observed with VYVANSE use. These changes were small in magnitude and are known effects of amphetamine use. No significant differences were observed among the treatment groups in systolic blood pressure and diastolic blood pressure.

Table 1 Adverse Drug Reactions Reported by 1% or More of Child Patients (Aged 6 to 12 Years) Taking VYVANSE in a 4-Week Clinical Trial
Body System Preferred Term VYVANSE
(n=218)
Placebo
(n=72)
Gastrointestinal Disorders Abdominal Pain Upper
Vomiting
Nausea
Dry Mouth
11.9%
8.7%
6.0%
4.6%
5.6%
4.2%
2.8%
0%
General Disorder and Administration Site Conditions Pyrexia 2.3% 1.4%
Investigations Weight Decreased 9.2% 1.4%
Metabolism and Nutrition Disorders Decreased Appetite
Anorexia
39.0%
1.8%
4.2%
0%
Nervous System Disorders Headache
Dizziness
Somnolence
Psychomotor Hyperactivity
11.9%
5.0%
2.3%
1.4%
9.7%
0%
1.4%
0%
Psychiatric Disorders Insomnia
Irritability
Initial Insomnia
Affect Lability
Tic
Aggression
Agitation
Obsessive-Compulsive Symptoms
18.8%
9.6%
4.1%
3.2%
2.3%
1.4%
1.4%
1.4%
2.8%
0%
0%
0%
0%
0%
0%
0%
Skin and Subcutaneous Tissue Disorders Rash 2.8% 0%

Note: This table includes those events for which the incidence in patients taking VYVANSE was greater than the incidence in patients taking placebo. ADRs for which the incidence was greater or equal in patients taking placebo: Fatigue.

Uncommon adverse drug reactions (reported by ≥0.1% to <1% of pediatric patients taking VYVANSE) in a 4-week clinical trial include:
Cardiac Disorders: Palpitation, tachycardia
Eye Disorders: Mydriasis, vision blurred
Gastrointestinal Disorders: Diarrhea
General Disorders and Administration Site Conditions: Feeling jittery
Immune System Disorders: Hypersensitivity
Investigations: Blood pressure increased
Psychiatric Disorders: Depression, dysphoria, logorrhea
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea

Table 2 Adverse Drug Reactions Reported by 1% or More of Adolescent Patients(Aged 13 to 17 Years) Taking VYVANSE in a 4-Week Clinical Trial
Body System Preferred Term VYVANSE
(n=233)
Placebo
(n=77)
Cardiac Disorders Palpitations 2.1% 1.3%
Gastrointestinal Disorders Dry Mouth
Nausea
4.3%
3.9%
1.3%
2.6%
General Disorder and
Administration Site

Conditions
Fatigue 4.3% 2.6%
Investigations Weight Decreased
Blood Pressure Increased
9.4%
1.3%
0%
0%
Metabolism and Nutrition Decreased Appetite
Anorexia
33.9%
1.7%
2.6%
0%
Nervous System Disorders Headache
Dizziness
Tremor
14.6%
4.3%
1.7%
13.0%
3.9%
0%
Psychiatric Disorders Insomnia
Irritability
Initial Insomnia
Affect Lability
11.2%
6.9%
2.6%
1.3%
3.9%
3.9%
0%
0%
Respiratory, Thoracic and
Mediastinal Disorders
Dyspnea 1.3% 0%

Note: This table includes those events for which the incidence in patients taking VYVANSE was greater than the incidence in patients taking placebo. ADRs for which the incidence was greater or equal in patients taking placebo: Diarrhea and Vomiting.

Uncommon adverse drug reactions (reported by ≥0.1% to <1% of adolescent patients taking VYVANSE) in a 4-week clinical trial include:
Cardiac Disorders: Tachycardia
Gastrointestinal Disorders: Abdominal pain upper
General Disorders and Administration Site Conditions: Feeling jittery, pyrexia
Psychiatric Disorders: Aggression, anxiety, dermatillomania, restlessness
Nervous System Disorders: Psychomotor hyperactivity, somnolence
Skin and Subcutaneous Tissue Disorders: Rash, urticaria
Reproductive System and Breast Disorders: Erectile dysfunction

Table 3 Adverse Drug Reactions Reported by 1% or More of Adult Patients Taking VYVANSE in a 4-Week Clinical Trial
Body System Preferred Term VYVANSE
(n=358)
Placebo
(n=62)
Cardiac DisordersPalpitations
Tachycardia
1.7%
1.1%
0%
0%
Gastrointestinal Disorders Dry Mouth
Nausea
Diarrhea
Abdominal Pain Upper
25.7%
7.0%
6.7%
2.5%
3.2%
0%
0%
1.6%
General Disorder and
Administration Site
Conditions
Feeling Jittery 4.2% 0%
Investigations Weight Decreased
Blood Pressure Increased
3.1%
2.8%
0%
0%
Metabolism and Nutrition Decreased Appetite
Anorexia
26.5%
5.0%
1.6%
0%
Nervous System Disorders Headache
Tremor
20.7%
2.2%
12.9%
0%
Psychiatric Disorders Insomnia
Anxiety
Initial Insomnia
Middle Insomnia
Agitation
Restlessness
Libido Decreased
Logorrhea
19.3%
5.9%
5.0%
3.6%
3.1%
2.5%
1.4%
1.1%
4.8%
0%
3.2%
0%
0%
0%
0%
0%
Reproductive System and
Breast Disorders
Erectile Dysfunction 1.4% 0%
Respiratory, Thoracic and
Mediastinal Disorders
Dyspnea 2.2% 0%
Skin and Subcutaneous Tissue
Disorders
Hyperhidrosis
Rash
2.8%
1.1%
0%
0%

Note: This table includes those events for which the incidence in patients taking VYVANSE was greater than the incidence in patients taking placebo. ADRs for which the incidence was greater or equal in patients taking placebo: Dizziness, Fatigue and Irritability.

Uncommon adverse drug reactions (reported by ≥0.1% to <1% of adult patients taking VYVANSE) in a 4-week clinical trial include:
Eye Disorders: Vision blurred
Gastrointestinal Disorders: Vomiting
General Disorders and Administration Site Conditions: Pyrexia
Psychiatric Disorders: Affect lability, depression, dermatillomania, dysphoria, euphoria, tic
Nervous System Disorders: Psychomotor hyperactivity, somnolence
Skin and Subcutaneous Tissue Disorders: Urticaria

Weight Loss and Suppression of Growth in Pediatric Patients

In the studies conducted in children and adolescents, VYVANSE demonstrated a dose-dependent effect on subjects′ body weight over four weeks (see Warnings and Precautions, Suppression of Growth).

Weight Loss in Adults

In the 4-week adult trial, the dose-dependent effect of VYVANSE on body weight was similar to the pediatric studies.

Long-Term Extension Studies

Three long-term, open-label extension studies were conducted over 12 months in 274 children (aged 6-12 years; 147 subjects completed), 269 adolescents (aged 13-17 years; 156 subjects completed), and 349 adults (aged 18-55 years; 191 subjects completed), respectively. VYVANSE was generally safe and well tolerated in each study with a safety profile consistent with stimulant treatment.

Post-Market Adverse Drug Reactions

Body System Preferred Term
Cardiac Disorders Cardiomyopathy
Palpitations
Eye Disorders Diplopia
Mydriasis
Vision Blurred
Gastrointestinal Disorders Constipation
General Disorders and Administration Site Disorders Fatigue
Hepatobiliary Disorders Eosinophilic Hepatitis
Immune System Disorders Anaphylactic Reaction
Hypersensitivity
Nervous System Disorders Dyskinesia
Restlessness
Seizure
Somnolence
Tremor
Psychiatric Disorders Aggression
Agitation
Anxiety
Bruxism
Depression
Dermatillomania
Dysphoria
Euphoria
Hallucination
Logorrhea
Mania
Psychotic Episodes
Suicidal Behavior
Tic
Skin and Subcutaneous Tissue Disorders Angioedema
Hyperhidrosis
Stevens-Johnson Syndrome
Urticaria
Vascular Disorders Raynaud′s Phenomenon

Suicidal Behavior and Ideation

There have been post-marketing reports of suicide-related events, including completed suicide, suicide attempt, and suicidal ideation in patients treated with ADHD drugs. In some of these reports, comorbid conditions may have contributed to the event. (see Warnings and Precautions, Suicidal Behavior and Ideation)

Drug Interactions

Drug-Drug Interactions

Proton Pump Inhibitors

These agents act on proton pumps by blocking acid production thereby reducing gastric acidity. A proton pump inhibitor (omeprazole) had no effect on the pharmacokinetics of VYVANSE (lisdexamfetamine dimesylate capsules).

In Vivo Study on Cytochrome P450 (CYP) Substrates

An in vivo human study of lisdexamfetamine dimesylate (70mg) in healthy adults did not result in any clinically meaningful effect on the pharmacokinetics of drug substrates metabolized by CYP1A2 (200mg caffeine), CYP2D6 (30mg dextromethorphan), CYP2C19 (40mg omeprazole), or CYP3A (0.025mg/kg midazolam).

Agents Whose Blood Levels May be Impacted by Vyvanse

Extended-release guanfacine: In a drug interaction study, administration of an extended-release guanfacine (4mg) to healthy adult volunteers in combination with VYVANSE (50mg) induced a 19% increase in guanfacine maximum plasma concentrations; whereas, exposure (area under the curve; AUC) was increased by 7%. These small changes are not expected to be clinically meaningful. In this study, no effect on d-amphetamine exposure was observed following coadministration of extended-release guanfacine and VYVANSE. Drug interaction studies have not been conducted with higher doses of lisdexamfetamine dimesylate.

Extended-release venlafaxine: In a drug interaction study, administration of 225mg extended-release venlafaxine, a CYP2D6 substrate, in combination with 70mg VYVANSE induced a 9% decrease in the Cmax and 17% decrease in the AUC for the primary active metabolite o-desmethylvenlafaxine and a 10% increase in Cmax and 13% increase in AUC for venlafaxine. These small changes are not expected to be clinically meaningful. In this study, no effect on d-amphetamine exposure was observed following co-administration of extendedrelease venlafaxine and VYVANSE. VYVANSE (d-amphetamine) may be a weak inhibitor of CYP2D6. Lisdexamfetamine has no effect on the AUC and Cmax of the composite of venlafaxine and o-desmethylvenlafaxine.

Agents and Conditions that Alter Urinary pH and Impact the Urinary Excretion and Half-Life of Amphetamines

Ascorbic acid and other agents and conditions that acidify urine increase urinary excretion and decrease the half-life of amphetamines. Sodium bicarbonate and other agents and conditions that alkalinize urine, decrease urinary excretion and extend the half-life of amphetamines.

Monoamine Oxidase Inhibitors

VYVANSE is contraindicated during or within 14 days following the administration of monoamine oxidase inhibitors (MAOIs). MAOIs and amphetamines, when co-administered, can increase the release of norepinephrine and other monoamines. This can cause severe headaches and other signs of hypertensive crisis. A variety of toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results (see Contraindications).

Serotonergic Drugs

On rare occasions, serotonin syndrome has occurred in association with the use of amphetamines, such as VYVANSE, when given in conjunction with serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). It has also been reported in association with overdose of amphetamines, including VYVANSE (see Overdosage). There were no reported cases of serotonin syndrome when VYVANSE was administered with SSRIs and SNRIs in clinical trials. As this syndrome may result in potentially life-threatening conditions (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma), treatment with serotonergic drugs should be discontinued if such events occur and supportive symptomatic treatment should be initiated. VYVANSE should be used with caution in combination with serotonergic and/or neuroleptic drugs (e.g. triptans, certain tricyclic antidepressants and opiate analgesics, lithium, St. John′s Wort, MAOI) due to the risk of serotonergic syndrome (see Contraindications).

Agents Whose Effects May be Reduced by Amphetamines

Adrenergic blockers: As expected by their pharmacologic action, adrenergic blockers are inhibited by amphetamines.

Agents Whose Effects May be Potentiated by Amphetamines

Norepinephrine: Amphetamines enhance the adrenergic effect of norepinephrine.

Modafinil: Modafinil with amphetamines may cause increases in blood pressure and heart rate and may result in additive effects; their concomitant use is not recommended.

Agents that May Reduce the Effects of Amphetamines

Chlorpromazine: Chlorpromazine blocks dopamine and norepinephrine receptors, thus inhibiting the central stimulant effects of amphetamines.

Haloperidol: Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant effects of amphetamines.

Pimozide: Pimozide may block the action of amphetamines, and concomitant use of the two medications is not recommended.

Drug-Food Interactions

Food (a high fat meal or yogurt) or orange juice does not affect the observed AUC and Cmax of d-amphetamine in healthy adults after single-dose oral administration of 70mg of VYVANSE capsules. Food prolongs Tmax by approximately 1 hour (from 3.8 hrs at fasted state to 4.7 hrs after a high-fat meal or to 4.8 hours with orange juice). After an 8-hour fast, the AUC for d-amphetamine following oral administration of lisdexamfetamine dimesylate in solution and as intact capsules were equivalent.

Drug-Laboratory Interactions

Amphetamines can cause a significant elevation in plasma corticosteroid levels particularly in the evening, and thus may affect urinary steroid determinations.

Dosage and Administration

Dosing Considerations

Dosage should be individualized according to the therapeutic needs and response of the patient. VYVANSE should be administered at the lowest effective dosage.

VYVANSE should not be used in patients with symptomatic cardiovascular disease including coronary artery disease and should generally not be used in patients with known serious structural cardiac abnormalities or other serious heart problems (e.g., cardiomyopathy, serious heart rhythm abnormalities) that may place them at increased vulnerability to the sympathomimetic effects of ADHD drugs (see Contraindications and Warnings and Precautions).

Theoretically there exists a pharmacological potential for all ADHD drugs to increase the risk of sudden/cardiac death. Although confirmation of an incremental risk for adverse cardiac events arising from treatment with ADHD medications is lacking, prescribers should consider this potential risk.

All drugs with sympathomimetic effects prescribed in the management of ADHD should be used with caution in patients who: a) are involved in strenuous exercise or activities b) use other sympathomimetic drugs or c) have a family history of sudden/cardiac death. Prior to the initiation of treatment with sympathomimetic medications, a personal and family history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam should be obtained to assess for the presence of cardiac disease. In patients with relevant risk factors and based on the clinician′s judgment, further cardiovascular evaluation may be considered (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during ADHD treatment should undergo a prompt cardiac evaluation.

Patients who are considered to need extended treatment with VYVANSE should undergo periodic evaluation of their cardiovascular status (see Warnings and Precautions).

In patients with severe renal insufficiency (GFR 15 to <30 mL/min/1.73 m2), the maximum dose should not exceed 50mg/day. Further dosage reduction should be considered in patients undergoing dialysis (see Warnings and Precautions, Special Populations; Action and Clinical Pharmacology, Special Populations and Conditions).

Recommended Dose and Dosage Adjustment (Adults, Adolescents and Children)

VYVANSE should not be used in patients under 6 years of age.

The usual starting dose is 30mg once daily in the morning, whether a patient is starting ADHD treatment for the first time or switching from another medication. When in the judgment of the clinician a lower dose is appropriate, a patient may begin treatment with 20mg once daily in the morning.

If a dose increase is warranted in the judgment of the physician, daily dosage may be adjusted in increments of 10mg or 20mg at approximately weekly intervals.

The maximum VYVANSE dose should not exceed 60 mg/day. In clinical studies, doses of up to 70mg/day were shown to be effective, although no additional benefit was demonstrated at doses greater than 30mg/day, and adverse events and discontinuations were more frequent at higher doses. Doses greater than 70mg/day of VYVANSE have not been studied.

If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

The effectiveness of VYVANSE has not been studied in adults over 55 years of age (see Action and Clinical Pharmacology).

VYVANSE should be taken in the morning. Afternoon doses should be avoided because of the potential for insomnia.

VYVANSE may be taken with or without food.

VYVANSE capsules may be taken whole, or the capsule may be opened and the entire contents emptied and mixed with yogurt or in a glass of water or orange juice. If the contents of the capsule include any compacted powder, a spoon may be used to break apart the powder in the yogurt or liquid. The contents should be mixed until completely dispersed. The patient should consume the entire mixture of yogurt or liquid immediately; it should not be stored. The active ingredient dissolves completely once dispersed; however, a film containing the inactive ingredients may remain in the glass or container once the mixture is consumed. The patient should not take anything less than one capsule per day and a single capsule should not be divided.

Long-term Use

Pharmacological treatment of ADHD may be needed for extended periods. The efficacy of VYVANSE in maintaining symptom response in children and adolescent patients (aged 6 to 17 years) with ADHD was studied in a 6-week, placebo-controlled randomized withdrawal trial in subjects following treatment with open-label VYVANSE for at least 26 weeks. The efficacy of VYVANSE in maintaining symptom response in adult patients (aged 18 to 55 years) with ADHD was studied in a 6-week, placebo-controlled randomized withdrawal trial in subjects with documentation of open-label treatment with VYVANSE for a minimum of 6 months. Subjects assigned to VYVANSE in the randomized withdrawal phase continued on the same dose used to confirm response in the open-label phase.

The efficacy of VYVANSE has been evaluated separately in both children and adolescents for up to four weeks, and in adults for up to ten weeks. In a separate controlled trial of a combined population of children and adolescents, the efficacy of VYVANSE has been evaluated for up to seven weeks.

The clinician who elects to use VYVANSE for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy.

Overdosage

Individual patient response to amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses.

Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rapid respiration, confusion, aggression, hallucinations, panic states, hyperpyrexia and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma.

Management of acute amphetamine intoxication is largely symptomatic and includes gastric lavage, administration of activated charcoal, administration of a cathartic and sedation. Acidification of the urine increases amphetamine excretion, but is believed to increase risk of acute renal failure if myoglobinuria is present. If acute severe hypertension complicates amphetamine overdosage, administration of intravenous phentolamine has been suggested. However, a gradual drop in blood pressure will usually result when sufficient sedation has been achieved.

The prolonged duration of action of VYVANSE should be considered when treating patients with overdose.

Lisdexamfetamine and d-amphetamine are not dialyzable.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and Clinical Pharmacology

Mechanism of Action

Lisdexamfetamine dimesylate is a prodrug of d-amphetamine. Amphetamines are noncatecholamine sympathomimetic amines with CNS stimulant activity. Amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. The parent drug, lisdexamfetamine, does not bind to the sites responsible for the reuptake of norepinephrine and dopamine in vitro. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known.

Pharmacokinetics

Pharmacokinetic studies of d-amphetamine after oral administration of lisdexamfetamine dimesylate have been conducted in healthy adult and pediatric (aged 6 to 12 years) patients with ADHD.

Absorption

After oral administration, lisdexamfetamine dimesylate is rapidly absorbed from the gastrointestinal tract.

In 18 pediatric patients (aged 6 to 12 years) with ADHD, the Tmax of d-amphetamine was approximately 3.5 hours following single-dose oral administration of lisdexamfetamine dimesylate 30mg, 50mg, or 70mg after an 8-hour overnight fast. The Tmax of lisdexamfetamine dimesylate was approximately one hour. Linear pharmacokinetics of d-amphetamine after single-dose oral administration of VYVANSE capsules was established over the dose range of 30mg to 70mg in children aged 6 to 12 years; and in adults over a range of 50mg to supratherapeutic dose of 150mg.

Food (a high fat meal or yogurt) or orange juice does not affect the observed AUC and Cmax of d-amphetamine in healthy adults after single-dose oral administration of 70mg of VYVANSE capsules. Food prolongs Tmax by approximately one hour (from 3.8 hrs at fasted state to 4.7 hrs after a high-fat meal or to 4.8 hrs with orange juice). After an 8-hour fast, the AUC for d-amphetamine following oral administration of lisdexamfetamine dimesylate in solution and as intact capsules were equivalent.

Weight/Dose normalized AUC and Cmax were 22% and 12% lower, respectively, in adult females than in males on Day 7 following a 70mg/day dose of lisdexamfetamine for seven days. Weight/Dose normalized AUC and Cmax values were the same in girls and boys following single doses of 30mg to 70mg.

Distribution

There is no accumulation of d-amphetamine (as measured by AUC) at steady state in healthy adults and no accumulation of lisdexamfetamine dimesylate after once-daily dosing for seven consecutive days.

Metabolism

Lisdexamfetamine dimesylate is hydrolyzed in the blood to d-amphetamine, which is responsible for the drug′s activity, and L-lysine. Lisdexamfetamine is not metabolized by cytochrome P450 enzymes.

Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain α or β carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxy-amphetamine are both active and each is subsequently oxidized to form 4-hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid.

Although the enzymes involved in amphetamine metabolism have not been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy-amphetamine. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility.

Excretion

Following the oral administration of a 70mg dose of radiolabeled lisdexamfetamine dimesylate to six healthy subjects, approximately 96% of the oral dose radioactivity was recovered in the urine and only 0.3% recovered in the feces over a period of 120 hours. Of the radioactivity recovered in the urine, 42% of the dose was related to amphetamine, 25% to hippuric acid, and 2% intact lisdexamfetamine. Plasma concentrations of unconverted lisdexamfetamine are low and transient, generally becoming non-quantifiable by eight hours after administration. The plasma elimination half-life of lisdexamfetamine typically averaged less than one hour in studies of lisdexamfetamine dimesylate in volunteers.

Special Populations and Conditions

Age: The pharmacokinetics of d-amphetamine is similar in pediatric (aged 6 to 12 years) and adolescent (aged 13 to 17 years) ADHD patients, and healthy adult volunteers. Any differences in kinetics seen after oral administration are a result of differences in mg/kg dosing.

In a study of 47 subjects aged 55 years of age or older, amphetamine clearance was approximately 0.7L/hr/kg for subjects 55-74 years of age and 0.55 L/hr/kg for subjects ≥75 years of age. This is slightly reduced compared to younger adults (approximately 1L/hr/kg for subjects 18-45 years of age). Reduced amphetamine clearance does not appear to be related to kidney function as measured by creatinine clearance

Gender: Systemic exposure to d-amphetamine is similar for men and women given the same mg/kg dose.

Race: Formal pharmacokinetic studies for race have not been conducted.

Renal Impairment: In a pharmacokinetic study of lisdexamfetamine in subjects with normal and impaired renal function, d-amphetamine clearance was reduced from 0.7 L/hr/kg in normal subjects to 0.4 L/hr/kg in subjects with severe renal impairment (GFR 15 to < 30mL/min/1.73m2) (see Warnings and Precautions, Special Populations; Dosage and Administration).

Storage and Stability

Dispense in a tight, light-resistant container as defined in the USP.
Store at 25°C (77°F). Excursions permitted to 15-30°C (59-86°F).

Dosage Forms, Composition and Packaging

VYVANSE is designed as a capsule for once-a-day oral administration.

VYVANSE capsules contain 10mg, 20mg, 30mg, 40mg, 50mg, and 60mg of lisdexamfetamine dimesylate. Corresponding d-amphetamine base equivalence as follows:

Lisdexamfetamine dimesylate 10mg 20mg 30mg 40mg 50mg 60mg
d-amphetamine base equivalence 3.0mg 5.9mg 8.9mg 11.9mg 14.8mg 17.8mg

VYVANSE capsules contain the following inactive ingredients: croscarmellose sodium, magnesium stearate and microcrystalline cellulose. The capsule shells contain edible ink, gelatin, titanium dioxide (E171), and one or more of the following: FD and C Yellow #6 (E110), FD and C Blue #1 (E133), FD and C Red #3 (E127), FDA/E172 Black Iron Oxide, FDA/E172 Yellow Iron Oxide.

VYVANSE capsules 10mg: pink body/pink cap (imprinted S489 10mg), bottles of 100.
VYVANSE capsules 20mg: ivory body/ivory cap (imprinted S489 20mg), bottles of 100.
VYVANSE capsules 30mg: white body/orange cap (imprinted S489 30mg), bottles of 100.
VYVANSE capsules 40mg: white body/blue green cap (imprinted S489 40mg), bottles of 100.
VYVANSE capsules 50mg: white body/blue cap (imprinted S489 50mg), bottles of 100.
VYVANSE capsules 60mg: aqua blue body/aqua blue cap (imprinted S489 60mg), bottles of 100.