Equasym XL 10 mg, 20 mg or 30 mg Capsules: Indications, Dosage, Precautions, Adverse Effects
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Equasym XL 10 mg, 20 mg or 30 mg Capsules - Product Information

Manufacture: Shire, Inc.
Country: Great Britain
Condition: ADHD (Attention Deficit Hyperactivity Disorder), Depression, Narcolepsy
Class: CNS stimulants
Form: Capsules
Ingredients: methylphenidate hydrochloride, crospovidone, fumaric acid, glyceryl behenate, green pigment blend PB-1763 (3mg and 4mg tablets only), hypromellose, lactose, methacrylic acid copolymer, microcrystalline cellulose, povidone

guanfacine hydrochloride extended-release tablets

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Nonmedicinal Ingredients
oralTablet / 1mg, 2mg, 3mg, 4mg guanfacine as guanfacine HClCrospovidone, fumaric acid, glyceryl behenate, green pigment blend PB-1763 (3mg and 4mg tablets only), hypromellose, lactose, methacrylic acid copolymer, microcrystalline cellulose, and povidone.

Indications and Clinical Use

Pediatrics (6 -17 Years of Age)

INTUNIV XR (guanfacine hydrochloride extended-release tablets) is indicated as monotherapy for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents aged 6 to 17 years.

INTUNIV XR is also indicated as adjunctive therapy to psychostimulants for the treatment of ADHD in children and adolescents, aged 6 to 17 years, with a sub-optimal response to psychostimulants.

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 6 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 6 months: 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

INTUNIV XR 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 for 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 child's symptoms and on the level of functional impairment.

Long-term Use

The effectiveness of INTUNIV XR for long-term use, i.e., for more than 9 weeks in 6-12 year olds and more than 15 weeks in 13-17 year olds, has not been systematically evaluated in controlled monotherapy trials, nor has it been systematically evaluated in controlled adjunctive trials for longer than 9 weeks in 6-17 year olds. Therefore the physician electing to use INTUNIV XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Pediatrics (<6 Years of Age)

The safety and efficacy of INTUNIV XR in children less than 6 years of age have not been studied.

Adults (≥18 Years of Age)

INTUNIV XR has not been systematically studied in and is therefore not indicated for use in adults (over 18 years of age).

Contraindications

Hypersensitivity

Patients with a history of hypersensitivity to this drug, to any ingredient in the formulation or component of the container, or to any other product containing guanfacine (see Dosage Forms, Composition and Packaging).

Warnings and Precautions

General

Somnolence and Sedation

Sedative events, especially during initial use, were commonly reported adverse reactions in clinical trials. In two 8-and 9-week monotherapy trials (Studies 1 and 2) in 6-17 year olds, sedative events reported as adverse reactions were 38% for INTUNIV XR vs. 12% for placebo and in a separate monotherapy trial in adolescents (Study 3), were 54% for INTUNIV XR vs. 23% for placebo. In an adjunctive trial (Study 4) in 6-17 year olds, sedative events reported as adverse events were 18% for INTUNIV XR vs. 7% for placebo. INTUNIV XR should be dosed based on clinical response and tolerability. Advise patients that sedation can occur, particularly early in treatment or with dose increases. If sedation is judged to be clinically concerning or persistent, a dose decrease or discontinuation should be considered. Before INTUNIV XR is used with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), the potential for additive sedative effects should be considered. Patients should avoid performing tasks which may require special attention, such as riding a bike, driving/operating machinery or doing other dangerous activities, until they are reasonably certain that treatment with INTUNIV XR does not adversely affect them. Patients should avoid use with alcohol (see Drug Interactions, Drug-Drug Interactions - CNS Depressant Drugs; Dosage and Administration, Dosing Considerations).

Cardiovascular

Hypotension, Bradycardia and Syncope

INTUNIV XR can cause syncope and dose-dependent decreases in heart rate and blood pressure (systolic and diastolic) (see Adverse Reactions, Clinical Trial Adverse Drug Reactions – Effects on Blood Pressure and Heart Rate; Action and Clinical Pharmacology, Cardiovascular Safety). In pediatric (6-17 year olds), short-term (8-9 weeks), controlled monotherapy trials (Studies 1 and 2), the maximum mean changes from baseline in systolic blood pressure, diastolic blood pressure, and heart rate were decreases of 5mmHg, 3mmHg, and 6bpm, respectively, for all dose groups combined (generally one week after reaching target doses of 1mg/day, 2mg/day, 3mg/day or 4mg/day). In the adolescent controlled monotherapy trial (Study 3), the maximum mean change from baseline in systolic blood pressure, diastolic blood pressure and heart rate were decreases of 5mmHg, 4mmHg, and 6bpm for all dose groups combined. Decreases in blood pressure and heart rate were usually asymptomatic; however, hypotension and bradycardia can occur. In long-term, open-label studies (mean exposure of approximately 10 months), maximum decreases in systolic and diastolic blood pressure occurred in the first month of therapy. Decreases were less pronounced over time. The majority of syncope cases occurred in the long-term, open-label studies.

In a 9-week controlled adjunctive trial, the maximum mean changes from baseline in supine systolic blood pressure, diastolic blood pressure, and heart rate were decreases of 4mmHg, 3mmHg, and 9bpm, respectively, between weeks 3 and 5 of the study. Decreases in blood pressure and heart rate were usually asymptomatic; however, hypotension and bradycardia can occur.

Measurements of heart rate and blood pressure should be performed prior to initiating therapy, following dose adjustments, periodically during treatment and following drug discontinuation. Observe caution if using INTUNIV XR in patients who have a history of hypotension, heart block, bradycardia, or other cardiovascular disease (e.g., arrhythmia, sick sinus syndrome, ischemic heart disease, congestive heart failure, or congenital long QT syndrome), as INTUNIV XR can decrease blood pressure and heart rate. Caution is advised when treating patients with INTUNIV XR who have a history of syncope or a condition that may predispose them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Given the effect on blood pressure and heart rate, caution is advised when treating patients with INTUNIV XR who are being treated concomitantly with antihypertensives or other drugs that reduce blood pressure or heart rate, QT prolonging drugs, and drugs that increase the risk of syncope (see Drug Interactions, Drug-Drug Interactions - Heart Rate Lowering Drugs - QT Prolonging Drugs; Adverse Reactions, Clinical Trial Adverse Drug Reactions - Effects on Heart Rate and QT Interval). Patients/caregivers should be advised that patients should avoid becoming dehydrated or overheated.

Elevated Blood Pressure and Heart Rate Upon Discontinuation

Patients/caregivers should be instructed not to discontinue INTUNIV XR without consulting their physician.

Elevations in blood pressure and heart rate above original baseline (i.e., rebound) have been reported to occur upon discontinuation of INTUNIV XR. In randomized controlled monotherapy trials, increases of up to 10mmHg persisted in a few individuals at approximately 30 days postdose and were not considered serious. In a 26-week long-term randomized withdrawal study in children and adolescents, increases in mean systolic and diastolic blood pressure, of approximately 3mmHg and 1mmHg respectively were observed upon discontinuation of INTUNIV XR. Increases up to 36mmHg above normal baseline persisted in a few individuals, which ranged between 3 and 26 weeks post-dose upon discontinuation of INTUNIV XR. More than 90% of patients` blood pressure measurements remained within normal limits (i.e. less than the 95th percentile based on age, sex and stature). Mean increases in pulse of approximately 1.5bpm were observed at approximately 2 weeks after the last dose of INTUNIV XR and then decreased to baseline 4 weeks later. A few cases of hypertension were observed in this study, however, the increases in blood pressure and pulse were not considered serious or associated with adverse events.

Patients should be monitored during dose downward titration (decrements of no more than 1mg every 3 to 7 days) and following INTUNIV XR discontinuation until blood pressure and heart rate have returned to baseline. Because of the psychostimulant potential for increasing blood pressure and heart rate, there is a theoretical increased risk of rebound or a risk of greater rebound when discontinuing INTUNIV XR treatments in patients on adjunctive therapy. Caution is warranted if a patient stops INTUNIV XR while maintaining its psychostimulant therapy. Use caution when prescribing drugs that can elevate blood pressure and heart rate immediately following INTUNIV XR discontinuation (see Warnings and Precautions, Monitoring and Laboratory Tests; Dosage and Administration, Discontinuation; Adverse Reactions, Clinical Trial Adverse Drug Reactions – Effects on Blood Pressure and Heart Rate).

QTc Interval

QTc increase (placebo-adjusted mean change from baseline approximately 5msec) has been observed in patients aged 6-17 years with ADHD receiving therapeutic doses of INTUNIV XR at steady-state. In clinical trials of INTUNIV XR in ADHD patients, there were no reports of torsade de pointes. Given the effect of INTUNIV XR on cardiac electrophysiology, consider this observation in clinical decisions to prescribe INTUNIV XR to patients with a known history of QT prolongation, risk factors for torsades de pointes (e.g. heart block, bradycardia, hypokalemia) or patients who are taking medications known to prolong the QT interval (see Adverse Reactions, Clinical Trial Adverse Drug Reactions - Effects on Heart Rate and QT Interval; Drug Interactions, Drug-Drug Interactions - QT Prolonging Drugs).

Psychiatric

Pre-existing Psychosis

Administration of medications for ADHD 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 treating 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 INTUNIV XR, 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 and adolescents without a prior history of psychotic illness or mania can occur with guanfacine use at usual doses. If such symptoms occur, consideration should be given to a possible causal role of guanfacine, and discontinuation of treatment should be considered.

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 guanfacine causes 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.

Dependence Liability

INTUNIV XR is not a controlled substance or a stimulant drug. INTUNIV XR has not been studied for abuse or dependence potential.

Effects on Growth

Pediatric patients aged 6-17 years taking INTUNIV XR demonstrated similar growth compared to normative data. Patients taking INTUNIV XR had a mean increase in weight of 0.5kg (1 pound) compared to those receiving placebo over a comparative treatment period. Patients receiving INTUNIV XR for at least 12 months in open-label studies gained an average of 8kg (17 pounds) in weight and 8cm (3 inches) in height. The height, weight, and BMI percentile remained stable in patients at 12 months in the long-term studies compared to when they began receiving INTUNIV XR. Nevertheless, height, weight and BMI should be routinely monitored.

Special Populations

Pregnant Women

There are no adequate and well-controlled studies of INTUNIV XR in pregnant women. Non-clinical studies showed fetal and maternal toxicity (see Toxicology). INTUNIV XR should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

Nursing Women

There are no clinical data on the use of INTUNIV XR in women who are breast feeding. In nonclinical studies, guanfacine was excreted into rat milk. It is not known if guanfacine would also be excreted into human milk. Use caution when INTUNIV XR is administered to a woman who is breast feeding.

Pediatrics (<6 years of age)

The safety and efficacy of INTUNIV XR in children less than 6 years of age have not been studied.

Adults (≥18 years of age)

The safety and efficacy of INTUNIV XR in adults (≥18 years) have not been studied.

Use in Renally Impaired Patients

The impact of renal impairment on the pharmacokinetics of guanfacine in children and adolescents, 6-17 years old, was not assessed. In adult patients with impaired renal function, the cumulative urinary excretion of immediate-release guanfacine and the renal clearance diminished as renal function decreased. In patients on hemodialysis, the dialysis clearance was about 15% of the total clearance. The low dialysis clearance suggests that the hepatic elimination (metabolism) increases as renal function decreases. Guanfacine in adults is cleared both by the liver and the kidney, and approximately 50% of the clearance of guanfacine is hepatic. It may be necessary to adjust the dose in patients with significant impairment of renal function (see Dosage and Administration, Dosage Adjustment for Special Populations).

Use in Hepatically Impaired Patients

The impact of hepatic impairment on the pharmacokinetics of guanfacine in children and adolescents, 6-17 years old, was not assessed. Because guanfacine is metabolized primarily by cytochrome P450 (CYP)3A4, diminished CYP3A4 activity as a result of hepatic impairment would be expected to increase guanfacine exposure. It may be necessary to adjust the dose in patients with significant impairment of hepatic function (see Dosage and Administration, Dosage Adjustment for Special Populations).

Monitoring and Laboratory Tests

Routine laboratory tests are not required. Heart rate and blood pressure should be monitored at baseline, after dose adjustments, periodically during treatment and following drug discontinuation (see Warnings and Precautions, Cardiovascular; Dosage and Administration, Dosing Considerations; Discontinuation). Particular caution should be observed in patients with pre-existing hypotension, bradycardia, heart block, or other cardiovascular disease (e.g., arrhythmia, sick sinus syndrome, ischemic heart disease, congestive heart failure, or congenital long QT syndrome) or a history of syncope. Patients/caregivers should be advised that patients should avoid dehydration or becoming overheated. Advise patients that sedation can occur, particularly early in treatment or with dose increases. If sedation is judged to be clinically concerning or persistent, a dose decrease or discontinuation should be considered.

Adverse Reactions

Adverse Drug Reaction Overview

The developmental program for INTUNIV XR included exposures in a total of 2411 participants in clinical trials (1718 children aged 6-12 years, 693 adolescent patients aged 13-17 years).

The information included in this section is based on data from 2 monotherapy forced-dose clinical trials in children and adolescents aged 6-17 years (Studies 1 and 2), 1 dose-optimized monotherapy trial in adolescents aged 13-17 years (Study 3) and 1 dose-optimized adjunctive trial in children and adolescents aged 6-17 years (Study 4).

Adverse Events Leading to Discontinuation of Treatment

Twelve percent (12%) of patients (6-17 years) receiving INTUNIV XR discontinued from the two pediatric monotherapy clinical studies (Studies 1 and 2) due to adverse events, compared to 4% in the placebo group. The most common adverse reactions leading to discontinuation of INTUNIV XR-treated patients from the studies were somnolence/sedation (6%) and fatigue (2%). Less common adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included: hypotension/decreased blood pressure, headache, dizziness.

Six percent (5.7%) of patients (13-17 years) receiving INTUNIV XR discontinued from the adolescent monotherapy clinical trial (Study 3) due to adverse events, compared to 1.9% in the placebo group. The most common adverse event leading to discontinuation of INTUNIV XRtreated patients was fatigue (1.3%).

Three percent (3%) of patients receiving INTUNIV XR discontinued from the adjunctive clinical study (Study 4) due to adverse events, compared to 1% in the placebo group. No adverse event to INTUNIV XR causing discontinuation was reported more than once.

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.

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

Short-Term Monotherapy Trials (children/adolescents aged 6-17 years)

The two forced-dose clinical trials (Studies 1 and 2) with INTUNIV XR alone, one 8-week and one 9-week, were randomized, multi-center, double-blind, parallel-group, placebo-controlled studies in 664 children/adolescents aged 6-17 years with ADHD. Treatment-emergent adverse events with the highest subject incidence rates in INTUNIV XR treatment group combined were fatigue (14%), headache (23.8%) and somnolence/sedation (38%).

Table 1: Treatment-Emergent Adverse Events Reported by 1% or More and Greater Than Placebo in Pediatric Patients (aged 6-17 years) Taking INTUNIV XR Alone up to 4mg in One 8-Week or One 9-Week Controlled Clinical Trial (Studies 1 and 2)
System Organ ClassesPreferred TermINTUNIV XR
n=513
(%)
Placebo
n=149
(%)
Gastrointestinal DisordersAbdominal pain upper9.97.4
Nausea5.72.0
Dry mouth4.11.3
Constipation2.70.7
Dyspepsia1.20.7
General Disorders and Administration Site ConditionsFatigue14.03.4
InvestigationsBlood pressure decreased1.90
Weight increased1.40
Metabolism and Nutrition DisordersDecreased appetite6.04.0
Nervous System DisordersSomnolence29.26.7
Headache23.819.5
Sedation9.94.7
Dizziness6.44.0
Lethargy5.72.7
Psychiatric DisordersIrritability5.84.0
Nightmare1.60
Affect lability1.40.7
Renal and Urinary DisordersEnuresis1.40.7
Vascular DisordersHypotension2.50.7
Orthostatic hypotension1.00

Other common treatment-emergent adverse events (1% to 5%) included Diarrhea, Vomiting, and Insomnia.

Uncommon Treatment-Emergent Adverse Events (reported by ≥0.1% and <1% of pediatricpatients taking INTUNIV XR) in controlled clinical trials:

Cardiac Disorders:Atrioventricular block first degree, sinus arrhythmia

General Disorders and Administration Site Conditions:Asthenia, chest pain

Immune System Disorders:Hypersensitivity

Investigations:Alanine aminotransferase increased, heart rate decreased

Nervous System Disorders:Convulsion, dizziness postural, hypersomnia

Psychiatric Disorders:Agitation

Renal and Urinary Disorders:Pollakiuria

Vascular Disorders:Hypertension, pallor.

Treatment-Emergent Adverse Events (reported by ≥1% of pediatric patients taking INTUNIV XR) in other Phase 2/3 clinical trials:

Cardiac Disorders:Bradycardia

Gastrointestinal Disorders:Abdominal pain, stomach discomfort

Investigations:Blood pressure increased

Nervous System Disorders:Syncope/syncope vasovagal/loss of consciousness

Psychiatric Disorders:Anxiety, depression, middle insomnia

Respiratory, Thoracic, and Mediastinal Disorders:Asthma.

Two long-term extension studies of the above mentioned clinical studies were conducted up to 24 months. INTUNIV XR was generally safe and well tolerated.

Short-Term Monotherapy Trial (adolescents aged 13-17 years)

This clinical trial (Study 3) was a 15-week, double-blind, placebo-controlled study conducted in adolescents aged 13-17 years with ADHD. Treatment-emergent adverse events with the highest subject incidence rates in the INTUNIV XR treatment group were decreased appetite (14.6%), dizziness (15.9%), fatigue (22.3%), headache (26.8%), sedation (11.5%) and somnolence (43.9%).

Table 2: Treatment-Emergent Adverse Events Reported by 1% or More and Greater Than Placebo in Adolescent Patients (aged 13-17 years) Taking INTUNIV XR Alone up to 7mg in One 15-Week Controlled Clinical Trial (Study 3)
System Organ ClassesPreferred TermINTUNIV XR
n=157
(%)
Placebo
n=155
(%)
Cardiovascular DisordersBradycardia4.50
Gastrointestinal DisordersDry mouth7.60
Abdominal pain upper6.44.5
Abdominal pain5.73.9
Constipation3.20
Abdominal discomfort1.91.3
General Disorders and Administration Site ConditionsFatigue22.312.3
Asthenia1.30
InvestigationsBlood pressure diastolic decreased3.20
Weight increased2.51.9
Blood pressure decreased1.90
Metabolism and Nutrition DisordersDecreased appetite14.613.5
Nervous System DisordersSomnolence43.921.3
Headache26.818.1
Dizziness15.910.3
Sedation11.51.9
Insomnia8.93.9
Dizziness postural5.11.9
Initial insomnia2.51.3
Middle insomnia2.50
Psychiatric DisordersIrritability73.9
Nervousness3.21.3
Anxiety2.51.9
Depressed mood1.90
Renal and Urinary DisordersEnuresis1.30.6
Skin and Subcutaneous Tissue DisordersRash3.20.6
Pruritus1.91.3
Vascular disordersOrthostatic hypotension3.81.9

Uncommon Treatment-Emergent Adverse Events (reported by ≥0.1% and <1% of adolescent patients taking INTUNIV XR) in controlled clinical trials:

Cardiac Disorders:Tachycardia

Eye Disorders:Vision blurred

Gastrointestinal Disorders:Dyspepsia

Investigations:Heart rate decreased, heart rate increased

Nervous System Disorders:Lethargy, syncope/loss of consciousness, tremor

Psychiatric Disorders:Affect lability, dysphoria, nightmare, sleep disorder

Renal and Urinary Disorders:Pollakiuria

Skin and Subcutaneous Tissue Disorders:Alopecia

Vascular Disorders:Hypotension, withdrawal hypertension.

Short-Term Adjunctive Trial (children/adolescents aged 6-17 years)

This clinical trial (Study 4) was a 9-week, placebo-controlled, double-blind study conducted in children and adolescents aged 6-17 years treated with psychostimulants who were identified as having a sub-optimal response to psychostimulants. INTUNIV XR was evaluated as adjunct therapy to their psychostimulant treatment. Treatment-Emergent Adverse Events with the highest subject incidence rates were headache and somnolence.

Table 3: Treatment-Emergent Adverse Events Reported by 1% or More and Greater Than Placebo in Pediatric Patients (aged 6-17 years) Taking INTUNIV XR up to 4mg as an Adjunct to a Stable Dose of Psychostimulant in a Controlled Clinical Trial (Study 4)
System Organ ClassesPreferred TermINTUNIV XR
n=302
(%)
Placebo
n=153
(%)
Cardiac DisordersBradycardia1.70
Gastrointestinal DisordersAbdominal pain upper8.32
Nausea5.03.3
Diarrhea3.60.7
Constipation2.30
Dry mouth2.00
Abdominal pain1.70.7
General Disorders and Administration Site ConditionsFatigue9.62.6
Metabolism and Nutrition DisordersDecreased appetite6.63.9
Nervous System DisordersHeadache21.213.1
Somnolence13.64.6
Dizziness7.63.9
Sedation4.32.0
Dizziness postural1.70
Lethargy1.30
Psychiatric DisordersInsomnia8.63.9
Affect lability2.30.7
Middle insomnia2.30
Nightmare1.30.7
Respiratory, Thoracic and Mediastinal DisordersAsthma1.30.7
Vascular DisordersOrthostatic hypotension2.30

Other common treatment-emergent adverse events (1% to 5%) included Vomiting, Stomach discomfort, Irritability, and Enuresis.

Uncommon Treatment-Emergent Adverse Events (reported by ≥0.1% and <1% of pediatric/adolescent patients taking INTUNIV XR as an adjunct to psychostimulant) in a controlled clinical trial:

General Disorders and Administration Site Conditions:Asthenia

Investigations Disorders:Heart rate decreased, weight increased

Nervous System Disorders:Hypersomnia, syncope/syncope vasovagal/loss of consciousness

Psychiatric Disorders:Anxiety, depression

Renal and Urinary Disorders:Pollakiuria

Vascular Disorders:Hypotension, pallor.

A 9-week, open-label safety study was conducted in children and adolescents aged 6-17 years with ADHD whose symptoms were not adequately controlled with psychostimulants alone. In this study, 75 patients who were receiving a stable dose of amphetamine or methylphenidate (with sub-optimal response) were provided an adjunctive, maximum tolerated INTUNIV XR dose up to 4mg/day for 9 weeks. There was no evidence of additive or unique adverse effects with the combination of INTUNIV XR and psychostimulants relative to what is observed with either medication alone. There were no serious adverse events in this study. Five of 75 subjects (7%) discontinued due to adverse events. There were no evident patterns of clinical importance with regard to hematology, clinical chemistry, urinalysis or physical examination results.

Effects on Heart Rate and QT Interval

In five double-blind, randomized, placebo-controlled clinical trials in pediatric patients aged 6-17 years, the following effects on heart rate and QTc interval were observed:

Study
No.
Assessment
day
NPlacebo-Adjusted Mean
Change from Baseline in HR
Placebo-Adjusted Mean
Change from Baseline in QTc
1⚹⚹Day 21217−11.4bpm (90% CI −13.9, −8.9)4.3ms (90% CI 0.9, 7.7)
2⚹⚹Day 42176−4.2bpm (90% CI −7.3, −1.1)5.9ms (90% CI 2.0, 9.9)
3⚹⚹Day 91109−6.1bpm (90% CI −8.1, −4.0)4.0ms (90% CI 1.0, 7.0)
4⚹⚹⚹Day 28116−11.2bpm (90% CI −13.8, −8.6)5.3ms (90% CI 1.8, 8.7)
5⚹⚹⚹Day 56107−10.4bpm (90% CI −13.6, −7.2)4.7ms (90% CI 0.4, 9.1)

Fridericia heart rate correction QTcF=QT/RR0.33 for studies 1,2, & 4 and study population-based heart rate correction QTcP=QT/RR0.31 for study5; ⚹⚹pivotal studies;⚹⚹⚹other clinical studies

Effects on Blood Pressure and Heart Rate

In the monotherapy, short-term (8-9 weeks), pivotal trials (Studies 1 and 2), hypotension including orthostatic hypotension was reported as an adverse drug event for 7% of the INTUNIV XR group and 3% of the placebo group. Orthostatic hypotension was reported for 1% of the INTUNIV XR group and none in the placebo group. In the adolescent monotherapy trial (Study 3), hypotension including orthostatic hypotension was reported as an adverse event for 8.9% of the INTUNIV XR group and 3.2% in the placebo group. Orthostatic hypotension was reported as an adverse event for 3.8% of the INTUNIV XR group and 1.9% of the placebo group. In the adjunctive trial (Study 4), hypotension was reported as an adverse drug event for 0.7% of the INTUNIV XR group and none of the placebo group. Orthostatic hypotension was reported in 2.3% of the INTUNIV XR group and none in the placebo group.

Elevations in blood pressure (up to 10mmHg) and heart rate above original baseline following withdrawal of INTUNIV XR have been reported to persist in a few individuals at approximately 30 days post-dose and were not considered serious. In a 26-week long-term randomized withdrawal study in children and adolescents, increases in mean systolic and diastolic blood pressure, of approximately 3mmHg and 1mmHg respectively were observed upon discontinuation of INTUNIV XR. Increases up to 36mmHg above normal baseline persisted in a few individuals, which ranged between 3 and 26 weeks post-dose upon discontinuation of INTUNIV XR. More than 90% of patients` blood pressure measurements remained within normal limits (i.e. less than the 95th percentile based on age, sex and stature). Mean increases in pulse of approximately 1.5bpm were observed at approximately 2 weeks after the last dose of INTUNIV XR and then decreased to baseline 4 weeks later.

A few cases of hypertension were observed in this study, however, the increases in blood pressure and pulse were not considered serious or associated with adverse events.

Post-Market Adverse Drug Reactions

The following adverse events have been identified during post-marketing experience with guanfacine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

An open-label post-marketing study involving 21,718 patients was conducted to assess the safety of immediate-release guanfacine 1mg/day given at bedtime for 28 days. Guanfacine was administered with or without other antihypertensive agents. Adverse events reported in the post-marketing study at an incidence greater than 1% included dry mouth, dizziness, somnolence, fatigue, headache and nausea. The most commonly reported adverse events in this study were the same as those observed in controlled clinical trials.

Less frequent, possibly guanfacine-related events observed in the post-marketing study and/or reported spontaneously, not included in the INTUNIV XR clinical trial adverse reactions (see Clinical Trial Adverse Drug Reactions), include:

Cardiovascular: Palpitations, tachycardia

Central Nervous System: Paresthesia, vertigo

Eye Disorders: Blurred vision

General and Administration Site Conditions: Edema, malaise, tremor

Musculo-Skeletal System: Arthralgia, leg cramps, leg pain, myalgia

Psychiatric: Confusion, hallucination

Reproductive System, Male: Impotence

Respiratory System: Dyspnea

Skin and Appendages: Alopecia, dermatitis, exfoliative dermatitis, pruritus, rash

Special Senses: Alterations in taste

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

CYP3A4 and CYP3A5 Inhibitors

Use caution when INTUNIV XR is administered to patients taking ketoconazole and other moderate and strong CYP3A4/5 inhibitors (see Dosage and Administration, Dosage Adjustment for Special Populations), since elevation of plasma guanfacine concentration increases the risk of adverse events such as hypotension, bradycardia, and sedation. There was a substantial increase in the rate and extent of guanfacine exposure when administered with ketoconazole; the guanfacine exposure (AUC) increased 3-fold.

CYP3A4 Inducers

When patients are taking INTUNIV XR concomitantly with a CYP3A4 inducer, an increase in the dose of INTUNIV XR within the recommended dose range may be considered (see Dosage and Administration, Dosage Adjustment for Special Populations). There was a significant decrease in the rate and extent of guanfacine exposure when co-administered with rifampin, a CYP3A4 inducer. The exposure (AUC) to guanfacine decreased by 70%.

Valproic Acid

Co-administration of INTUNIV XR and valproic acid can result in increased concentrations of valproic acid. The mechanism of this interaction is unknown, although both guanfacine and valproic acid are metabolized by glucuronidation, possibly resulting in competitive inhibition. When INTUNIV XR is co-administered with valproic acid, monitor patients for potential additive central nervous system (CNS) effects, and give consideration to the monitoring of serum valproic acid concentrations. Adjustments in the dose of valproic acid and INTUNIV XR may be indicated when co-administered.

Heart Rate-Lowering Drugs

INTUNIV XR causes a decrease in heart rate (see Warnings and Precautions, Cardiovascular; Adverse Reactions, Clinical Trial Adverse Drug Reactions - Effects on Heart Rate and QT Interval). The concomitant use of INTUNIV XR with other heart rate-lowering drugs, such as antiarrhythmics, beta blockers, non-dihydropyridine calcium channel blockers, cholinesterase inhibitors, and sphingosine-1 phosphate receptor modulators is not recommended.

QT Prolonging Drugs

QTc interval increase (placebo-adjusted mean change from baseline approximately 5msec) has been observed in patients aged 6-17 years with ADHD receiving therapeutic doses of INTUNIV XR at steady-state (see Warnings and Precautions, Cardiovascular - QTc Interval; Adverse Reactions, Clinical Trial Adverse Drug Reactions - Effects on Heart Rate and QT Interval).

INTUNIV XR causes a decrease in heart rate (see Warnings and Precautions, Cardiovascular; Adverse Reactions, Effects on Heart Rate and QT Interval). Given the effect of INTUNIV XR on heart rate, the concomitant use of INTUNIV XR with QT prolonging drugs is generally not recommended.

Drugs that have been associated with QTc interval prolongation and/or torsade de pointes (a polymorphic ventricular tachyarrhythmia) that can be fatal include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some, although not necessarily all class members have been implicated in QT/QTc prolongation and/or torsade de pointes:

Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide); Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide, dronedarone); Class 1C antiarrhythmics (e.g., flecainide, propafenone); antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone, olanzapine, risperidone); antidepressants (e.g., fluoxetine, citalopram, venlafaxine, tricyclic/tetracyclic antidepressants e.g., amitriptyline, imipramine, maprotiline); opioids (e.g., methadone); macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, tacrolimus); quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin); antimalarials (e.g., quinine, chloroquine); azole antifungals (e.g., ketoconazole, fluconazole, voriconazole); domperidone; 5-HT3 receptor antagonists (e.g., ondansetron); tyrosine kinase inhibitors (e.g., sunitinib, nilotinib, lapatinib, vandetanib); arsenic trioxide; histone deacetylase inhibitors (e.g., vorinostat); beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol).

The above list of potentially interacting drugs is not comprehensive. Current information sources should be consulted for newly approved drugs that decrease heart rate, prolong the QTc interval, or inhibit CYP3A4/CYP3A5 as well as for older drugs for which these effects have recently been established.

Antihypertensive Drugs

Use caution when INTUNIV XR is administered concomitantly with antihypertensive drugs, due to the potential for additive pharmacodynamic effects such as hypotension and syncope (see Warnings and Precautions, Cardiovascular).

CNS Depressant Drugs

Use caution when INTUNIV XR is administered concomitantly with CNS depressant drugs (e.g., alcohol, sedatives, hypnotics, benzodiazepines, barbiturates, and antipsychotics) due to the potential for additive pharmacodynamic effects such as sedation and somnolence (see Warnings and Precautions, General).

Oral Methylphenidate

In a drug interaction study, neither INTUNIV XR (4mg) nor methylphenidate HCl extended-release (36mg) were found to affect the pharmacokinetics of the other drug when administered concomitantly in healthy adult volunteers. The effect of methylphenidate HCl at a dose of 54mg when administered concomitantly with INTUNIV XR was not studied.

Lisdexamfetamine Dimesylate

In a drug interaction study, administration of INTUNIV XR (4mg) to healthy adult volunteers in combination with lisdexamfetamine dimesylate (50mg) induced a 19% increase in guanfacine maximum plasma concentrations, whereas exposure (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 concomitant administration of INTUNIV XR and lisdexamfetamine dimesylate. Drug interaction studies have not been conducted with higher doses of lisdexamfetamine dimesylate.

Drugs That are 5-HT2B Receptor Agonists

Drugs that are potent 5-HT2B receptor agonists should not be used during treatment with INTUNIV XR since the risk of fibrotic complications have not been specifically studied with INTUNIV XR and therefore should not be used (see Detailed Pharmacology, Pharmacodynamics).

Drug-Food Interactions

INTUNIV XR should not be administered with high-fat meals due to increased exposure (see Action and Clinical Pharmacology, Pharmacokinetics).

Grapefruit, grapefruit juice, or products containing grapefruit extract should not be used during treatment with INTUNIV XR because of the risk of CYP3A4 inhibition but has not been specifically studied.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Dosage and Administration

Dosing Considerations

INTUNIV XR is an extended-release tablet and should be dosed once daily. Tablets should not be crushed, chewed or broken before swallowing because this will increase the rate of guanfacine release.

The initial starting dose for INTUNIV XR as an adjunctive therapy with psychostimulants is 1mg, taken orally once a day; evening dosing may be considered (see Clinical Trials).

The tablets should not be administered with high-fat meals, due to increased exposure. (see Action and Clinical Pharmacology, Pharmacokinetics).

Do not substitute for immediate-release guanfacine tablets on a milligram for milligram basis, because of differing pharmacokinetic profiles. INTUNIV XR has a delayed Tmax, reduced Cmax and lower bioavailability compared to those of the same dose of immediate-release guanfacine.

The safety and efficacy of INTUNIV XR in pediatric patients less than 25kg/55lbs in weight have not been studied.

Heart rate and blood pressure should be monitored at baseline, after dose adjustments, periodically during treatment and following drug discontinuation (see Warnings and Precautions, Cardiovascular; Monitoring and Laboratory Tests).

Advise patients that sedation can occur, particularly early in treatment or with dose increases. If sedation is judged to be clinically concerning or persistent, a dose decrease or discontinuation should be considered (see Warnings and Precautions, Cardiovascular; Dosage and Administration, Discontinuation).

Recommended Dose and Dosage Adjustment in Children (6-17 Years Old)

The recommended starting dose for both INTUNIV XR monotherapy and adjunct therapy to psychostimulants is 1mg, taken orally once a day (morning or evening).

The dose should be adjusted, depending on clinical response and tolerability, in increments of no more than 1mg per week up to a maximum daily dose of 4mg (6-12 years) or 7mg (13-17 years), for monotherapy and up to a maximum daily dose of 4mg for adjunctive therapy to psychostimulants.

In monotherapy clinical trials, there were dose-related and exposure-related risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). To balance the exposure-related potential benefits and risks, the recommended dose range, depending on clinical response and tolerability for INTUNIV XR, is 0.05-0.12 mg/kg/day (total daily dose 1- 7mg).

Recommended Target Dose Range for INTUNIV XR monotherapy (depending on clinical response and tolerability)
WeightTarget dose range (0.05 - 0.12 mg/kg/day)
25.0-33.9kg2- 3 mg/day
34.0-41.4kg2- 4 mg/day
41.5-49.4kg3- 5 mg/day
49.5-58.4kg3- 6 mg/day
≥58.5kg4- 7 mg/day

Doses above 4mg/day have not been evaluated in children (ages 6-12 years) and doses above 7mg/day have not been evaluated in adolescents (ages 13-17 years)

In the adjunctive clinical trial which evaluated INTUNIV XR treatment added to psychostimulants, the majority of subjects reached their optimal doses in the 0.05-0.12mg/kg/day range. Doses above 4mg/day have not been studied in adjunctive trials.

Missed Dose

If two or more consecutive doses are missed, re-titration is recommended based on the patient`s tolerability to INTUNIV XR (see Dosage and Administration, Discontinuation).

Discontinuation

Elevations in blood pressure and heart rate above original baseline (i.e., rebound) have been reported to occur upon discontinuation of INTUNIV XR monotherapy. Patients should be monitored during dose downward titration (decrements of no more than 1mg every 3 to 7 days) and following INTUNIV XR discontinuation until blood pressure and heart rate have returned to baseline. Caution is warranted when ending INTUNIV XR treatments in patients on the adjunctive to psychostimulant therapy while maintaining psychostimulant treatments (see Warnings and Precautions, Elevated Blood Pressure and Heart Rate Upon Discontinuation). Use caution when prescribing drugs that can elevate blood pressure and heart rate immediately following INTUNIV XR discontinuation (see Warnings and Precautions, General).

Dosage Adjustment for Special Populations

Renal Impairment

The impact of renal impairment on the pharmacokinetics of guanfacine in children and adolescents, 6-17 years old, was not assessed. In adult patients with impaired renal function, the cumulative urinary excretion of guanfacine and the renal clearance diminished as renal function decreased. In patients on hemodialysis, the dialysis clearance was about 15% of the total clearance. The low dialysis clearance suggests that the hepatic elimination (metabolism) increases as renal function decreases. It may be necessary to adjust the dose in patients with significant impairment of renal function (see Warnings and Precautions, Special Populations – Use in Renally Impaired Patients).

Hepatic Impairment

The impact of hepatic impairment on the pharmacokinetics of guanfacine in children and adolescents, 6-17 years old, was not assessed. Guanfacine in adults is cleared both by the liver and the kidney, and approximately 50% of the clearance of guanfacine is hepatic. It may be necessary to adjust the dose in patients with significant impairment of hepatic function (see Warnings and Precautions, Special Populations – Use in Hepatically Impaired Patients).

Patients treated with CYP3A4/5 inhibitors /inducers

CYP3A4/5 inhibitors and inducers have been shown to have a significant effect on the pharmacokinetics of guanfacine when co-administered (see Drug Interactions, Drug-Drug Interactions). Dose adjustment is recommended with concomitant use of moderate/strong CYP3A4/5 inhibitors (e.g. ketoconazole, grapefruit juice), or strong CYP3A4 inducers (e.g. carbamazepine). In the case of concomitant use of strong and moderate CYP3A inhibitors, an initial 50% reduction of the guanfacine dose is recommended. Further individualized dose titration may then be needed. If guanfacine is combined with strong enzyme inducers, a retitration to increase the dose up to a maximum daily dose 7mg, may be considered if needed. If the inducing treatment is ended, retitration to reduce the guanfacine dose is recommended during the following weeks.

Overdosage

Signs and symptoms of overdose may include hypotension, bradycardia, lethargy, and respiratory depression. Initial hypertension may develop early and may be followed by hypotension. Management of INTUNIV XR overdose should include monitoring for and the treatment of these signs and symptoms. ECG monitoring is recommended. Children and adolescents who develop lethargy should be observed for the development of more serious toxicity including coma, bradycardia and hypotension for up to 24 hours, due to the possibility of delayed onset of these symptoms.

Treatment of overdose may include gastric lavage if it is performed soon after ingestion. Activated charcoal may be useful in limiting the absorption. Guanfacine is not dialyzable in clinically significant amounts (2.4%).

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

Action and Clinical Pharmacology

Mechanism of Action

Guanfacine is a selective alpha2A-adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) psychostimulant. The mechanism of action of guanfacine in ADHD is not known.

Pharmacodynamics

Guanfacine is a selective alpha2A-adrenergic receptor agonist in that it has a 15-20 times higher affinity for this receptor subtype than for the alpha2B or alpha2C subtypes.

Guanfacine is a known antihypertensive agent. By stimulating alpha2A-adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate.

Other Clinical Trials

A 9-week, double-blind, randomized, placebo-controlled, dose-optimization study in children aged 6-12 years with ADHD and oppositional symptoms (n=217) was conducted. Oppositional symptoms were evaluated as the change from baseline to endpoint in the Oppositional Subscale of the Conners` Parent Rating Scale – revised Long Form (CPRS-R:L) score. The mean reduction in the CPRS-R:L at endpoint was significantly greater for INTUNIV XR compared to placebo. ADHD-RS-IV Hyperactivity/Impulsivity and Inattention subscales results supported the pivotal study primary endpoint results. CGI-I and CGI-S rating scales and the 40-item Conduct Problem Scale of the New York Parent`s Rating Scale (NYPRS-S) results also support the primary efficacy endpoint in treating oppositional symptoms and conduct problems in children with a diagnosis of ADHD.

A 9-week, double-blind, randomized, placebo-controlled, dose-optimization study in children aged 6-12 years to assess the efficacy of once daily dosing with optimized INTUNIV XR administered either in the morning or the evening was conducted. Symptoms of ADHD were evaluated as the change from baseline to endpoint in ADHD Rating Scale (ADHD-RS-IV) Total Score. INTUNIV XR showed significantly (p<0.001) greater improvement compared to placebo on the change from baseline to endpoint in the ADHD rating scale (ADHD-RS-IV) score regardless of time of administration (morning or evening) of INTUNIV XR. Conners` Parent Rating Scale – Revised Short Form (CPRS-R:S) results were supportive of the primary endpoint. CPRS total scores, Weiss Functional Impairment Rating Scale - Parent (WFIRS-P) global score and WFIRS-P domain subscale scores for Family, Learning and School, Academic Performance, Behavior in School, Social Score, and Risk score results were also supportive of the primary endpoint.

A 15-week, double-blind, dose-optimization, safety and tolerability study compared the effects of INTUNIV XR to placebo using the Choice Reaction Time Test from the Cambridge Neuropsychological Test Automated Battery (CANTAB) in patients aged 6-17 years (n=182). Patients were titrated to an optimal dose within a 1-3mg range. There was no evidence of impairment in speed processing compared to placebo. The 5-point Pictorial Sleepiness Scale (PSS), designed to assess sleepiness in school-age children and adolescents, was used to measure sleepiness throughout the course of the day and study. Patient and observer (healthcare professional) reported outcomes on the PSS were similar during the daytime in a classroom setting for the INTUNIV XR and placebo groups. However, patients and observer (parent) scores suggested a greater degree of sleepiness in the evening hours before bedtime in the INTUNIV XR group compared to the placebo group. These trends were consistent throughout the study. The frequency and intensity of sedative adverse events was similar in this study to that observed in the pivotal studies.

Cardiovascular Safety

Effects on Heart Rate and QT Interval: (see Warnings and Precautions, Cardiovascular - Hypotension, Bradycardia and Syncope; QTc Interval; Adverse Reactions, Clinical Trial Adverse Drug Reactions).

The effect of two dose levels of immediate-release guanfacine (4mg/day and 8mg/day) on the QT interval was evaluated in a double-blind, randomized, placebo- and active-controlled (moxifloxacin 400mg) cross-over thorough QT study in 83 healthy adults. On Days 1 (4mg/day) and 6 (8mg/day), 12-lead ECGs were obtained by a continuous digital 12-lead ECG recording starting 30 minutes prior to dose administration. The ECGs were extracted within 30 to 10 minutes of dose administration and within 10 minutes before each of the 1, 2, 3, 4, 5, 6, 8, 12, and 24-hour timepoints after dose administration. A dose-dependent decrease in heart rate was observed. The maximal placebo-adjusted mean change in heart rate was -13bpm at 8h post-dosing on day 1 in subjects receiving 4mg/day and -22bpm at 8h post-dosing on day 6 at the supratherapeutic dose of 8mg/day. The maximal placebo-adjusted mean change in the QTcF interval was 5msec at 12h post-dosing on day 1 in subjects receiving 4mg/day and 8msec at 12h post-dosing on day 6 at the supratherapeutic dose of 8mg/day. The 12h post-dose time point at which maximal QTcF effects are seen occurs 7 hours or more after peak plasma guanfacine concentrations. Guanfacine has not been demonstrated to inhibit hERG potassium channels.

Pharmacokinetics

Absorption

Guanfacine is readily absorbed after administration with INTUNIV XR, with peak plasma concentrations reached approximately 5 hours after oral administration in pediatric patients (children and adolescents). In adults, the mean exposure of guanfacine increased (Cmax ∼75% and AUC ∼40%) when INTUNIV XR was taken together with a high-fat meal, compared to intake in the fasted state.

Immediate-release guanfacine and INTUNIV XR have different pharmacokinetic characteristics, so dose substitution on a milligram for milligram basis is not appropriate because of differing pharmacokinetic profiles. INTUNIV XR has a delayed Tmax, reduced Cmax and lower bioavailability compared to those of the same dose of immediate-release guanfacine.

Distribution

Guanfacine is moderately bound to plasma proteins (approximately 70%), independent of drug concentration.

Metabolism

Guanfacine is metabolized via oxidation and glucuronidation. Guanfacine is primarily metabolized by the CYP3A4 isoenzyme. In human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 or CYP3A5). Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers and inhibitors (see Drug Interactions, Drug-Drug Interactions – CYP3A4 and CYP3A5 Inhibitors; CYP3A4 Inducers).

Excretion

Guanfacine is cleared by the kidney and the liver. The main excretion route for guanfacine is the liver. The elimination half-life of guanfacine is approximately 18 hours.

Special Populations and Conditions

Pediatrics

Exposure to guanfacine was higher in children (aged 6-12 years) compared to adolescents (aged 13-17 years) and adults. After oral administration of multiple doses of INTUNIV XR 4mg, the Cmax was 10ng/mL compared to 7ng/mL and the AUC was 162ng·h/mL compared to 116ng·h/mL in children (aged 6-12 years) and adolescents (aged 13-17 years), respectively. These differences are probably attributable to the lower body weight of children compared to adolescents and adults.

Hepatic Impairment

The impact of hepatic impairment on the pharmacokinetics of guanfacine in children and adolescents, 6-17 years old, was not assessed. Approximately 50% of the clearance of guanfacine in adults is hepatic (see Warnings and Precautions, Special Populations - Use in Hepatically Impaired Patients).

Renal Impairment

The impact of renal impairment on the pharmacokinetics of guanfacine in children and adolescents, 6-17 years old, was not assessed. In patients on hemodialysis, the dialysis clearance was about 15% of the total clearance (see Warnings and Precautions, Special Populations - Use in Renally Impaired Patients).

Storage and Stability

Store at 25°C (77°F); excursions permitted from 15° to 30°C (59° to 86°F).

Dosage Forms, Composition and Packaging

INTUNIV XR (guanfacine hydrochloride extended-release tablets) is designed as a tablet for once-a-day oral administration.

Each INTUNIV XR tablet contains guanfacine hydrochloride equivalent to 1mg, 2mg, 3mg and 4mg of guanfacine base and the following inactive ingredients: crospovidone, fumaric acid, glyceryl behenate, hypromellose, lactose, methacrylic acid copolymer, microcrystalline cellulose and povidone. In addition, the 3mg and 4mg tablets also contain green pigment blend PB-1763.

INTUNIV XR tablets 1mg:white/off-white, round (debossed on top 503/on bottom 1mg), bottles of 100.

INTUNIV XR tablets 2mg:white/off-white, oblong (debossed on top 503/on bottom 2mg), bottles of 100.

INTUNIV XR tablets 3mg:green, round (debossed on top 503/on bottom 3mg), bottles of 100.

INTUNIV XR tablets 4mg:green, oblong (debossed on top 503/on bottom 4mg), bottles of 100.