Intuniv Information
Intuniv (Guanfacine hcl) Indications And Usage
A diagnosis of ADHD 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 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. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met.
Specific etiology of this syndrome 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.
Intuniv (Guanfacine hcl) is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Intuniv (Guanfacine hcl) is not intended for use in patients who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational/vocational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe Intuniv (Guanfacine hcl) will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms and on the level of functional impairment.
Intuniv (Guanfacine hcl) Dosage And Administration
Intuniv (Guanfacine hcl) is an extended-release tablet and should be dosed once daily. Do not administer with high fat meals, due to increased exposure.
Do not substitute for immediate-release guanfacine tablets on a mg-per-mg basis, because of differing pharmacokinetic profiles. Intuniv (Guanfacine hcl) has a delayed T, reduced C and lower bioavailability compared to those of the same dose of immediate-release guanfacine [].
If switching from immediate-release guanfacine, discontinue that treatment, and titrate with Intuniv (Guanfacine hcl) according to the following recommended schedule.
Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week, for both monotherapy and adjunctive therapy to a psychostimulant.
Maintain the dose within the range of 1 mg to 4 mg once daily, depending on clinical response and tolerability, for both monotherapy and adjunctive therapy to a psychostimulant. In clinical trials, patients were randomized or dose optomized to doses of 1 mg, 2 mg, 3 mg or 4 mg and received Intuniv (Guanfacine hcl) once daily in the morning in monotherapy trials and once daily in the morning or the evening in the adjunctive therapy trial [].
In monotherapy trials, clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg once daily. Efficacy increased with increasing weight-adjusted dose (mg/kg). If well tolerated, doses up to 0.12 mg/kg once daily may provide additional benefit. Doses above 4 mg/day have not been systematically studied in controlled clinical trials.
In the adjunctive trial, the majority of subjects reached optimal doses in the 0.05-0.12 mg/kg/day range.
In clinical trials, there were dose-related and exposure-related risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). Thus, consideration should be given to dosing Intuniv (Guanfacine hcl) on a mg/kg basis, in order to balance the exposure-related potential benefits and risks of treatment.
Intuniv (Guanfacine hcl) Dosage Forms And Strengths
1 mg, 2 mg, 3 mg and 4 mg extended-release tablets
Intuniv (Guanfacine hcl) Contraindications
Patients with a history of hypersensitivity to Intuniv (Guanfacine hcl) , its inactive ingredients [], or other products containing guanfacine (e.g. TENEX) should not take Intuniv (Guanfacine hcl) .
Intuniv (Guanfacine hcl) Warnings And Precautions
Treatment with Intuniv (Guanfacine hcl) can cause decreases in blood pressure and heart rate. In the monotherapy, pediatric, short-term (8-9 weeks), controlled trials, the maximum mean changes from baseline in systolic blood pressure, diastolic blood pressure, and pulse were -5 mm Hg, -3 mm Hg, and -6 bpm, respectively, for all dose groups combined (generally one week after reaching target doses of 1 mg/day, 2 mg/day, 3 mg/day or 4 mg/day). These changes were dose dependent. Decreases in blood pressure and heart rate were usually modest and asymptomatic; however, hypotension and bradycardia can occur. Hypotension was reported as an adverse event for 7% of the Intuniv (Guanfacine hcl) group and 3% of the placebo group. This includes orthostatic hypotension, which was reported for 1% of the Intuniv (Guanfacine hcl) group and none in the placebo group. In the adjunctive trial, hypotension (3%) and bradycardia (2%) were observed in patients treated with Intuniv (Guanfacine hcl) as compared to none in the placebo group. 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. Syncope occurred in 1% of pediatric subjects in the clinical program. The majority of these cases occurred in the long-term, open-label studies.
Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Use Intuniv (Guanfacine hcl) with caution in patients with a history of hypotension, heart block, bradycardia, or cardiovascular disease, because it can decrease blood pressure and heart rate. Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use Intuniv (Guanfacine hcl) with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Advise patients to avoid becoming dehydrated or overheated.
Somnolence and sedation were commonly reported adverse reactions in clinical studies (38% for Intuniv (Guanfacine hcl) vs. 12% for placebo in monotherapy studies and 18% for Intuniv (Guanfacine hcl) vs. 7% for placebo in the adjunctive study) in children and adolescents with ADHD, especially during initial use []. Before using Intuniv (Guanfacine hcl) with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with Intuniv (Guanfacine hcl) . Advise patients to avoid use with alcohol.
Intuniv (Guanfacine hcl) Adverse Reactions
The following serious adverse reactions are described elsewhere in the labelling:
The most commonly observed adverse reactions (incidence ≥ 5% and at least twice the rate for placebo) in the monotherapy trials with Intuniv (Guanfacine hcl) were: somnolence, fatigue, nausea, lethargy, and hypotension.
Twelve percent (12%) of patients receiving Intuniv (Guanfacine hcl) discontinued from the monotherapy clinical studies due to adverse events, compared to 4% in the placebo group. The most common adverse reactions leading to discontinuation of Intuniv (Guanfacine hcl) -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, headache, and dizziness.
The most commonly observed adverse reactions (incidence ≥ 5% and at least twice the rate for placebo) in the adjunctive trial with Intuniv (Guanfacine hcl) were: somnolence, fatigue, insomnia, dizziness, and abdominal pain.
Three percent of patients receiving Intuniv (Guanfacine hcl) discontinued from the adjunctive clinical study due to adverse events, compared to 1% in the placebo group.
Intuniv (Guanfacine hcl) Use In Specific Populations
Pregnancy Category B
Rat experiments have shown that guanfacine crosses the placenta. However, administration of guanfacine to rats and rabbits at 6 and 4 times, respectively, the maximum recommended human dose of 4 mg/day on a mg/m basis resulted in no evidence of harm to the fetus. Higher doses (20 times the maximum recommended human dose in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity. There are no adequate and well-controlled studies of guanfacine in pregnant women. Intuniv (Guanfacine hcl) should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.
Renal Impairment
The impact of renal impairment on the pharmacokinetics of guanfacine in children 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.
Hepatic Impairment
The impact of hepatic impairment on PK of guanfacine in children 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.
Intuniv (Guanfacine hcl) Overdosage
Two cases of accidental overdose of Intuniv (Guanfacine hcl) were reported in clinical trials in pediatric ADHD patients. These reports included adverse reactions of sedation and bradycardia in one patient and somnolence and dizziness in the other patient.
Post-marketing reports of guanfacine overdosage indicate that hypotension, drowsiness, lethargy, and bradycardia have been observed following overdose. Initial hypertension may develop early and may be followed by hypotension. Similar symptoms have been described in voluntary reports to the American Association of Poison Control Center's National Poison Data System. Miosis of the pupils may be noted on examination No fatal overdoses of guanfacine have been reported in published literature.
Consult a Certified Poison Control Center by calling 1-800-222-1222 for up to date guidance and advice.
Management of Intuniv (Guanfacine hcl) overdose should include monitoring for and the treatment of initial hypertension, if that occurs, as well as hypotension, bradycardia, lethargy and respiratory depression. 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 hypotension.
Intuniv (Guanfacine hcl) Description
Intuniv (Guanfacine hcl) is a once-daily, extended-release formulation of guanfacine hydrochloride (HCl) in a matrix tablet formulation for oral administration only. The chemical designation is N-amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride. The molecular formula is CHCl NO·HCl corresponding to a molecular weight of 282.55. The chemical structure is:
Guanfacine HCl is a white to off-white crystalline powder, sparingly soluble in water (approximately 1 mg/mL) and alcohol and slightly soluble in acetone. The only organic solvent in which it has relatively high solubility is methanol (>30 mg/mL). Each tablet contains guanfacine HCl equivalent to 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine base. The tablets also contain hypromellose, methacrylic acid copolymer, lactose, povidone, crospovidone, microcrystalline cellulose, fumaric acid, and glyceryl behenate. In addition, the 3mg and 4mg tablets also contain green pigment blend PB-1763.
Intuniv (Guanfacine hcl) Clinical Pharmacology
Guanfacine is a selective alpha-adrenergic receptor agonist in that it has a 15-20 times higher affinity for this receptor subtype than for the alpha or alpha subtypes.
Guanfacine is a known antihypertensive agent. By stimulating alpha-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.
Absorption and Distribution
Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration. After oral administration of Intuniv (Guanfacine hcl) the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD.
Immediate-release guanfacine and Intuniv (Guanfacine hcl) have different pharmacokinetic characteristics; dose substitution on a milligram for milligram basis will result in differences in exposure.
A comparison across studies suggests that the C is 60% lower and AUC43% lower, respectively, for Intuniv (Guanfacine hcl) compared to immediate-release guanfacine. Therefore, the relative bioavailability of Intuniv (Guanfacine hcl) to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of Intuniv (Guanfacine hcl) 1 mg once daily and immediate-release guanfacine 1mg once daily are summarized in Table 4.
Exposure to guanfacine was higher in children (ages 6-12) compared to adolescents (ages 13-17) and adults. After oral administration of multiple doses of Intuniv (Guanfacine hcl) 4 mg, the C was 10 ng/mL compared to 7 ng/mL and the AUC was 162 ng h/mL compared to 116 ng h/mL in children (ages 6-12) and adolescents (ages 13-17), respectively. These differences are probably attributable to the lower body weight of children compared to adolescents and adults.
The pharmacokinetics were affected by intake of food when a single dose of Intuniv (Guanfacine hcl) 4 mg was administered with a high-fat breakfast. The mean exposure increased (C ~75% and AUC ~40%) compared to dosing in a fasted state.
Dose Proportionality
Following administration of Intuniv (Guanfacine hcl) in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, C and AUC of guanfacine were proportional to dose.
Metabolism and Elimination
In vitro studies with human liver microsomes and recombinant CYP's demonstrated that guanfacine was primarily metabolized by CYP3A4. In pooled human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5). Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors.
Renal and Hepatic Impairment
The impact of renal impairment on PK of guanfacine in children was not assessed [].
Intuniv (Guanfacine hcl) How Supplied/storage And Handling
Intuniv (Guanfacine hcl) is supplied in 1 mg, 2 mg, 3 mg, and 4 mg strength extended-release tablets in 100 count bottles.
Intuniv (Guanfacine hcl) Patient Counseling Information
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Instruct patients to swallow Intuniv (Guanfacine hcl) whole with water, milk or other liquid. Patients should not take Intuniv (Guanfacine hcl) together with a high-fat meal, since this can raise blood levels of Intuniv (Guanfacine hcl) . Instruct the parent or caregiver to supervise the child or adolescent taking Intuniv (Guanfacine hcl) and to keep the bottle of tablets out of reach of children.
Instruct patients on how to properly taper the medication, if the physician decides to discontinue treatment.
Advise patients that sedation can occur, particularly early in treatment or with dose increases. Caution against operating heavy equipment or driving until they know how they respond to treatment with Intuniv (Guanfacine hcl) . Headache and abdominal pain can also occur. If any of these symptoms persist, or other symptoms occur, the patient should be advised to discuss the symptoms with the physician.
Advise patients to avoid becoming dehydrated or overheated, and to avoid use with alcohol.
Intuniv (Guanfacine hcl) Patient Information
Read the Patient Information that comes with Intuniv (Guanfacine hcl) before you start taking it and each time you get a refill. There may be new information.
Intuniv (Guanfacine hcl) is a prescription medicine used to treat the symptoms of attention deficit/hyperactivity disorder (ADHD).
Intuniv (Guanfacine hcl) is not a central nervous system (CNS) stimulant.
Intuniv (Guanfacine hcl) should be used as a part of a total treatment program for ADHD that may include counselling or other therapies.
It is not known if Intuniv (Guanfacine hcl) is effective:
It is not known if Intuniv (Guanfacine hcl) is safe or effective:
Tell your doctor about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
Intuniv (Guanfacine hcl) may affect the way other medicines work, and other medicines may affect how Intuniv (Guanfacine hcl) works.
Especially tell your doctor if you take:
Ask your doctor or pharmacist for a list of these medicines, if you are not sure.
Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.
Get medical help right away, if you have any of the symptoms listed above.
Tell the doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Intuniv (Guanfacine hcl) . For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use Intuniv (Guanfacine hcl) for a condition for which it was not prescribed. Do not give Intuniv (Guanfacine hcl) to other people, even if they have the same symptoms that you have. It may harm them.
This leaflet summarizes the most important information about Intuniv (Guanfacine hcl) . If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Intuniv (Guanfacine hcl) that is written for health professionals.
For more information, go to
Manufactured for Shire US Inc., Wayne, PA 19087.
Intuniv (Guanfacine hcl) is a registered trademark of Shire LLC.
©2011 Shire Pharmaceuticals Inc.
This product is covered by US patents including 5,854,290; 6,287,599; 6,811,794.
Version: 06 2011
