24 HR guanfacine 2 MG Extended Release Oral Tablet [Intuniv]

INDICATIONS AND USAGE Guanfacine extended-release tablets are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [see Clinical Studies (14 )] . Guanfacine extended-release tablets are a central alpha 2A -adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications ( 1 , 1 4 ).

DOSAGE AND ADMINISTRATION • Recommended dose: 1 mg to 7 mg (0.05-0.12 mg/kg target weight based dose range) once daily in the morning or evening based on clinical response and tolerability ( 2.2 ) . • Begin at a dose of 1 mg once daily and adjust in increments of no more than 1 mg/week ( 2.2 ) . • Do not crush, chew or break tablets before swallowing ( 2.1 ) . • Do not administer with high-fat meals, because of increased exposure ( 2.1 ) . • Do not substitute for immediate-release guanfacine tablets on a mg-per-mg basis, because of differing pharmacokinetic profiles ( 2.3 ) . • If switching from immediate-release guanfacine, discontinue that treatment and titrate with guanfacine extended-release tablets as directed ( 2.3 ) . • When discontinuing, taper the dose in decrements of no more than 1 mg every 3 to 7 days to avoid rebound hypertension ( 2.5 ) . 2.1 General Instruction for Use Swallow tablets whole. Do not crush, chew, or break tablets because this will increase the rate of guanfacine release. Do not administer with high fat meals, due to increased exposure. 2.2 Dose Selection Take guanfacine extended-release tablets orally once daily, either in the morning or evening, at approximately the same time each day. Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week. In monotherapy clinical trials, there was dose- and exposure-related clinical improvement as well as risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). To balance the exposure-related potential benefits and risks, the recommended target dose range depending on clinical response and tolerability for guanfacine extended-release tablets is 0.05 to 0.12 mg/kg/day (total daily dose between 1 to 7 mg) (See Table 1 ). Table 1: Recommended Target Dose Range for Therapy with Guanfacine Extended-Release Tablets Doses above 4 mg/day have not been evaluated in children (ages 6 to 12 years) and doses above 7 mg/day have not been evaluated in adolescents (ages 13 to 17 years) Weight Target dose range (0.05 to 0.12 mg/kg/day) 25 to 33.9 kg 2 to 3 mg/day 34 to 41.4 kg 2 to 4 mg/day 41.5 to 49.4 kg 3 to 5 mg/day 49.5 to 58.4 kg 3 to 6 mg/day 58.5 to 91 kg 4 to 7 mg/day >91 kg 5 to 7 mg/day In the adjunctive trial which evaluated guanfacine extended-release tablets treatment with psychostimulants, the majority of patients reached optimal doses in the 0.05 to 0.12 mg/kg/day range. Doses above 4 mg/day have not been studied in adjunctive trials. 2.3 Switching from Immediate-Release Guanfacine to Guanfacine Extended-Release Tablets If switching from immediate-release guanfacine, discontinue that treatment, and titrate with guanfacine extended-release tablets following above recommended schedule. Do not substitute for immediate-release guanfacine tablets on a milligram-per-milligram basis, because of differing pharmacokinetic profiles. Guanfacine extended-release tablets have significantly reduced C max (60% lower), bioavailability (43% lower), and a delayed T max (3 hours later) compared to those of the same dose of immediate-release guanfacine [see Clinical Pharmacology ( 12.3 ) ] . 2.4 Maintenance Treatment Pharmacological treatment of ADHD may be needed for extended periods. Healthcare providers should periodically re-evaluate the long-term use of guanfacine extended-release tablets, and adjust weight-based dosage as needed. The majority of children and adolescents reach optimal doses in the 0.05 to 0.12 mg/kg/day range. Doses above 4 mg/day have not been evaluated in children (ages 6 to 12 years) and above 7 mg/day have not been evaluated in adolescents (ages 13 to 17 years) [see Clinical Studies ( 14 ) ] . 2.5 Discontinuation of Treatment Following discontinuation of guanfacine extended-release tablets, patients may experience increases in blood pressure and heart rate [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6 ) ]. Patients/caregivers should be instructed not to discontinue guanfacine extended-release tablets without consulting their health care provider. Monitor blood pressure and pulse when reducing the dose or discontinuing the drug. Taper the daily dose in decrements of no more than 1 mg every 3 to 7 days to minimize the risk of rebound hypertension. 2.6 Missed Doses When reinitiating patients to the previous maintenance dose after two or more missed consecutive doses, consider titration based on patient tolerability. 2.7 Dosage Adjustment with Concomitant Use of Strong and Moderate CYP3A4 Inhibitors or Inducers Dosage adjustments for guanfacine extended-release tablets are recommended with concomitant use of strong and moderate CYP3A4 inhibitors (e.g., ketoconazole), or CYP3A4 inducers (e.g., carbamazepine) ( Table 2 ) [see Drug Interactions ( 7 ) ] . Table 2: Guanfacine Extended-Release Tablets Dosage Adjustments for Patients Taking Concomitant CYP3A4 Inhibitors or Inducers Clinical Scenarios Starting guanfacine extended-release tablets while currently on a CYP3A4 modulator Continuing guanfacine extended-release tablets while adding a CYP3A4 modulator Continuing guanfacine extended-release tablets while stopping a CYP3A4 modulator CYP3A4 Strong and moderate Inhibitors Decrease guanfacine extended-release tablets dosage to half the recommended level. (see Table 1 ) Decrease guanfacine extended-release tablets dosage to half the recommended level. (see Table 1 ) Increase guanfacine extended-release tablets dosage to recommended level. (see Table 1 ) CYP3A4 Strong and moderate Inducers Consider increasing guanfacine extended-release tablets dosage up to double the recommended level. (see Table 1 ) Consider increasing guanfacine extended-release tablets dosage up to double the recommended level over 1 to 2 weeks. (see Table 1 ) Decrease guanfacine extended-release tablets dosage to recommended level over 1 to 2 weeks. (see Table 1 )

WARNINGS AND PRECAUTIONS Hypotension, bradycardia, syncope: Titrate slowly and monitor vital signs frequently in patients at risk for hypotension, heart block, bradycardia, syncope, cardiovascular disease, vascular disease, cerebrovascular disease or chronic renal failure. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Avoid concomitant use of drugs with additive effects unless clinically indicated. Advise patients to avoid becoming dehydrated or overheated ( 5.1 ). Sedation and somnolence: Occur commonly with guanfacine extended-release tablets. Consider the potential for additive sedative effects with CNS depressant drugs. Caution patients against operating heavy equipment or driving until they know how they respond to guanfacine extended-release tablets ( 5.2 ). Cardiac Conduction Abnormalities: May worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. Titrate slowly and monitor vital signs frequently ( 5.3 ). Rebound Hypertension: Abrupt discontinuation of guanfacine extended-release tablets can lead to clinically significant and persistent rebound hypertension. Subsequent hypertensive encephalopathy was also reported. To minimize the risk of rebound hypertension upon discontinuation, the total daily dose of guanfacine extended-release tablets should be tapered in decrements of no more than 1 mg every 3 to 7 days ( 5.4 ). 5.1 Hypotension, Bradycardia, and Syncope Treatment with guanfacine extended-release tablets can cause dose-dependent decreases in blood pressure and heart rate. Decreases were less pronounced over time of treatment. Orthostatic hypotension and syncope have been reported [see Adverse Reactions (6.1) ] . Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Titrate guanfacine extended-release tablets slowly in patients with a history of hypotension, and those with underlying conditions that may be worsened by hypotension and bradycardia; e.g., heart block, bradycardia, cardiovascular disease, vascular disease, cerebrovascular disease, or chronic renal failure. In 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, advise patients to avoid becoming dehydrated or overheated. Monitor blood pressure and heart rate, and adjust dosages accordingly in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. 5.2 Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies [see Adverse Reactions (6.1) ] . Before using guanfacine extended-release tablets with other centrally active depressants, consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with guanfacine extended-release tablets . Advise patients to avoid use with alcohol. 5.3 Cardiac Conduction Abnormalities The sympatholytic action of guanfacine extended-release tablets may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. Titrate guanfacine extended-release tablets slowly and monitor vital signs frequently in patients with cardiac conduction abnormalities or patients concomitantly treated with other sympatholytic drugs. 5.4 Rebound Hypertension In post marketing experience, abrupt discontinuation of guanfacine extended-release tablets has resulted in clinically significant and persistent rebound hypertension above baseline levels and increases in heart rate. Hypertensive encephalopathy has also been reported in association with rebound hypertension with both guanfacine extended-release tablets and immediate release guanfacine [see Adverse Reactions (6.2) ] . In these cases, high-dosage guanfacine was discontinued; concomitant stimulant use was also reported, which may potentially increase hypertensive response upon abrupt discontinuation of guanfacine. Children commonly have gastrointestinal illnesses that lead to vomiting, and a resulting inability to take medications, so they may be especially at risk for rebound hypertension. To minimize the risk of rebound hypertension upon discontinuation, the total daily dose of guanfacine extended-release tablets should be tapered in decrements of no more than 1 mg every 3 to 7 days [see Dosage and Administration (2.5) ] . Blood pressure and heart rate should be monitored when reducing the dose or discontinuing guanfacine extended-release tablets. If abrupt discontinuation occurs (especially with concomitant stimulant use), patients should be closely followed for rebound hypertension. 5.5 Risk of Allergic Reactions Due to Tartrazine This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

CONTRAINDICATIONS Guanfacine extended-release tablets are contraindicated in patients with a history of a hypersensitivity reaction to guanfacine extended-release tablets or their inactive ingredients, or other products containing guanfacine. Rash and pruritus have been reported. History of hypersensitivity to guanfacine extended-release tablets, its inactive ingredients, or other products containing guanfacine ( 4 ).

CLINICAL PHARMACOLOGY Guanfacine hydrochloride is an orally active antihypertensive agent whose principal mechanism of action appears to be stimulation of central α 2 -adrenergic receptors. By stimulating these 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. The dose-response relationship for blood pressure and adverse effects of guanfacine given once a day as monotherapy has been evaluated in patients with mild to moderate hypertension. In this study patients were randomized to placebo or to 0.5 mg, 1 mg, 2 mg, 3 mg, or 5 mg of guanfacine tablets. Results are shown in the following table. A useful effect was not observed overall until doses of 2 mg were reached, although responses in white patients were seen at 1 mg; 24 hour effectiveness of 1 mg to 3 mg doses was documented using 24 hour ambulatory monitoring. While the 5 mg dose added an increment of effectiveness, it caused an unacceptable increase in adverse reactions. Mean Changes (mm Hg) from Baseline in Seated Systolic and Diastolic Blood Pressure for Patients Completing 4 Weeks to 8 Weeks of Treatment with Guanfacine Monotherapy * S/D = Systolic/diastolic blood pressure Mean change S/D* Seated n = (range) Placebo 0.5 mg 1 mg 2 mg 3 mg 5 mg White Patients 11 to 30 -1/-5 -6/-8 -8/-9 -12/-11 -15/-12 -18/-16 Black Patients 8 to 28 -3/-5 0/-2 -3/-5 -7/-7 -8/-9 -19/-15 Controlled clinical trials in patients with mild to moderate hypertension who were receiving a thiazide-type diuretic have defined the dose-response relationship for blood pressure response and adverse reactions of guanfacine given at bedtime and have shown that the blood pressure response to guanfacine can persist for 24 hours after a single dose. In the 12-week placebo-controlled dose-response study, patients were randomized to placebo or to doses of 0.5 mg, 1 mg, 2 mg, and 3 mg of guanfacine, in addition to 25 mg chlorthalidone, each given at bedtime. The observed mean changes from baseline, tabulated below, indicate the similarity of response for placebo and the 0.5 mg dose. Doses of 1 mg, 2 mg, and 3 mg resulted in decreased blood pressure in the sitting position with no real differences among the three doses. In the standing position, there was some increase in response with dose. Mean Decreases (mm Hg) in Seated and Standing Blood Pressure for Patients Treated with Guanfacine in Combination with Chlorthalidone * S/D = Systolic/diastolic blood pressure Mean Change n = Placebo 63 0.5 mg 63 1 mg 64 2 mg 58 3 mg 59 SD * Seated -5/-7 -5/-6 -14/-13 -12/-13 -16/-13 SD Standing -3/-5 -5/-4 -11/-9 -9/-10 -15/-12 While most of the effectiveness of guanfacine in combination (and as monotherapy in white patients) was present at 1 mg, adverse reactions at this dose were not clearly distinguishable from those associated with placebo. Adverse reactions were clearly present at 2 mg and 3 mg (see ADVERSE REACTIONS ). In a second 12-week placebo-controlled study of 1 mg, 2 mg or 3 mg of guanfacine hydrochloride administered with 25 mg of chlorthalidone once daily, a significant decrease in blood pressure was maintained for a full 24 hours after dosing. While there was no significant difference between the 12 hour and 24 hour blood pressure readings, the fall in blood pressure at 24 hours was numerically smaller, suggesting possible escape of blood pressure in some patients and the need for individualization of therapy. In a double-blind, randomized trial, either guanfacine or clonidine was given at recommended doses with 25 mg chlorthalidone for 24 weeks and then abruptly discontinued. Results showed equal degrees of blood pressure reduction with the two drugs and there was no tendency for blood pressures to increase despite maintenance of the same daily dose of the two drugs. Signs and symptoms of rebound phenomena were infrequent upon discontinuation of either drug. Abrupt withdrawal of clonidine produced a rapid return of diastolic and especially systolic blood pressure to approximately pretreatment levels, with occasional values significantly greater than baseline, whereas guanfacine withdrawal produced a more gradual increase to pretreatment levels, but also with occasional values significantly greater than baseline. Pharmacodynamics Hemodynamic studies in man showed that the decrease in blood pressure observed after single-dose or long-term oral treatment with guanfacine was accompanied by a significant decrease in peripheral resistance and a slight reduction in heart rate (5 beats/min). Cardiac output under conditions of rest or exercise was not altered by guanfacine. Guanfacine hydrochloride lowered elevated plasma renin activity and plasma catecholamine levels in hypertensive patients, but this does not correlate with individual blood-pressure responses. Growth hormone secretion was stimulated with single oral doses of 2 mg and 4 mg of guanfacine. Long-term use of guanfacine tablets had no effect on growth hormone levels. Guanfacine had no effect on plasma aldosterone. A slight but insignificant decrease in plasma volume occurred after one month of guanfacine therapy. There were no changes in mean body weight or electrolytes. Pharmacokinetics Relative to an intravenous dose of 3 mg, the absolute oral bioavailability of guanfacine is about 80 %. Peak plasma concentrations occur from 1 hour to 4 hours with an average of 2.6 hours after single oral doses or at steady state. The area under the concentration-time curve (AUC) increases linearly with the dose. In individuals with normal renal function, the average elimination half-life is approximately 17 hours (range 10 hours to 30 hours). Younger patients tend to have shorter elimination half-lives (13 hours to 14 hours) while older patients tend to have half-lives at the upper end of the range. Steady state blood levels were attained within 4 days in most subjects. In individuals with normal renal function, guanfacine and its metabolites are excreted primarily in the urine. Approximately 50 % (40 % to 75 %) of the dose is eliminated in the urine as unchanged drug; the remainder is eliminated mostly as conjugates of metabolites produced by oxidative metabolism of the aromatic ring. The guanfacine-to-creatinine clearance ratio is greater than 1.0, which would suggest that tubular secretion of drug occurs. The drug is approximately 70 % bound to plasma proteins, independent of drug concentration. The whole body volume of distribution is high (a mean of 6.3 L/kg), which suggests a high distribution of drug to the tissues. The clearance of guanfacine in patients with varying degrees of renal insufficiency is reduced, but plasma levels of drug are only slightly increased compared to patients with normal renal function. When prescribing for patients with renal impairment, the low end of the dosing range should be used. Patients on dialysis also can be given usual doses of guanfacine hydrochloride as the drug is poorly dialyzed.