Intuniv

1 INDICATIONS AND USAGE INTUNIV ® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [see Clinical Studies (14) ]. INTUNIV is 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 , 14 ).

2 DOSAGE AND ADMINISTRATION Recommended dose: 1 mg to 7 mg (0.05 to 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 INTUNIV 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 INTUNIV 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 INTUNIV 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 INTUNIV Weight Target dose range (0.05 to 0.12 mg/kg/day) 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) 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 INTUNIV 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 INTUNIV If switching from immediate-release guanfacine, discontinue that treatment, and titrate with INTUNIV following above recommended schedule. Do not substitute for immediate-release guanfacine tablets on a milligram-per-milligram basis, because of differing pharmacokinetic profiles. INTUNIV has 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 INTUNIV, 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 INTUNIV, 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 INTUNIV 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 INTUNIV 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: INTUNIV Dosage Adjustments for Patients Taking Concomitant CYP3A4 Inhibitors or Inducers Clinical Scenarios Starting INTUNIV while currently on a CYP3A4 modulator Continuing INTUNIV while adding a CYP3A4 modulator Continuing INTUNIV while stopping a CYP3A4 modulator CYP3A4 Strong and moderate Inhibitors Decrease INTUNIV dosage to half the recommended level. (see Table 1 ) Decrease INTUNIV dosage to half the recommended level. (see Table 1 ) Increase INTUNIV dosage to recommended level. (see Table 1 ) CYP3A4 Strong and moderate Inducers Consider increasing INTUNIV dosage up to double the recommended level. (see Table 1 ) Consider increasing INTUNIV dosage up to double the recommended level over 1 to 2 weeks. (see Table 1 ) Decrease INTUNIV dosage to recommended level over 1 to 2 weeks. (see Table 1 )

4 CONTRAINDICATIONS INTUNIV is contraindicated in patients with a history of a hypersensitivity reaction to INTUNIV or its inactive ingredients, or other products containing guanfacine. Rash and pruritus have been reported. History of hypersensitivity to INTUNIV , its inactive ingredients, or other products containing guanfacine ( 4 ).

5 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 INTUNIV . 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 INTUNIV ( 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 INTUNIV 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 INTUNIV 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 INTUNIV 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 INTUNIV 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 INTUNIV 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 INTUNIV . Advise patients to avoid use with alcohol. 5.3 Cardiac Conduction Abnormalities The sympatholytic action of INTUNIV may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. Titrate INTUNIV 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 INTUNIV 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 INTUNIV 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 INTUNIV 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 INTUNIV. If abrupt discontinuation occurs (especially with concomitant stimulant use), patients should be closely followed for rebound hypertension.

7 DRUG INTERACTIONS Table 14 contains clinically important drug interactions with INTUNIV [see Clinical Pharmacology (12.3) ]. Table 14: Clinically Important Drug Interactions: Effect of other Drugs on INTUNIV Concomitant Drug Name or Drug Class Clinical Rationale and Magnitude of Drug Interaction Clinical Recommendation Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure Consider dose reduction [see Dosage and administration (2.7) ] Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure Consider dose increase [see Dosage and administration (2.7) ] Strong and moderate CYP3A4 inhibitors increase guanfacine exposure. Decrease INTUNIV to 50% of target dosage when coadministered with strong and moderate CYP3A4 inhibitors ( 2.7 ). Strong and moderate CYP3A4 inducers decrease guanfacine exposure. Based on patient response, consider titrating INTUNIV dosage up to double the target dosage over 1 to 2 weeks ( 2.7 ).

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Hypotension, bradycardia, and syncope [see Warnings and Precautions (5.1) ] Sedation and somnolence [see Warnings and Precautions (5.2) ] Cardiac conduction abnormalities [see Warnings and Precautions (5.3) ] Rebound Hypertension [see Warnings and Precautions (5.4) ] Most common adverse reactions (≥5% and at least twice placebo rate) in fixed-dose monotherapy ADHD trials in children and adolescents (6 to 17 years): hypotension, somnolence, fatigue, nausea, and lethargy ( 6.1 ) Flexible dose-optimization ADHD trials in children (6 to 12 years) and adolescents (13 to 17 years): somnolence, hypotension, abdominal pain, insomnia, fatigue, dizziness, dry mouth, irritability, nausea, vomiting, and bradycardia ( 6.1 ). Adjunctive treatment to psychostimulant ADHD trial in children and adolescents (6 to 17 years): somnolence, fatigue, insomnia, dizziness, and abdominal pain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect clinical trial exposure to INTUNIV in 2,825 patients. This includes 2,330 patients from completed studies in children and adolescents, ages 6 to 17 years and 495 patients in completed studies in adult healthy volunteers. The mean duration of exposure of 446 patients that previously participated in two 2-year, open-label long-term studies was approximately 10 months. Fixed Dose Trials Table 3: Percentage of Patients Experiencing Most Common (≥5% and at least twice the rate for placebo) Adverse Reactions in Fixed Dose Studies 1 and 2 INTUNIV (mg) Adverse Reaction Term Placebo (N=149) 1 mg The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. (N=61) 2 mg (N=150) 3 mg (N=151) 4 mg (N=151) All Doses of INTUNIV (N=513) Somnolence The somnolence term includes somnolence, sedation, and hypersomnia. 11% 28% 30% 38% 51% 38% Fatigue 3% 10% 13% 17% 15% 14% Hypotension The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). 3% 8% 5% 7% 8% 7% Dizziness 4% 5% 3% 7% 10% 6% Lethargy 3% 2% 3% 8% 7% 6% Nausea 2% 7% 5% 5% 6% 6% Dry mouth 1% 0% 1% 6% 7% 4% Table 4: Adverse Reactions Leading to Discontinuation (≥2% for all doses of INTUNIV and >rate than in placebo) in Fixed Dose Studies 1 and 2 INTUNIV (mg) Adverse Reaction Term Placebo (N=149) 1 mg The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. (N=61) 2 mg (N=150) 3 mg (N=151) 4 mg (N=151) All Doses of INTUNIV (N=513) n (%) n (%) n (%) n (%) n (%) n (%) Adverse reactions leading to discontinuation in ≥2% in any dose group but did not meet this criteria in all doses combined: hypotension (hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased), headache, and dizziness. Total patients 4 (3%) 2 (3%) 10 (7%) 15 (10%) 27 (18%) 54 (11%) Somnolence The somnolence term includes somnolence, sedation, and hypersomnia. 1 (1%) 2 (3%) 5 (3%) 6 (4%) 17 (11%) 30 (6%) Fatigue 0 (0%) 0 (0%) 2 (1%) 2 (1%) 4 (3%) 8 (2%) Table 5: Other Common Adverse Reactions (≥2% for all doses of INTUNIV and >rate than in placebo) in Fixed Dose Studies 1 and 2 INTUNIV (mg) Adverse Reaction Term Placebo (N=149) 1 mg The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. (N=61) 2 mg (N=150) 3 mg (N=151) 4 mg (N=151) All Doses of INTUNIV (N=513) Adverse reactions ≥2% for all doses of INTUNIV and >rate in placebo in any dose group but did not meet this criteria in all doses combined: insomnia (insomnia, initial insomnia, middle insomnia, terminal insomnia, sleep disorder), vomiting, diarrhea, abdominal/stomach discomfort (abdominal discomfort, epigastric discomfort, stomach discomfort), rash (rash, rash generalized, rash papular), dyspepsia, increased weight, bradycardia (bradycardia, sinus bradycardia), asthma (asthma, bronchospasm, wheezing), agitation, anxiety (anxiety, nervousness), sinus arrhythmia, blood pressure increased (blood pressure increased, blood pressure diastolic increased), and first degree atrioventricular block. Headache 19% 26% 25% 16% 28% 23% Abdominal Pain The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. 9% 10% 7% 11% 15% 11% Decreased Appetite 4% 5% 4% 9% 6% 6% Irritability 4% 5% 8% 3% 7% 6% Constipation 1% 2% 2% 3% 4% 3% Nightmare The nightmare term includes abnormal dreams, nightmare, and sleep terror. 0% 0% 0% 3% 4% 2% Enuresis The enuresis term includes enuresis, nocturia, and urinary incontinence. 1% 0% 1% 3% 2% 2% Affect Lability The affect lability term includes affect lability and mood swings. 1% 2% 1% 3% 1% 2% Monotherapy Flexible Dose Trials Table 6: Percentage of Patients Experiencing Most Common (≥5% and at least twice the rate for placebo) Adverse Reactions in the Monotherapy Flexible Dose Study 4 INTUNIV Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of INTUNIV (N=221) Somnolence The somnolence term includes somnolence, sedation, and hypersomnia. 15% 57% 54% 56% Abdominal Pain The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness 7% 8% 19% 14% Fatigue 3% 10% 11% 11% Irritability 3% 7% 7% 7% Nausea 1% 6% 5% 5% Dizziness 3% 6% 4% 5% Vomiting 2% 7% 4% 5% Hypotension The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). 0% 6% 4% 5% Decreased Appetite 3% 6% 3% 4% Enuresis The enuresis term includes enuresis, nocturia, and urinary incontinence. 1% 2% 5% 4% Table 7: Adverse Reactions Leading to Discontinuation (≥2% for all doses of INTUNIV and >rate than in placebo) in Monotherapy Flexible Dose Study 4 INTUNIV Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of INTUNIV (N=221) n (%) n (%) n (%) n (%) Adverse reactions leading to discontinuation in ≥2% in any dose group but did not meet this criteria in all doses combined: fatigue Total patients 0 (0%) 8 (7%) 7 (6%) 15 (7%) Somnolence The somnolence term includes somnolence, sedation, and hypersomnia. 0 (0%) 4 (4%) 3 (3%) 7 (3%) Table 8: Other Common Adverse Reactions (≥2% for all doses of INTUNIV and >rate than in placebo) in the Monotherapy Flexible Dose Study 4 INTUNIV Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of INTUNIV (N=221) Adverse reactions ≥2% for all doses of INTUNIV and >rate in placebo in any dose group but did not meet this criteria in all doses combined: affect lability (affect lability, mood swings), increased weight, syncope/loss of consciousness (loss of consciousness, presyncope, syncope), dyspepsia, tachycardia (tachycardia, sinus tachycardia), and bradycardia (bradycardia, sinus bradycardia). Headache 11% 18% 16% 17% Insomnia The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. 6% 8% 6% 7% Diarrhea 4% 4% 6% 5% Lethargy 0% 4% 3% 3% Constipation 2% 2% 4% 3% Dry Mouth 1% 3% 3% 3% Table 9: Percentage of Patients Experiencing Most Common (≥5% and at least twice the rate for placebo) Adverse Reactions in the Monotherapy Flexible Dose Study 5 Adverse Reaction Term Placebo (N=155) All Doses of INTUNIV (N=157) Somnolence The somnolence term includes somnolence, sedation, and hypersomnia. 23% 54% Insomnia The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. 6% 13% Hypotension The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). 3% 9% Dry Mouth 0% 8% Postural Dizziness 2% 5% Bradycardia The bradycardia term includes bradycardia and sinus bradycardia. 0% 5% There were no specific adverse reactions ≥2% in any treatment group that led to discontinuation in the monotherapy flexible dose study (Study 5). Table 10: Other Common Adverse Reactions (≥2% for all doses of INTUNIV and >rate than in placebo) in the Monotherapy Flexible Dose Study 5 INTUNIV Adverse Reaction Term Placebo (N=155) All Doses of INTUNIV (N=157) Adverse reactions ≥2% for all doses of INTUNIV and >rate in placebo in any dose group but did not meet this criteria in all doses combined: nausea, diarrhea, vomiting, and depression (depressed mood, depression, depressive symptom). Headache 18% 27% Fatigue 12% 22% Dizziness 10% 16% Decreased Appetite 14% 15% Abdominal Pain The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. 8% 12% Irritability 4% 7% Anxiety The anxiety term includes anxiety and nervousness. 3% 5% Rash The rash term includes rash, rash generalized, and rash papular. 1% 3% Constipation 0% 3% Increased Weight 2% 3% Abdominal/Stomach Discomfort The abdominal/stomach discomfort term includes abdominal discomfort, epigastric discomfort, and stomach discomfort. 1% 2% Pruritus 1% 2% Adjunctive Trial Table 11: Percentage of Patients Experiencing Most Common (≥5% and at least twice the rate for placebo) Adverse Reactions in the Short-Term Adjunctive Study 3 INTUNIV + stimulant Adverse Reaction Term Placebo+ stimulant (N=153) AM (N=150) PM (N=152) All Doses (N=302) Somnolence The somnolence term includes somnolence, sedation, and hypersomnia. 7% 18% 18% 18% Insomnia The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. 6% 10% 14% 12% Abdominal Pain The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. 3% 8% 12% 10% Fatigue 3% 12% 7% 10% Dizziness 4% 10% 5% 8% Decreased Appetite 4% 7% 8% 7% Nausea 3% 3% 7% 5% There were no specific adverse reactions ≥2% in any treatment group that led to discontinuation in the short-term adjunctive study (Study 3). Table 12: Other Common Adverse Reactions (≥2% for all doses of INTUNIV and >rate than in placebo) in the Short-Term Adjunctive Study 3 INTUNIV + stimulant Adverse Reaction Term Placebo (N=153) AM (N=150) PM (N=152) All Doses of INTUNIV (N=302) Adverse reactions ≥2% for all doses of INTUNIV and >rate in placebo in any dose group but did not meet this criteria in all doses combined: irritability, vomiting, asthma (asthma, bronchospasm, wheezing), and enuresis (enuresis, nocturia, urinary incontinence). Headache 13% 21% 21% 21% Diarrhea 1% 4% 3% 4% Hypotension The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased. 0% 4% 2% 3% Constipation 0% 2% 3% 2% Affect Lability The affect lability term includes affect lability and mood swings. 1% 3% 2% 2% Dry Mouth 0% 1% 3% 2% Bradycardia The bradycardia term includes bradycardia and sinus bradycardia. 0% 1% 3% 2% Postural Dizziness 0% 1% 3% 2% Rash The rash term includes rash, rash generalized, and rash papular. 1% 1% 2% 2% Nightmare The nightmare term includes abnormal dreams, nightmare, and sleep terror. 1% 2% 1% 2% Tachycardia The tachycardia term includes tachycardia and sinus tachycardia. 1% 2% 1% 2% Effects on Blood Pressure and Heart Rate In the monotherapy pediatric, short-term, controlled trials (Studies 1 and 2), the maximum mean changes from baseline in seated systolic blood pressure, diastolic blood pressure, and pulse were −5.4 mmHg, −3.4 mmHg, and −5.5 bpm, respectively, for all doses combined (generally one week after reaching target doses). For the respective fixed doses 1 mg/day, 2 mg/day, 3 mg/day, or 4 mg/day the maximum mean changes in seated systolic blood pressure were -4.3 mmHg, -5.5 mmHg, -5.4 mmHg, and -8.2 mmHg. For these respective fixed doses the maximum mean changes in seated diastolic blood pressure were -3.4 mmHg, -3.3 mmHg, -4.4 mmHg, and -5.4 mmHg. For these respective fixed doses the maximum mean changes in seated pulse were -4.8 bpm, -3.1 bpm, -6.5 bpm, and -8.6 bpm. Decreases in blood pressure and heart rate were usually modest and asymptomatic; however, hypotension and bradycardia can occur. Hypotension was reported as an adverse reaction for 7% of the INTUNIV group and 3% of the placebo group. This includes orthostatic hypotension, which was reported for 1% of the INTUNIV group and none in the placebo group. These findings were generally similar in the monotherapy flexible dose trials (Studies 4 and 5). In the adjunctive trial, hypotension (3%) and bradycardia (2%) were observed in patients treated with INTUNIV 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 patients in the clinical program. The majority of these cases occurred in the long-term, open-label studies. Discontinuation of Treatment Blood pressure and pulse may increase above baseline values following discontinuation of INTUNIV. In five studies of children and adolescents [see Clinical Studies (14) ] , increases in mean systolic and diastolic blood pressure averaging approximately 3 mmHg and increases in heart rate averaging 5 beats per minute above original baseline were observed upon discontinuation with tapering of INTUNIV. In a maintenance of efficacy study, increases in blood pressure and heart rate above baseline slowly diminished over the follow up period, which ranged between 3 and 26 weeks post final dose; the estimated average time to return to baseline was between six and twelve months. In this study, the increases in blood pressure and pulse were not considered serious or associated with adverse events. However, individuals may have larger increases than reflected by the mean changes. In postmarketing experience, following abrupt discontinuation of INTUNIV, rebound hypertension and hypertensive encephalopathy have been reported [see Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] . Effects on Height, Weight, and Body Mass Index (BMI) Patients taking INTUNIV demonstrated similar growth compared to normative data. Patients taking INTUNIV had a mean increase in weight of 0.5 kg compared to those receiving placebo over a comparable treatment period. Patients receiving INTUNIV for at least 12 months in open-label studies gained an average of 8 kg in weight and 8 cm (3 in) 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. Other Adverse Reactions Observed in Clinical Studies Table 13 includes additional adverse reactions observed in short-term, placebo-controlled and long-term, open-label clinical studies not included elsewhere in section 6.1, listed by organ system. Table 13: Other adverse reactions observed in clinical studies Body System Adverse Reaction Cardiac Atrioventricular block General Asthenia, chest pain Immune System Disorders Hypersensitivity Investigations Increased alanine amino transferase Nervous system Convulsion Renal Increased urinary frequency Vascular Hypertension, pallor 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of 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. Less frequent, possibly guanfacine-related events observed in the post-marketing study and/or reported spontaneously, not included in section 6.1, include: General: edema, malaise, tremor Cardiovascular: palpitations, tachycardia, rebound hypertension, hypertensive encephalopathy Central Nervous System: paresthesias, vertigo Eye Disorders: blurred vision Musculo-Skeletal System: arthralgia, leg cramps, leg pain, myalgia Psychiatric: confusion, hallucinations Reproductive System, Male: erectile dysfunction Respiratory System: dyspnea Skin and Appendages: alopecia, dermatitis, exfoliative dermatitis, pruritus, rash Special Senses: alterations in taste

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including INTUNIV, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388. Risk Summary Available data with guanfacine over decades of use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. However, use of guanfacine in pregnant women over this time has been infrequent. In animal reproduction studies, rabbits and rats exposed to 3 and 4 times the maximum recommended human dose (MRHD), respectively, showed no adverse outcomes. However, higher doses were associated with reduced fetal survival and maternal toxicity ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Reproduction studies conducted in rats have shown that guanfacine crosses the placenta. However, administration of guanfacine to rabbits and rats during organogenesis at 3 (rabbit) and 4 (rat) times the MRHD of 0.12 mg/kg/day on a mg/m 2 basis resulted in no evidence of harm to the fetus. Higher doses (13.5 times the MRHD in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity.