Guanfacine Extended-Release

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: To report SUSPECTED ADVERSE REACTIONS, contact TWi Pharmaceuticals, Inc. 1-844-518-2989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 TWi Pharmaceuticals, Inc. 1-844-518-2989 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. 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 Guanfacine Extended-Release Tablets (mg) Adverse Reaction Term Placebo (N=149) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of guanfacine extended-release tablets (N=513) Somnolence a 11% 28% 30% 38% 51% 38% Fatigue 3% 10% 13% 17% 15% 14% Hypotension b 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% *The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). Table 4: Adverse Reactions Leading to Discontinuation (≥ 2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in Fixed Dose Studies 1 and 2 Guanfacine Extended-Release Tablets (mg) Adverse Reaction Term Placebo (N=149) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of guanfacine extended-release tablets (N=513) n (%) n (%) n (%) n (%) n (%) n (%) Total patients 4 (3%) 2 (3%) 10 (7%) 15 (10%) 27 (18%) 54 (11%) Somnolence a 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%) 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. * The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. a: The somnolence term includes somnolence, sedation, and hypersomnia. Table 5: Other Common Adverse Reactions (≥ 2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in Fixed Dose Studies 1 and 2 Guanfacine Extended-Release Tablets (mg) Adverse Reaction Term Placebo (N=149) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of guanfacine extended-release tablets (N=513) Headache 19% 26% 25% 16% 28% 23% Abdominal Pain a 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 b 0% 0% 0% 3% 4% 2% Enuresis c 1% 0% 1% 3% 2% 2% Affect Lability d 1% 2% 1% 3% 1% 2% Adverse reactions ≥ 2% for all doses of guanfacine extended-release tablets 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. * The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. a: The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. b: The nightmare term includes abnormal dreams, nightmare, and sleep terror. c: The enuresis term includes enuresis, nocturia, and urinary incontinence. d: The affect lability term includes affect lability and mood swings. 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 Guanfacine Extended-Release Tablets Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of guanfacine extended-release tablets (N=221) Somnolence a 15% 57% 54% 56% Abdominal Pain b 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 c 0% 6% 4% 5% Decreased Appetite 3% 6% 3% 4% Enursis d 1% 2% 5% 4% a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness c: The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). d: The enuresis term includes enuresis, nocturia, and urinary incontinence. Table 7: Adverse Reactions Leading to Discontinuation (≥ 2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in Monotherapy Flexible Dose Studies 4 Guanfacine Extended-Release Tablets Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of guanfacine extended-release tablets (N=221) n (%) n (%) n (%) n (%) Total patients 0 (0%) 8 (7%) 7 (6%) 15 (7%) Somnolence a 0 (0%) 4 (4%) 3 (3%) 7 (3%) Adverse reactions leading to discontinuation in ≥ 2% in any dose group but did not meet this criteria in all doses combined: fatigue a: The somnolence term includes somnolence, sedation, and hypersomnia. Table 8: Other Common Adverse Reactions (≥2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in the Monotherapy Flexible Dose Study 4 Adverse reactions ≥ 2% for all doses of guanfacine extended-release tablets and > rate in placebo in any dose group but did not meet this criteria inall doses combined: affect lability (affect lability, mood swings), increased weight, syncope/loss of consciousness (loss ofconsciousness, presyncope, syncope), dyspepsia, tachycardia (tachycardia, sinus tachycardia), and bradycardia (bradycardia, sinus bradycardia). a: The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. Guanfacine Extended-Release Tablets Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of guanfacine extended-release tablets (N=221) Headache 11% 18% 16% 17% Insomnia a 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 guanfacine extended-release tablets (N=157) Somnolence a 23% 54% Insomnia b 6% 13% Hypotension c 3% 9% Dry Mouth 0% 8% Postural Dizziness 2% 5% Bradycardia d 0% 5% a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. c: The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). d: The bradycardia term includes bradycardia and sinus bradycardia. Table 10: Other Common Adverse Reactions (≥ 2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in the Monotherapy Flexible Dose Study 5 Guanfacine Extended-Release Tablets Adverse Reaction Term Placebo (N=155) All Doses of guanfacine extended-release tablets (N=157) Headache 18% 27% Fatigue 12% 22% Dizziness 10% 16% Decreased Appetite 14% 15% Abdominal Pain a 8% 12% Irritability 4% 7% Anxiety b 3% 5% Rash c 1% 3% Constipation 0% 3% Increased Weight 2% 3% Abdominal/Stomach Discomfort d 1% 2% Pruritus 1% 2% Adverse reactions ≥ 2% for all doses of guanfacine extended-release tablets 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). a: The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. b: The anxiety term includes anxiety and nervousness. c: The rash term includes rash, rash generalized, and rash papular. d: The abdominal/stomach discomfort term includes abdominal discomfort, epigastric discomfort, and stomach discomfort. 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 Guanfacine Extended-Release Tablets + stimulant Adverse Reaction Term Placebo+stimulant (N=153) AM (N=150) PM (N=152) All Doses (N=302) Somnolence a 7% 18% 18% 18% Insomnia b 6% 10% 14% 12% Abdominal Pain c 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% a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. c: The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. 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 guanfacine extended-release tablets and > rate than in placebo) in the Short-Term Adjunctive Study 3 Guanfacine Extended-Release Tablets + stimulant Adverse Reaction Term Placebo (N=153) AM (N=150) PM (N=152) All Doses of Guanfacine Extended-Release Tablets (N=302) Headache 13% 21% 21% 21% Diarrhea 1% 4% 3% 4% Hypotension a 0% 4% 2% 3% Constipation 0% 2% 3% 2% Affect Lability b 1% 3% 2% 2% Dry Mouth 0% 1% 3% 2% Bradycardia c 0% 1% 3% 2% Postural Dizziness 0% 1% 3% 2% Rash d 1% 1% 2% 2% Nightmare e 1% 2% 1% 2% Tachycardia f 1% 2% 1% 2% Adverse reactions ≥ 2% for all doses of guanfacine extended-release tablets 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). a: The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased. b: The affect lability term includes affect lability and mood swings. c: The bradycardia term includes bradycardia and sinus bradycardia. d: The rash term includes rash, rash generalized, and rash papular. e: The nightmare term includes abnormal dreams, nightmare, and sleep terror. f: The tachycardia term includes tachycardia and sinus tachycardia. 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 -4.8bpm, -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 guanfacine extended-release tabletsgroup and 3% of the placebo group. This includes orthostatic hypotension, which was reported for 1% of the guanfacine extended-release tablets 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 guanfacine extended-release tablets 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 guanfacine extended-release tablets. 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 guanfacine extended-release tablets. 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 guanfacine extended-release tablets, 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 guanfacine extended-release tablets demonstrated similar growth compared to normative data. Patients taking guanfacine extended-release tablets had a mean increase in weight of 0.5 kg compared to those receiving placebo over a comparable treatment period. Patients receiving guanfacine extended-release tablets for at least 12 months in open-label studies gained an average of 8 kg inweight 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 guanfacine extended-release tablets. 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. 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

4 CONTRAINDICATIONS Guanfacine extended-release tablets are contraindicated in patients with a history of a hypersensitivity reaction to guanfacine extended-release tablets or its 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 ) .

11 DESCRIPTION Guanfacine extended-release tablets are 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 C 9 H 9 Cl 2 N 3 O·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 microcrystalline cellulose, hypromellose, polyvinyl acetate, povidone, lactose monohydrate, magnesium stearate, sodium lauryl sulfate and silica. In addition, the 3-mg and 4-mg tablets also contain FD&C Blue #1. molecular-structure.jpg

2 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. Table 1: Recommended Target Dose Range for Therapy with Guanfacine Extended-Release Tablets 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 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) 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. 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 ( 6.1 ) ]. 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 )

1 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 central alpha 2A -adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapyand as adjunctive therapy to stimulant medications ( 1 , 14 ) .

9.1 Controlled Substance Guanfacine extended-release tablets are not controlled substance and have no known potential for abuse or dependence.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Guanfacine extended-release tablets are not controlled substance and have no known potential for abuse or dependence.

10 OVERDOSAGE Symptoms Postmarketing 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. Treatment Consult a Certified Poison Control Center by calling 1-800-222-1222 for up-to-date guidance and advice. Management of guanfacine extended-release tablets 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.

7 DRUG INTERACTIONS Table 14 contains clinically important drug interactions with guanfacine extended-release tablets [see Clinical Pharmacology ( 12.3 ) ] . Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release Tablets 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 guanfacine extended-release tablets 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 guanfacine extended-release tablets dosage up to double the target dosage over 1 to 2 weeks ( 2.7 ) .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Guanfacine is a central alpha 2A -adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) stimulant. The mechanism of action of guanfacine in ADHD is not known. 12.2 Pharmacodynamics Guanfacine is a selective central alpha 2A -adrenergic receptor agonist in that it has a 15 to 20 times higher affinity for this receptor subtype than for the alpha 2B or alpha 2C subtypes. In a thorough QT study, the administration of two dose levels of immediate-release guanfacine (4 mg and 8 mg) produced concentrations approximately 2 to 4 times the concentrations observed with the maximum recommended dose of guanfacine extended-release tablets of 0.12 mg/kg. Guanfacine was not shown to prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics Absorption and Distribution Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration. After oral administration of guanfacine extended-release tablets the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD. Immediate-release guanfacine and guanfacine extended-release tablets have different pharmacokinetic characteristics; dose substitution on a milligram per milligram basis will result in differences in exposure. A comparison across studies suggests that the C max is 60% lower and AUC 0-∞ 43% lower, respectively, for guanfacine extended-release tablets compared to immediate-release guanfacine. Therefore, the relative bioavailability of guanfacine extended-release tablets to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of guanfacine extended-release tablets 1 mg once daily and immediate-release guanfacine 1 mg once daily are summarized in Table 15 . Table 15: Comparison of Pharmacokinetics: Guanfacine Extended-Release Tablets vs. Immediate release Guanfacine in Adults Parameter Guanfacine Extended-Release Tablets 1 mg once daily (n=52) Immediate-release guanfacine 1 mg once daily (n=12) C max (ng/mL) 1.0 ± 0.3 2.5 ± 0.6 AUC 0-∞ (ng∙h/mL) 32 ± 9 56 ± 15 t max (h) 6.0 (4.0 - 8.0) 3.0 (1.5-4.0) t ½ (h) 18 ± 4 16 ± 3 Note: Values are mean +/- SD, except for t max which is median (range) Figure 1: Comparison of Pharmacokinetics: Guanfacine Extended-Release Tablets vs. Immediate-release guanfacine in Adults Exposure to guanfacine was higher in children (ages 6 to 12) compared to adolescents (ages 13 to 17) and adults. After oral administration of multiple doses of guanfacine extended-release tablets 4 mg, the C max 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 to 12) and adolescents (ages 13 to 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 guanfacine extended-release tablets 4 mg was administered with a high-fat breakfast. The mean exposure increased (C max ~75% and AUC ~40%) compared to dosing in a fasted state. Dose Proportionality Following administration of guanfacine extended-release tablets in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, C max and AUC 0-∞ 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,CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5); guanfacine is also not an inducer of CYP3A, CYP1A2 and CYP2B6. Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors. Guanfacine inhibits MATE1 and OCT1, but does not inhibit BSEP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, or MATE2K. Guanfacine is a substrate of OCT1 and OCT2, but not BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, or MATE2. Concomitant administration of guanfacine with OCT1 substrates might potentially increase the exposure of these OCT1 substrates. Studies in Specific Populations 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. 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 [see Hepatic Impairment ( 8.7 ) ] . Drug Interaction Studies Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be affected significantly by CYP3A4 inhibitors or inducers ( Figure 2 ). Figure 2: Effect of Other Drugs on the Pharmacokinetics (PK) of Guanfacine Extended-Release Tablets Guanfacine does not significantly affect exposures of methylphenidate and lisdexamfetamine when coadministered ( Figure 3 ). Figure 3: Effect of Guanfacine Extended-Release Tablets on the Pharmacokinetics (PK) of Other Drugs figure-1.jpg figure-2.jpg figure-3.jpg

12.1 Mechanism of Action Guanfacine is a central alpha 2A -adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) stimulant. The mechanism of action of guanfacine in ADHD is not known.

12.2 Pharmacodynamics Guanfacine is a selective central alpha 2A -adrenergic receptor agonist in that it has a 15 to 20 times higher affinity for this receptor subtype than for the alpha 2B or alpha 2C subtypes. In a thorough QT study, the administration of two dose levels of immediate-release guanfacine (4 mg and 8 mg) produced concentrations approximately 2 to 4 times the concentrations observed with the maximum recommended dose of guanfacine extended-release tablets of 0.12 mg/kg. Guanfacine was not shown to prolong the QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics Absorption and Distribution Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration. After oral administration of guanfacine extended-release tablets the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD. Immediate-release guanfacine and guanfacine extended-release tablets have different pharmacokinetic characteristics; dose substitution on a milligram per milligram basis will result in differences in exposure. A comparison across studies suggests that the C max is 60% lower and AUC 0-∞ 43% lower, respectively, for guanfacine extended-release tablets compared to immediate-release guanfacine. Therefore, the relative bioavailability of guanfacine extended-release tablets to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of guanfacine extended-release tablets 1 mg once daily and immediate-release guanfacine 1 mg once daily are summarized in Table 15 . Table 15: Comparison of Pharmacokinetics: Guanfacine Extended-Release Tablets vs. Immediate release Guanfacine in Adults Parameter Guanfacine Extended-Release Tablets 1 mg once daily (n=52) Immediate-release guanfacine 1 mg once daily (n=12) C max (ng/mL) 1.0 ± 0.3 2.5 ± 0.6 AUC 0-∞ (ng∙h/mL) 32 ± 9 56 ± 15 t max (h) 6.0 (4.0 - 8.0) 3.0 (1.5-4.0) t ½ (h) 18 ± 4 16 ± 3 Note: Values are mean +/- SD, except for t max which is median (range) Figure 1: Comparison of Pharmacokinetics: Guanfacine Extended-Release Tablets vs. Immediate-release guanfacine in Adults Exposure to guanfacine was higher in children (ages 6 to 12) compared to adolescents (ages 13 to 17) and adults. After oral administration of multiple doses of guanfacine extended-release tablets 4 mg, the C max 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 to 12) and adolescents (ages 13 to 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 guanfacine extended-release tablets 4 mg was administered with a high-fat breakfast. The mean exposure increased (C max ~75% and AUC ~40%) compared to dosing in a fasted state. Dose Proportionality Following administration of guanfacine extended-release tablets in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, C max and AUC 0-∞ 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,CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5); guanfacine is also not an inducer of CYP3A, CYP1A2 and CYP2B6. Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors. Guanfacine inhibits MATE1 and OCT1, but does not inhibit BSEP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, or MATE2K. Guanfacine is a substrate of OCT1 and OCT2, but not BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, or MATE2. Concomitant administration of guanfacine with OCT1 substrates might potentially increase the exposure of these OCT1 substrates. Studies in Specific Populations 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. 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 [see Hepatic Impairment ( 8.7 ) ] . Drug Interaction Studies Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be affected significantly by CYP3A4 inhibitors or inducers ( Figure 2 ). Figure 2: Effect of Other Drugs on the Pharmacokinetics (PK) of Guanfacine Extended-Release Tablets Guanfacine does not significantly affect exposures of methylphenidate and lisdexamfetamine when coadministered ( Figure 3 ). Figure 3: Effect of Guanfacine Extended-Release Tablets on the Pharmacokinetics (PK) of Other Drugs figure-1.jpg figure-2.jpg figure-3.jpg

20220401

2

3 DOSAGE FORMS AND STRENGTHS 1 mg, 2 mg, 3 mg and 4 mg extended-release tablets Extended-release tablets: 1 mg, 2 mg, 3 mg and 4 mg ( 3 )

Guanfacine Extended-Release Guanfacine GUANFACINE GUANFACINE HYPROMELLOSE, UNSPECIFIED POLYVINYL ACETATE PHTHALATE POVIDONE K12 SODIUM LAURYL SULFATE SILICON DIOXIDE LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE A533;1;mg Guanfacine Extended-Release Guanfacine GUANFACINE GUANFACINE HYPROMELLOSE, UNSPECIFIED POLYVINYL ACETATE PHTHALATE POVIDONE K12 SODIUM LAURYL SULFATE SILICON DIOXIDE LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE A534;2;mg Guanfacine Extended-Release Guanfacine GUANFACINE GUANFACINE FD&C BLUE NO. 1 HYPROMELLOSE, UNSPECIFIED POLYVINYL ACETATE PHTHALATE POVIDONE K12 SODIUM LAURYL SULFATE SILICON DIOXIDE LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE A536;3;mg Guanfacine Extended-Release Guanfacine GUANFACINE GUANFACINE FD&C BLUE NO. 1 HYPROMELLOSE, UNSPECIFIED POLYVINYL ACETATE PHTHALATE POVIDONE K12 SODIUM LAURYL SULFATE SILICON DIOXIDE LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE A538;4;mg

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis

ANDA201408

Guanfacine Extended-Release

Guanfacine

71205-944

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 71205-944-30 Guanfacine Extended-Release Tablets 1 mg 30-count 71205-944-30

17 PATIENT COUNSELING INFORMATION Advise the patient to read theFDA-approved patient labeling (Patient Information). Dosing and Administration Instruct patients to swallow guanfacine extended-release tablets whole with water, milk or other liquid. Tablets should not be crushed, chewed or broken prior to administration because this may increase the rate of release of the active drug. Patients should not take guanfacine extended-release tablets together with a high-fat meal, since this can raise blood levels of guanfacine extended-release tablets. Instruct the parent or caregiver to supervise the child or adolescent taking guanfacine extended-release tablets and to keep the bottle of tablets out of reach of children. Adverse Reactions 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 guanfacine extended-release tablets [see Warnings and Precautions ( 5.2 ) ] . 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 health care provider. Patient Information Guanfacine Extended-Release Tablets (gwahn-fa-seen) Read the Patient Information that comes with guanfacine extended-release tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment. What are guanfacine extended-release tablets? Guanfacine extended-release tablets are prescription medicine used to treat the symptoms of attention deficit hyperactivity disorder (ADHD). Guanfacine extended-release tablets may be used alone or with ADHD stimulant medicines. Guanfacine extended-release tablets are not central nervous system (CNS) stimulant. It is not known if guanfacine extended-release tablets are safe and effective in children younger than 6 years of age. Who should not take guanfacine extended-release tablets? Do not take guanfacine extended-release tablets if you are allergic to guanfacine or any of the ingredients in guanfacine extended-release tablets. See the end of this leaflet for a complete list of ingredients in guanfacine extended-release tablets. What should I tell my doctor before taking guanfacine extended-release tablets? Before you take guanfacine extended-release tablets, tell your doctor if you: • have heart problems or a low heart rate • have fainted • have low or high blood pressure • have liver or kidney problems • have any other medical conditions • are pregnant or plan to become pregnant. It is not known if guanfacine extended-release tablets will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant. • are breastfeeding or plan to breastfeed. It is not known if guanfacine extended-release tablets pass into your breast milk. Talk to your doctor about the best way to feed your baby while taking guanfacine extended-release tablets. Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Guanfacine extended-release tablets may affect the way other medicines work, and other medicines may affect how guanfacine extended-release tablets work. Especially tell your doctor if you take: • ketoconazole • medicines that can affect enzyme metabolism • high blood pressure medicine • sedatives • benzodiazepines • barbiturates • antipsychotics 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. How should I take guanfacine extended-release tablets? • Take guanfacine extended-release tablets exactly as your doctor tells you. • Your doctor may change your dose. Do not change your dose of guanfacine extended-release tablets without talking to your doctor. • Do not stop taking guanfacine extended-release tablets without talking to your doctor. • Try not to miss your dose of guanfacine extended-release tablets. If you miss a dose of guanfacine extended-release tablets, take the next dose at your regular time. If you miss 2 or more doses, talk to your doctor, as you may need to restart guanfacine extended-release tablets with a lower dose. • Do not take a double dose to make up for a missed dose. • Guanfacine extended-release tablets should be taken 1 time a day in the morning or in the evening, either alone or in combination with an ADHD stimulant medicine that your doctor may prescribe. Your doctor will tell you when to take guanfacine extended-release tablets and when to take your ADHD stimulant medication. • Guanfacine extended-release tablets should be swallowed whole with a small amount of water, milk, or other liquid. • Do not crush, chew, or break guanfacine extended-release tablets. Tell your doctor if you cannot swallow guanfacine extended-release tablets whole. • Do not take guanfacine extended-release tablets with a high-fat meal. • Your doctor will check your blood pressure and heart rate while you take guanfacine extended-release tablets. • If you take too much guanfacine extended-release tablets, call your local Poison Control Center at 1-800-222-1222 or go to the nearest emergency room right away. What should I avoid while taking guanfacine extended-release tablets? • Do not drive, operate heavy machinery, or do other dangerous activities until you know how guanfacine extended-release tablets affect you. Guanfacine extended-release tablets can slow your thinking and motor skills. • Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking guanfacine extended-release tablets until you talk with your doctor. Guanfacine extended-release tablets taken with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse. • Do not become dehydrated or overheated. This may increase your chance of having low blood pressure or fainting while taking guanfacine extended-release tablets. • Do not suddenly stop guanfacine extended-release tablets. Tell your healthcare provider if you have been vomiting and cannot take guanfacine extended-release tablets, you may be at risk for rebound hypertension. What are the possible side effects of guanfacine extended-release tablets? Guanfacine extended-release tablets may cause serious side effects including: • low blood pressure • low heart rate • fainting • sleepiness • increased blood pressure and heart rate after suddenly stopping guanfacine extended-release tablets (rebound hypertension). Suddenly stopping guanfacine extended-release tablets can cause increased blood pressure and heart rate and other withdrawal symptoms such as headache, confusion, nervousness, agitation, and tremors. If these symptoms continue to get worse and are left untreated, it could lead to a very serious condition including very high blood pressure, feeling very sleepy or tired, severe headache, vomiting, vision problems, seizures. Get medical help right away, if you have any of the symptoms listed above. The most common side effects of guanfacine extended-release tablets include: • sleepiness • tiredness • trouble sleeping • low blood pressure • nausea • stomach pain • dizziness • dry mouth • irritability • vomiting • slow heart rate 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 guanfacine extended-release tablets. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to TWi Pharmaceuticals, inc. 1-844-518-2989 or FDA at 1-800-FDA-1088 or www. fda.gov/medwatch. How should I store guanfacine extended-release tablets? • Store guanfacine extended-release tablets at 20º to 25°C (68º to 77°F). [see USP Controlled Room Temperature]. Keep guanfacine extended-release tablets and all medicines out of the reach of children. General Information about the safe and effective use guanfacine extended-release tablets Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use guanfacine extended-release tablets for a condition for which it was not prescribed. Do not give guanfacine extended-release tablets 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 guanfacine extended-release tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about guanfacine extended-release tablets that is written for health professionals. What are the ingredients in guanfacine extended-release tablets? Active ingredient: guanfacine hydrochloride Inactive ingredients: microcrystalline cellulose, hypromellose, polyvinyl acetate, povidone, lactose monohydrate, magnesium stearate, sodium lauryl sulfate and silica. In addition, the 3 mg and 4 mg tablets also contain FD&C Blue #1. This Patient Information has been approved by the U.S. Food and Drug Administration. All other trademarks are the property of their respective owners. Manufactured for: TWi Pharmaceuticals USA, Inc. Paramus, NJ 07652 Manufactured by: TWi Pharmaceuticals, Inc. Taoyuan City, 32063, Taiwan Revised: 10/19 Repackaged and Relabeled by: Proficient Rx LP Thousand Oaks, CA 91320 OS24979533 figure-5

14 CLINICAL STUDIES Efficacy of guanfacine extended-release tablets in the treatment of ADHD was established in children and adolescents (6 to 17 years) in: Studies 1 and 2: Fixed-dose Guanfacine Extended-Release Tablets Monotherapy Study 1 (301 study) was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with guanfacine extended-release tablets (2 mg, 3 mg and 4 mg) was evaluated for 5 weeks (n=345) in children and adolescents aged 6 to 17 years. Study 2 (304 study) was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with guanfacine extended-release tablets (1 mg, 2 mg, 3 mg and 4 mg) was evaluated for 6 weeks (n=324) in children and adolescents aged 6 to 17 years. In both studies, randomized patients in 2 mg, 3 mg and 4 mg dose groups were titrated to their target fixed dose, and continued on the same dose until a dose tapering phase started. The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. Patients who weighed less than 25 kg were not included in either study. Table 16: Fixed dose Studies Study Number • (Age Range) Treatment Group Primary Efficacy Measure: ADHD-RS-IV Total Score Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI) Study 1 (6 to 17 years) Guanfacine Extended-Release Tablets 2 mg* 36.1 (9.99) -15.9 (1.37) -7.4 (-11.3, -3.5) Guanfacine Extended-Release Tablets 3 mg* 36.8 (8.72) -16.0 (1.38) -7.5 (-11.4, -3.6) Guanfacine Extended-Release Tablets 4 mg* 38.4 (9.21) -18.5 (1.39) -10.0 (-13.9, -6.1) Placebo 38.1 (9.34) -8.5 (1.42) -- Study 2 (6 to 17 years) Guanfacine Extended-Release Tablets 1 mg*^ 41.7 (7.81) -19.4 (1.69) -6.8 (-11.3, -2.2) Guanfacine Extended-Release Tablets 2 mg* 39.9 (8.74) -18.1 (1.60) -5.4 (-9.9, -0.9) Guanfacine Extended-Release Tablets 3 mg* 39.1 (9.22) -20.0 (1.64) -7.3 (-11.8, -2.8) Guanfacine Extended-Release Tablets 4 mg* 40.6 (8.57) -20.6 (1.60) -7.9 (-12.3, -3.4) Placebo 39.3 (8.85) -12.7 (1.60) -- SD:standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. * Doses statistically significantly superior to placebo. ^ The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. Study 3: Flexible-dose Guanfacine Extended-Release Tablets as Adjunctive Therapy to Psychostimulants Study 3 (313 study) was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily optimized dosing (morning or evening) with guanfacine extended-release tablets (1 mg, 2 mg, 3 mg and 4 mg), when co-administered with psychostimulants, was evaluated for 8 weeks, in children and adolescents aged 6 to 17 years with a diagnosis of ADHD, with a sub-optimal response to stimulants (n=455). Patients were started at the 1 mg guanfacine extended-release tablets dose level and were titrated weekly over a 5-week dose-optimization period to an optimal guanfacine extended-release tablets dose not to exceed 4 mg/day based on tolerability and clinical response. The dose was then maintained for a 3-week dose maintenance period before entry to 1 week of dose tapering. Patients took guanfacine extended-release tablets either in the morning or the evening while maintaining their current dose of psychostimulant treatment given each morning. Allowable psychostimulants in the study were ADDERALL XR ® , VYVANSE ® , CONCERTA ® , FOCALIN XR ® , RITALIN LA ® , METADATE CD ® or FDA-approved generic equivalents. Symptoms of ADHD were evaluated on a weekly basis by clinicians using the ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week prior to dose tapering for which a valid score was obtained (up to Week 8). Studies 4, 5 and 6: Flexible-dose Guanfacine Extended-Release Tablets Monotherapy Study 4 (314 study) was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily dosing (morning or evening) with guanfacine extended-release tablets (1mg, 2mg, 3mg, and 4mg) was evaluated for 8 weeks in children aged 6 to 12 years (n=340). Study 6 (316 study) was a 12-week (for children aged 6 to 12) or 15-week (for adolescents aged 13 to 17), randomized, double-blind, parallel-group, placebo- and active-reference, dose-optimization study conducted in pediatric patients (children and adolescents aged 6 to 17 years old inclusive) (n=337) to assess the efficacy and safety of once-daily dosing (children: 1 to 4 mg/day, adolescents: 1 to 7 mg/day; optimized dose range of 0.05 to 0.12 mg/kg/day) in the treatment of ADHD. Guanfacine extended-release tablets were statistically superior to placebo on symptoms of ADHD in patients 6 to 17 years as measured by change from baseline in ADHD-RS-IV total scores (see Table 17 ). Table 17: Flexible-Dose studies Study Number • (Age Range) Treatment Group Primary Efficacy Measure: ADHD-RS-IV Total Score Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference b (95% CI) • Study 3 a (6 to 17 years) Guanfacine Extended-Release Tablets 1 to 4 mg AM* 37.6 (8.13) -20.3 (0.97) -4.5 (-7.5, -1.4) Guanfacine Extended-Release Tablets 1 to 4 mg PM* 37.0 (7.65) -21.2 (0.97) -5.3 (-8.3, -2.3) Placebo 37.7 (7.75) -15.9 (0.96) -- Study 4 (6 to 12 years) Guanfacine Extended-Release Tablets 1 to 4 mg AM* 41.7 (6.39) -20.0 (1.23) -9.4 (-12.8, -6.0) Guanfacine Extended-Release Tablets 1 to 4 mg PM* 41.6 (6.66) -20.4 (1.19) -9.8 (-13.1, -6.4) Placebo 42.9 (6.29) -10.6 (1.20) -- Study 5 (13 to 17 years) Guanfacine Extended-Release Tablets 1 to 7 mg* 39.9 (5.57) -24.6 (1.06) -6.03 (-8.87, -3.19) Placebo 40.0 (6.11) -18.5 (1.08) -- Study 6 (6 to 17 years) Guanfacine Extended-Release Tablets 1 to 7 mg* 43.1 (5.47) -23.89 (1.15) -8.88 (-11.94, -5.81) Placebo 43.2 (5.60) -15.01 (1.16) -- SD:standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Treatment was given in combination with a psychostimulant. b Difference (drug minus placebo) in least-squares mean change from baseline. * Doses statistically significantly superior to placebo. Study 7: Long-Term Maintenance of Guanfacine Extended-Release Tablets Efficacy Study 7 (315 study) was a double-blind, placebo-controlled, randomized withdrawal trial in pediatric patients aged 6 to 17 years with DSM-IV-TR diagnosis of ADHD. The study consisted of an open-label phase, including a 7-week dose optimization period to titrate patients to an optimal dose (maximum 4 mg/day for children and 7 mg/day for adolescents; optimized dose range: 0.05 to 0.12 mg/kg/day) and a 6-week dose maintenance period. There were 526 patients included in the open-label phase. Among those, 315 patients who met response criteria in the open-label phase were then randomized (1:1, guanfacine extended-release tablets:placebo) in a 26-week, double-blind, randomized withdrawal phase. The response criteria were defined by ≥ 30% reduction in ADHD-RS-IV total score and a Clinical Global Impression-Improvement (CGI-I) score of 1 or 2 during the open-label phase. A statistically significantly lower proportion of treatment failures occurred among guanfacine extended-release tablets patients compared to placebo at the end of the randomized withdrawal period (Figure 4). Treatment failure was defined as a ≥ 50% increase (worsening) in ADHD-RS-IV total score and a ≥ 2-point increase in Clinical Global Impression-Severity (CGI-S) score. Patients who met the treatment failure criteria on two consecutive visits or discontinued for any reason were classified as treatment failure. Figure 4. Kaplan-Meier Estimation of Proportion of Patients with Treatment Failure for Children and Adolescents Ages 6 to 17 (Study 7) figure-4.jpg

8.5 Geriatric Use The safety and efficacy of guanfacine extended-release tablets in geriatric patients have not been established.

8.3 Nursing Mothers It is not known whether guanfacine is excreted in human milk; however, guanfacine is excreted in rat milk. Because many drugs are excreted in human milk, caution should be exercised when guanfacine extended-release tablets are administered to a nursing woman. Observe human milk-fed infants for sedation and somnolence.

8.4 Pediatric Use Safety and efficacy of guanfacine extended-release tabletsin pediatric patients less than 6 years of age have not been established. The efficacy of guanfacine extended-release tablets was studied for the treatment of ADHD in five controlled monotherapy clinical trials (up to 15 weeks in duration), one randomized withdrawal study and one controlled adjunctive trial with psychostimulants (8 weeks in duration) in children and adolescents ages 6 to 17 who met DSM-IV ® criteria for ADHD [see ADVERSE REACTIONS ( 6 ) and CLINICAL STUDIES ( 14 ) ] . Animal Data In studies in juvenile rats, guanfacine alone produced a slight delay in sexual maturation in males and females at 2 to 3 times the maximum recommended human dose (MRHD). Guanfacine in combination with methylphenidate produced a slight delay in sexual maturation and decreased growth as measured by a decrease in bone length in males at a dose of guanfacine comparable to the MRHD and a dose of methylphenidate approximately 4 times the MRHD. In a study where juvenile rats were treated with guanfacine alone from 7 to 59 days of age, development was delayed as indicated by a slight delay in sexual maturation and decreased body weight gain in males at 2 mg/kg/day and in females at 3 mg/kg/day. The No Adverse Effect Level (NOAEL) for delayed sexual maturation was 1 mg/kg/day, which is equivalent to the MRHD of 4 mg/day, on a mg/m 2 basis. The effects on fertility were not evaluated in this study.

8.1 Pregnancy Pregnancy Category B Risk Summary There are no adequate and well-controlled studies of guanfacine extended-release tablets in pregnant women. No fetal harm was observed in rats and rabbits with administration of guanfacine at 4 and 2.7 times, respectively, the maximum recommended human dose. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Animal data Reproduction studies conducted in rats have shown that guanfacine crosses the placenta. However, administration of guanfacine to rats and rabbits at 4 and 2.7 times, respectively, the maximum recommended human dose 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 maximum recommended human dose in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B Risk Summary There are no adequate and well-controlled studies of guanfacine extended-release tablets in pregnant women. No fetal harm was observed in rats and rabbits with administration of guanfacine at 4 and 2.7 times, respectively, the maximum recommended human dose. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Animal data Reproduction studies conducted in rats have shown that guanfacine crosses the placenta. However, administration of guanfacine to rats and rabbits at 4 and 2.7 times, respectively, the maximum recommended human dose 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 maximum recommended human dose in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity. 8.3 Nursing Mothers It is not known whether guanfacine is excreted in human milk; however, guanfacine is excreted in rat milk. Because many drugs are excreted in human milk, caution should be exercised when guanfacine extended-release tablets are administered to a nursing woman. Observe human milk-fed infants for sedation and somnolence. 8.4 Pediatric Use Safety and efficacy of guanfacine extended-release tabletsin pediatric patients less than 6 years of age have not been established. The efficacy of guanfacine extended-release tablets was studied for the treatment of ADHD in five controlled monotherapy clinical trials (up to 15 weeks in duration), one randomized withdrawal study and one controlled adjunctive trial with psychostimulants (8 weeks in duration) in children and adolescents ages 6 to 17 who met DSM-IV ® criteria for ADHD [see ADVERSE REACTIONS ( 6 ) and CLINICAL STUDIES ( 14 ) ] . Animal Data In studies in juvenile rats, guanfacine alone produced a slight delay in sexual maturation in males and females at 2 to 3 times the maximum recommended human dose (MRHD). Guanfacine in combination with methylphenidate produced a slight delay in sexual maturation and decreased growth as measured by a decrease in bone length in males at a dose of guanfacine comparable to the MRHD and a dose of methylphenidate approximately 4 times the MRHD. In a study where juvenile rats were treated with guanfacine alone from 7 to 59 days of age, development was delayed as indicated by a slight delay in sexual maturation and decreased body weight gain in males at 2 mg/kg/day and in females at 3 mg/kg/day. The No Adverse Effect Level (NOAEL) for delayed sexual maturation was 1 mg/kg/day, which is equivalent to the MRHD of 4 mg/day, on a mg/m 2 basis. The effects on fertility were not evaluated in this study. 8.5 Geriatric Use The safety and efficacy of guanfacine extended-release tablets in geriatric patients have not been established. 8.6 Renal Impairment It may be necessary to reduce the dosage in patients with significant impairment of renal function [see Clinical Pharmacology ( 12.3 ) ] . 8.7 Hepatic Impairment It may be necessary to reduce the dosage in patients with significant impairment of hepatic function [see Clinical Pharmacology ( 12.3 ) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Guanfacine extended-release tablets are supplied in 1 mg, 2 mg, 3 mg, and 4 mg strength extended-release tablets in 30, 60, 90, 100, and 500 count bottles. 1 mg 2 mg 3 mg 4 mg Color White White Blue Blue Shape Round Caplet Round Caplet Debossment (top/bottom) A533/ 1 mg A534/ 2 mg A536/ 3 mg A538/ 4 mg NDC number 30 count: 71205-944-30 60 count: 71205-944-60 90 count: 71205-944-90 30 count: 71205-945-30 60 count: 71205-945-60 90 count: 71205-945-90 30 count: 71205-946-30 60 count: 71205-946-60 90 count: 71205-946-90 30 count: 71205-947-30 60 count: 71205-947-60 90 count: 71205-947-90 100 count: 71205-944-00 500 count: 71205-944-55 100 count: 71205-945-00 500 count: 71205-945-55 100 count: 71205-946-00 500 count: 71205-946-55 100 count: 71205-947-00 500 count: 71205-947-55 Storage - Store at 20° to 25°C (68° to 77°F). [see USP Controlled Room Temperature].