Guanfacine

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 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 ).

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 (greater than or equal to 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): 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 AvKARE, Inc. at 1-855-361-3993 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 guanfacine extended-release in 2,028 patients. This includes 1,533 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 G uanfacine E xtended- R elease (mg) Adverse Reaction Term Placebo (N=149) 1 mg* (N=61) 2 mg (N=150) 3 mg (N=151) 4 mg (N=151) All Doses of G uanfacine E xtended- R elease (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 and > rate in placebo) in Fixed Dose Studies 1 and 2 G uanfacine E xtended- R elease (mg) Adverse Reaction Term Placebo (N=149) 1 mg* (N=61) 2 mg (N=150) 3 mg (N=151) 4 mg (N=151) All Doses of G uanfacine E xtended- R elease (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 and > rate than in placebo) in Fixed Dose Studies 1 and 2 G uanfacine E xtended- R elease (mg) Adverse Reaction Term Placebo (N=149) 1 mg* (N=61) 2 mg (N=150) 3 mg (N=151) 4 mg (N=151) All Doses of G uanfacine E xtended- R elease (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 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 G uanfacine E xtended- R elease Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of G uanfacine E xtended- R elease (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% Enuresis 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 and > rate than in placebo) in Monotherapy Flexible Dose Study 4 G uanfacine E xtended- R elease Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of G uanfacine E xtended- R elease (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 greater than or equal to 2% in any dose group bud 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 and > rate than in placebo) in the Monotherapy Flexible Dose Study 4 G uanfacine E xtended- R elease Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of G uanfacine E xtended- R elease (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% Adverse reactions ≥ 2% for all doses of guanfacine extended-release 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). a The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. 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 G uanfacine E xtended- R elease + 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 greater than or equal to 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 and > rate than in placebo) in the Short-Term Adjunctive Study 3 G uanfacine E xtended- R elease + stimulant Adverse Reaction Term Placebo (N=153) AM (N=150) PM (N=152) All Doses of G uanfacine E xtended- R elease (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 greater than or equal to 2% for all doses of guanfacine extended-release and greater than 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 -4.8 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 guanfacine extended-release group and 3% of the placebo group. This includes orthostatic hypotension, which was reported for 1% of the guanfacine extended-release group and none in the placebo group. These findings were generally similar in the monotherapy flexible dose trial (Study 4). In the adjunctive trial, hypotension (3%) and bradycardia (2%) were observed in patients treated with guanfacine extended-release 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. Effects on Height, Weight, and Body Mass Index (BMI) Patients taking guanfacine extended-release demonstrated similar growth compared to normative data. Patients taking guanfacine extended-release 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 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 guanfacine extended-release. 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 Additional pediatric use information for patients ages 6 to 17 years is approved for Shire US Inc.’s INTUNIV ® (guanfacine) extended-release tablet product. However, due to Shire US Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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 postmarketing 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 s keletal System: arthralgia, leg cramps, leg pain, myalgia Psychiatric: confusion, hallucinations Reproductive System, Male: impotence Respiratory System: dyspnea Skin and Appendages: alopecia, dermatitis, exfoliative dermatitis, pruritus, rash Special Senses: alterations in taste

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

11 DESCRIPTION Guanfacine extended-release is a once-daily, extended-release formulation of guanfacine hydrochloride (HCl), in a matrix tablet formulation for oral administration only. The chemical designation is N-amidino-2-(2, 6-dichlorophenyl) acetamide monohydrochloride. The chemical structure is: C 9 H 9 Cl 2 N 3 O•HCl M.W. 282.55 Guanfacine hydrochloride, USP 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 (greater than 30 mg/mL). Each tablet contains guanfacine hydrochloride, USP equivalent to 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine base. The tablets also contain colloidal silicon dioxide, crospovidone, fumaric acid, glyceryl behenate, hydroxypropyl cellulose, hypromellose, lactose monohydrate, microcrystalline cellulose, and povidone. In addition, the 1 mg and 2 mg tablets contain FD&C Yellow #6 Aluminum Lake and the 3 mg and 4 mg tablets contain D&C Yellow #10 Aluminum Lake. The following chemical structure of Guanfacine hydrochloride, USP is a white to off-white crystalline powder, sparingly soluble in water (approximately 1 mg/mL) and alcohol and slightly soluble in ace

2 DOSAGE AND ADMINISTRATION Recommended dose: 1 mg to 4 mg (0.05 mg/kg 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 guanfacine extended-release as directed ( 2.3 ). When discontinuing, taper the dose in decrements of no more than 1 mg every 3 to 7 days to avoid rebound hypertension ( 2.5 ). 2.1 General Instruction for Use Swallow tablets whole. Do not crush, chew, or break tablets because this will increase the rate of guanfacine release. Do not administer with high fat meals, due to increased exposure. 2.2 Dose Selection Take guanfacine extended-release tablets orally once daily, either in the morning or evening, at approximately the same time each day. Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week. In monotherapy-clinical trials, there was dose- and exposure-related clinical improvement as well as risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). To balance the exposure-related potential benefits and risks, the recommended target dose range depending on clinical response and tolerability for guanfacine extended-release is 0.05 to 0.12 mg/kg/day (total daily dose between 1 mg to 4 mg). In the adjunctive trial which evaluated guanfacine extended-release 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. Additional pediatric use information for patients ages 6 to 17 years is approved for Shire US Inc.’s INTUNIV ® (guanfacine) extended-release tablet product. However, due to Shire US Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.3 Switching from Immediate-Release Guanfacine to Guanfacine E xtended- R elease If switching from immediate-release guanfacine, discontinue that treatment, and titrate with guanfacine extended-release following above recommended schedule. Do not substitute for immediate-release guanfacine tablets on a milligram-per-milligram basis, because of differing pharmacokinetic profiles. Guanfacine extended-release 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 guanfacine extended-release, 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. Additional pediatric use information for patients ages 6 to 17 years is approved for Shire US Inc.’s INTUNIV ® (guanfacine) extended-release tablet product. However, due to Shire US Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.5 Discontinuation of Treatment Following discontinuation of guanfacine extended-release, patients may experience increases in blood pressure and heart rate [see Warnings and Precautions (5.4) and Adverse Reaction s (6) ] . Patients/caregivers should be instructed not to discontinue guanfacine extended-release 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 avoid 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 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 Dosage Adjustments for Patients Taking Concomitant CYP3A4 Inhibitors or Inducers Clinical Scenarios Starting guanfacine extended-release while currently on a CYP3A4 modulator Continuing guanfacine extended- release while adding a CYP3A4 modulator Continuing guanfacine extended-release while stopping a CYP3A4 modulator CYP3A4 Strong and M oderate Inhibitors Decrease guanfacine extended-release dosage to half the recommended level. Decrease guanfacine extended-release dosage to half the recommended level. Increase guanfacine extended-release dosage to recommended level. CYP3A4 Strong and M oderate Inducers Consider increasing guanfacine extended- release dosage up to double the recommended level. Consider increasing guanfacine extended-release dosage up to double the recommended level over 1 to 2 weeks. Decrease guanfacine extended-release dosage to recommended level over 1 to 2 weeks.

9.1 Controlled Substance Guanfacine extended-release is not a controlled substance and has no known potential for abuse or dependence.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Guanfacine extended-release is not a controlled substance and has 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 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 [see Clinical Pharmacology ( 12.3 )] . Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release 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 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 dosage up to double the target dosage over 1 to 2 weeks ( 2.7 ). Additional pediatric use information for patients ages 6 to 17 years is approved for Shire US Inc.’s INTUNIV ® (guanfacine) extended- release tablet product. However, due to Shire US Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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. Guanfacine is a known antihypertensive agent. By stimulating central alpha 2A -adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate. 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 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 the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD. Immediate-release guanfacine and guanfacine extended-release 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 compared to immediate-release guanfacine. Therefore, the relative bioavailability of guanfacine extended-release to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of guanfacine extended-release 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 vs. Immediate release Guanfacine in Adults Parameter G uanfacine E xtended- R elease 1 mg once daily (n=52) Immediate- r elease g uanfacine 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 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 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 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 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, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5). Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors. 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). Guanfacine does not significantly affect exposures of methylphenidate and lisdexamfetamine when coadministered (Figure 3). correct-figure Figure 2: Effect of Other Drugs on the Pharmacokinetics (PK) of Guanfacine Extended-Release Figure 3: Effect of Guanfacine Extended-Release on the Pharmacokinetics (PK) of Other Drugs

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. Guanfacine is a known antihypertensive agent. By stimulating central alpha 2A -adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate. 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 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 the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD. Immediate-release guanfacine and guanfacine extended-release 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 compared to immediate-release guanfacine. Therefore, the relative bioavailability of guanfacine extended-release to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of guanfacine extended-release 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 vs. Immediate release Guanfacine in Adults Parameter G uanfacine E xtended- R elease 1 mg once daily (n=52) Immediate- r elease g uanfacine 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 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 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 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 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, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5). Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors. 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). Guanfacine does not significantly affect exposures of methylphenidate and lisdexamfetamine when coadministered (Figure 3). correct-figure Figure 2: Effect of Other Drugs on the Pharmacokinetics (PK) of Guanfacine Extended-Release Figure 3: Effect of Guanfacine Extended-Release on the Pharmacokinetics (PK) of Other Drugs

20240109

8

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 guanfacine HYDROXYPROPYL CELLULOSE (TYPE M) SILICON DIOXIDE CROSPOVIDONE FUMARIC ACID GLYCERYL BEHENATE/EICOSADIOATE HYPROMELLOSES LACTOSE MONOHYDRATE CELLULOSE, MICROCRYSTALLINE POVIDONE FD&C YELLOW NO. 6 GUANFACINE HYDROCHLORIDE GUANFACINE 850 guanfacine guanfacine SILICON DIOXIDE CROSPOVIDONE FUMARIC ACID GLYCERYL BEHENATE/EICOSADIOATE HYPROMELLOSES LACTOSE MONOHYDRATE CELLULOSE, MICROCRYSTALLINE POVIDONE FD&C YELLOW NO. 6 GUANFACINE HYDROCHLORIDE GUANFACINE HYDROXYPROPYL CELLULOSE (TYPE M) 851 guanfacine guanfacine SILICON DIOXIDE CROSPOVIDONE FUMARIC ACID GLYCERYL BEHENATE/EICOSADIOATE HYPROMELLOSES LACTOSE MONOHYDRATE CELLULOSE, MICROCRYSTALLINE POVIDONE D&C YELLOW NO. 10 GUANFACINE HYDROCHLORIDE GUANFACINE HYDROXYPROPYL CELLULOSE (TYPE M) 853 guanfacine guanfacine GUANFACINE HYDROCHLORIDE GUANFACINE HYDROXYPROPYL CELLULOSE (TYPE M) SILICON DIOXIDE CROSPOVIDONE FUMARIC ACID GLYCERYL BEHENATE/EICOSADIOATE HYPROMELLOSES LACTOSE MONOHYDRATE CELLULOSE, MICROCRYSTALLINE POVIDONE D&C YELLOW NO. 10 855

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice or 102 weeks in rats at doses up to 6.8 times the maximum recommended human dose of 0.12 mg/kg/day on a mg/m 2 basis. Mutagenesis Guanfacine was not genotoxic in a variety of test models, including the Ames test and an in vitro chromosomal aberration test; however, a marginal increase in numerical aberrations (polyploidy) was observed in the latter study. Impairment of Fertility No adverse effects were observed in fertility studies in male and female rats at doses up to 22 times the maximum recommended human dose on a mg/m 2 basis.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice or 102 weeks in rats at doses up to 6.8 times the maximum recommended human dose of 0.12 mg/kg/day on a mg/m 2 basis. Mutagenesis Guanfacine was not genotoxic in a variety of test models, including the Ames test and an in vitro chromosomal aberration test; however, a marginal increase in numerical aberrations (polyploidy) was observed in the latter study. Impairment of Fertility No adverse effects were observed in fertility studies in male and female rats at doses up to 22 times the maximum recommended human dose on a mg/m 2 basis.

ANDA200881

Guanfacine

guanfacine

42291-326

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Label 1 2mg 3mg 4mg

RECENT MAJOR CHANGES Dosage and Administration ( 2.5 ) 11/2017 Warnings and Precautions ( 5.4 ) 11/2017

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-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. 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. Advise patients not to abruptly discontinue guanfacine extended-release tablets as abrupt discontinuation can result in clinically significant rebound hypertension. Concomitant stimulant use and abrupt discontinuation of guanfacine extended-release tablets may increase this hypertensive response. Instruct patients on how to properly taper the dose to minimize the risk of rebound hypertension [see Dosage and Administration ( 2.5 ) and Warnings and Precautions ( 5.4 )]. 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. Advise patients to avoid becoming dehydrated or overheated, which may potentially increase the risks of hypotension and syncope [see Warnings and Precautions ( 5.1 )]. Advise patients to avoid use with alcohol. Brands listed are the trademarks of their respective owners. Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 01/18 AV Rev. 10/18 (P)

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 guanfacine extended-release in 2,028 patients. This includes 1,533 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 G uanfacine E xtended- R elease (mg) Adverse Reaction Term Placebo (N=149) 1 mg* (N=61) 2 mg (N=150) 3 mg (N=151) 4 mg (N=151) All Doses of G uanfacine E xtended- R elease (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 and > rate in placebo) in Fixed Dose Studies 1 and 2 G uanfacine E xtended- R elease (mg) Adverse Reaction Term Placebo (N=149) 1 mg* (N=61) 2 mg (N=150) 3 mg (N=151) 4 mg (N=151) All Doses of G uanfacine E xtended- R elease (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 and > rate than in placebo) in Fixed Dose Studies 1 and 2 G uanfacine E xtended- R elease (mg) Adverse Reaction Term Placebo (N=149) 1 mg* (N=61) 2 mg (N=150) 3 mg (N=151) 4 mg (N=151) All Doses of G uanfacine E xtended- R elease (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 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 G uanfacine E xtended- R elease Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of G uanfacine E xtended- R elease (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% Enuresis 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 and > rate than in placebo) in Monotherapy Flexible Dose Study 4 G uanfacine E xtended- R elease Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of G uanfacine E xtended- R elease (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 greater than or equal to 2% in any dose group bud 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 and > rate than in placebo) in the Monotherapy Flexible Dose Study 4 G uanfacine E xtended- R elease Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of G uanfacine E xtended- R elease (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% Adverse reactions ≥ 2% for all doses of guanfacine extended-release 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). a The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. 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 G uanfacine E xtended- R elease + 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 greater than or equal to 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 and > rate than in placebo) in the Short-Term Adjunctive Study 3 G uanfacine E xtended- R elease + stimulant Adverse Reaction Term Placebo (N=153) AM (N=150) PM (N=152) All Doses of G uanfacine E xtended- R elease (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 greater than or equal to 2% for all doses of guanfacine extended-release and greater than 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 -4.8 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 guanfacine extended-release group and 3% of the placebo group. This includes orthostatic hypotension, which was reported for 1% of the guanfacine extended-release group and none in the placebo group. These findings were generally similar in the monotherapy flexible dose trial (Study 4). In the adjunctive trial, hypotension (3%) and bradycardia (2%) were observed in patients treated with guanfacine extended-release 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. Effects on Height, Weight, and Body Mass Index (BMI) Patients taking guanfacine extended-release demonstrated similar growth compared to normative data. Patients taking guanfacine extended-release 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 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 guanfacine extended-release. 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 Additional pediatric use information for patients ages 6 to 17 years is approved for Shire US Inc.’s INTUNIV ® (guanfacine) extended-release tablet product. However, due to Shire US Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.5 Geriatric Use The safety and efficacy of guanfacine extended-release 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 is 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 in pediatric patients less than 6 years of age have not been established. The efficacy of guanfacine extended-release was studied for the treatment of ADHD in three controlled monotherapy clinical trials (up to 8 weeks in duration), 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 )]. Additional pediatric use information for patients ages 6 to 17 years is approved for Shire US Inc.’s INTUNIV ® (guanfacine) extended-release tablet product. However, due to Shire US Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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. In a study where juvenile rats were treated with guanfacine in combination with methylphenidate from 7 to 59 days of age, a decrease in ulna bone length and a slight delay in sexual maturation were observed in males given 1 mg/kg/day of guanfacine in combination with 50 mg/kg/day of methylphenidate. The NOAELs for these findings were 0.3 mg/kg of guanfacine in combination with 16 mg/kg/day of methylphenidate, which are equivalent to 0.3 and 1.4 times the MRHD of 4 mg/day and 54 mg/day for guanfacine and methylphenidate, respectively, on a mg/m 2 basis. These findings were not observed with guanfacine alone at 1 mg/kg/day or methylphenidate alone at 50 mg/kg/day.

8.1 Pregnancy Pregnancy Category B Risk Summary There are no adequate and well-controlled studies of guanfacine extended-release 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 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 is 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 in pediatric patients less than 6 years of age have not been established. The efficacy of guanfacine extended-release was studied for the treatment of ADHD in three controlled monotherapy clinical trials (up to 8 weeks in duration), 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 )]. Additional pediatric use information for patients ages 6 to 17 years is approved for Shire US Inc.’s INTUNIV ® (guanfacine) extended-release tablet product. However, due to Shire US Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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. In a study where juvenile rats were treated with guanfacine in combination with methylphenidate from 7 to 59 days of age, a decrease in ulna bone length and a slight delay in sexual maturation were observed in males given 1 mg/kg/day of guanfacine in combination with 50 mg/kg/day of methylphenidate. The NOAELs for these findings were 0.3 mg/kg of guanfacine in combination with 16 mg/kg/day of methylphenidate, which are equivalent to 0.3 and 1.4 times the MRHD of 4 mg/day and 54 mg/day for guanfacine and methylphenidate, respectively, on a mg/m 2 basis. These findings were not observed with guanfacine alone at 1 mg/kg/day or methylphenidate alone at 50 mg/kg/day. 8.5 Geriatric Use The safety and efficacy of guanfacine extended-release 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 available as follows: 1 mg - Each orange, round tablet debossed with on one side and 850 on the other side contains guanfacine hydrochloride, USP equivalent to 1 mg of guanfacine base. Tablets are supplied in bottles of 100 (NDC 42291-324-01). 2 mg - Each orange, oval tablet debossed with on one side and 851 on the other side contains guanfacine hydrochloride, USP equivalent to 2 mg of guanfacine base. Tablets are supplied in bottles of 100 (NDC 42291-325-01). 3 mg - Each yellow, round tablet debossed with on one side and 853 on the other side contains guanfacine hydrochloride, USP equivalent to 3 mg of guanfacine base. Tablets are supplied in bottles of 100 (NDC 42291-326-01). 4 mg - Each yellow, oval tablet debossed with on one side and 855 on the other side contains guanfacine hydrochloride, USP equivalent to 4 mg of guanfacine base. Tablets are supplied in bottles of 100 (NDC 42291-327-01). Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP. round tablet debossed round tablet debossed round tablet debossed round tablet debossed