GUANFACINE

Guanfacine is a once-daily, extended-release formulation of guanfacine hydrochloride (HCl), USP 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 hydrochloride, USP is a white or almost white crystalline powder, sparingly soluble in water, methanol and ethanol. Each tablet contains guanfacine HCl equivalent to 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine base. The tablets also contain colloidal silicon dioxide, fumaric acid, glyceryl dibehenate, hypromellose, lactose monohydrate, methacrylic acid copolymer, microcrystalline cellulose, and povidone. In addition, the 3 mg and 4 mg tablets also contain FD&C blue #2/indigo carmine aluminum lake and ferric oxide yellow. Meets USP dissolution test 3

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

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

Guanfacine is 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, its inactive ingredients, or other products containing guanfacine (4).

The following serious adverse reactions are described elsewhere in the labeling: Hypotension, bradycardia, and syncope [see Warnings and Precautions (5.1)] Sedation and somnolence [see Warnings and Precautions (5.2)] Cardiac conduction abnormalities [see Warnings and Precautions (5.3)] Rebound Hypertension [see Warnings and Precautions (5.4)] Most common adverse reactions (≥ 5% and at least twice placebo rate) in fixed-dose monotherapy ADHD trials in children and adolescents (6 to 17 years): hypotension, somnolence, fatigue, nausea, and lethargy (6.1). Flexible dose-optimization ADHD trials in children (6 to 12 years) and adolescents (13 to 17 years): somnolence, hypotension, abdominal pain, insomnia, fatigue, dizziness, dry mouth, irritability, nausea, vomiting, and bradycardia (6.1). Adjunctive treatment to psychostimulant ADHD trial in children and adolescents (6 to 17 years): somnolence, fatigue, insomnia, dizziness, and abdominal pain (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 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 in 2,825 patients. This includes 2,330 patients from completed studies in children and adolescents, ages 6 to 17 years and 495 patients in completed studies in adult healthy volunteers. The mean duration of exposure of 446 patients that previously participated in two 2-year, open-label long-term studies was approximately 10 months. Fixed Dose Trials Table 3: Percentage of Patients Experiencing Most Common (≥ 5% and at least twice the rate for placebo) Adverse Reactions in Fixed Dose Studies 1 and 2 GUANFACINE (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 Guanfacine (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 and > rate than in placebo) in Fixed Dose Studies 1 and 2 GUANFACINE (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 Guanfacine (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 and > rate than in placebo) in Fixed Dose Studies 1 and 2 GUANFACINE(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 Guanfacine (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 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 Adverse Reaction Term Placebo (N = 112) AM (N = 107) PM (N = 114) All Doses of Guanfacine (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 and > rate than in placebo) in Monotherapy Flexible Dose Study 4 GUANFACINE Adverse Reaction Term Placebo (N = 112) AM (N = 107) PM (N = 114) All Doses of Guanfacine (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 and > rate than in placebo) in the Monotherapy Flexible Dose Study 4 GUANFACINE Adverse Reaction Term Placebo (N = 112) AM (N = 107) PM (N = 114) All Doses of Guanfacine (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 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. 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 (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. There were no specific adverse reactions ≥2% in any treatment group that led to discontinuation in the monotherapy flexible dose study (Study 5). Table 10: Other Common Adverse Reactions (≥2% for all doses of guanfacine and > rate than in placebo) in the Monotherapy Flexible Dose Study 5 Guanfacine Adverse Reaction Term Placebo (N = 155) All Doses of Guanfacine (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 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 + 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 and > rate than in placebo) in the Short-Term Adjunctive Study 3 GUANFACINE + stimulant Adverse Reaction Term Placebo (N = 153) AM (N = 150) PM (N = 152) All Doses of Guanfacine (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 guanfacineand > 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 group and 3% of the placebo group. This includes orthostatic hypotension, which was reported for 1% of the guanfacine 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 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. 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. 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, 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 demonstrated similar growth compared to normative data. Patients taking guanfacine had a mean increase in weight of 0.5 kg compared to those receiving placebo over a comparable treatment period. Patients receiving guanfacine 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. Other Adverse Reactions Observed in Clinical Studies Table 13 includes additional adverse reactions observed in short-term, placebo-controlled and long-term, open-label clinical studies not included elsewhere in section 6.1, listed by organ system. Table 13: Other adverse reactions observed in clinical studies Body System Adverse Reaction Cardiac Atrioventricular block General Asthenia, chest pain Immune System Disorders Hypersensitivity Investigations Increased alanine amino transferase Nervous system Convulsion Renal Increased urinary frequency Vascular Hypertension, pallor 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of guanfacine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Less frequent, possibly guanfacine-related events observed in the post-marketing study and/or reported spontaneously, not included in section 6.1, include: General: edema, malaise, tremor Cardiovascular: palpitations, tachycardia, rebound hypertension, hypertensive encephalopathy Central Nervous System: paresthesias, vertigo Eye Disorders: blurred vision Musculo-Skeletal System: arthralgia, leg cramps, leg pain, myalgia Psychiatric: confusion, hallucinations Reproductive System, Male: erectile dysfunction Respiratory System: dyspnea Skin and Appendages: alopecia, dermatitis, exfoliative dermatitis, pruritus, rash Special Senses: alterations in taste

Table 14 contains clinically important drug interactions with guanfacine [see Clinical Pharmacology (12.3)] . Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine 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 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 dosage up to double the target dosage over 1 to 2 weeks (2.7). See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.