Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action Guanfacine is a central alpha -adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) stimulant. The mechanism of action of guanfacine in ADHD is not known. Pharmacodynamics Guanfacine is a selective central alpha2A -adrenergic receptor agonist in that it has a 15-20 times higher affinity for this receptor subtype than for the alpha2B or alpha2C subtypes. Guanfacine is a known antihypertensive agent. By stimulating central alpha2A -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 INTUNIV® of 0.12 mg/kg. Guanfacine was not shown to prolong the QTc interval to any clinically relevant extent. Pharmacokinetics Absorption And Distribution Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration. After oral administration of INTUNIV® the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD. Immediate-release guanfacine and INTUNIV® 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 is 60% lower and AUC 43% lower, respectively, for INTUNIV® compared to immediate-release guanfacine. Therefore, the relative bioavailability of INTUNIV® to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of INTUNIV® 1 mg once daily and immediate-release guanfacine 1mg once daily are summarized in Table 15. Table 15: Comparison of Pharmacokinetics : INTUNIV® vs. Immediate release Guanfacine in Adults Parameter INTUNIV® 1 mg once daily (n=52) Immediate-release guanfacine 1 mg once daily (n=12) Cmax (ng/mL) 1.0 ± 0.3 2.5 ± 0.6 AUC0-∞ (ng•h/mL) 32 ± 9 56 ± 15 tmax (h) 6.0 (4.0 - 8.0) 3.0 (1.5-4.0) t½ (h) 18 ± 4 16 ± 3 Note: Values are mean +/- SD, except for t which is median (range) Figure 1: Comparison of Pharmacokinetics : INTUNIV® vs. Immediate-release guanfacine in Adults Exposure to guanfacine was higher in children (ages 6-12) compared to adolescents (ages 13-17) and adults. After oral administration of multiple doses of INTUNIV® 4 mg, the C 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 6-12) and adolescents (ages 13-17), 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 INTUNIV® 4 mg was administered with a high-fat breakfast. The mean exposure increased (Cmax ~75% and AUC ~40%) compared to dosing in a fasted state. Dose Proportionality Following administration of INTUNIV® in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, Cmax and AUC0-∞ 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]. 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 INTUNIV Guanfacine does not significantly affect exposures of methylphenidate and lisdexamfetamine when coadministered (Figure 3). Figure 3: Effect of INTUNIV® on the Pharmacokinetics (PK) of Other Drugs Clinical Studies Efficacy of INTUNIV® in the treatment of ADHD was established in children and adolescents (6 to 17 years) in: Five short-term, placebo-controlled monotherapy trials (Studies 1, 2, 4, 5, and 6). One short-term, placebo-controlled adjunctive trial with psychostimulants (Study 3). One long-term, placebo-controlled monotherapy maintenance trial (Study 7). Studies 1 And 2: Fixed-Dose INTUNIV® Monotherapy Study 1 (301 study) was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with INTUNIV® (2 mg, 3 mg and 4 mg) was evaluated for 5 weeks (n=345) in children and adolescents aged 6-17 years. Study 2 (304 study) was a double-blind, placebocontrolled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with INTUNIV® (1 mg, 2 mg, 3 mg and 4 mg) was evaluated for 6 weeks (n=324) in children and adolescents aged 6-17 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. Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored 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 for which a valid score was obtained prior to dose tapering (up to Week 5 in Study 1 and up to Week 6 in Study 2). The mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® compared to placebo for Studies 1 and 2. Placebo-adjusted changes from baseline were statistically significant for each of the 2 mg, 3 mg, and 4 mg INTUNIV® randomized treatment groups in both studies, as well as the 1 mg INTUNIV® treatment group that was included only in Study 2 (see Table 16). Dose-responsive efficacy was evident, particularly when data were examined on a weight-adjusted (mg/kg) basis. When evaluated over the dose range of 0.01-0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg/day. Doses up to 0.12 mg/kg/day were shown to provide additional benefit. In the monotherapy trials (Studies 1 and 2), subgroup analyses were performed to identify any differences in response based on gender or age (6-12 vs. 13-17). Analyses of the primary outcome did not suggest any differential responsiveness on the basis of gender. Analyses by age revealed a statistically significant treatment effect only in the 6-12 age subgroup. Due to the relatively small proportion of adolescent patients (ages 13-17) enrolled into these studies (approximately 25%), these data may not have been sufficient to demonstrate efficacy in the adolescent patients. In these studies, patients were randomized to a fixed dose of INTUNIV® rather than optimized by body weight. Therefore, some adolescent patients were randomized to a dose that might have resulted in relatively lower plasma guanfacine concentrations compared to the younger patients. Over half (55%) of the adolescent patients received doses of 0.01-0.04 mg/kg. In studies in which systematic pharmacokinetic data were obtained, there was a strong inverse correlation between body weight and plasma guanfacine concentrations. 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 Bas eline (SE) Placebos ubtracted Difference (95% CI) Study 1 (6—17 years) INTUNIV® 2 mg† 36.1 (9.99) -15.9 (1.37) -7.4 (-11.3, -3.5) INTUNIV® 3 mg† 36.8 (8.72) -16.0 (1.38) -7.5 (-11.4, -3.6) INTUNIV® 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—17 years) INTUNIV® 1 mg†‡ 41.7 (7.81) -19.4 (1.69) -6.8 (-11.3, -2.2) INTUNIV® 2 mg† 39.9 (8.74) -18.1 (1.60) -5.4 (-9.9, -0.9) INTUNIV® 3 mg† 39.1 (9.22) -20.0 (1.64) -7.3 (-11.8, -2.8) INTUNIV® 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. *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 INTUNIV® 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 INTUNIV® (1 mg, 2 mg, 3 mg and 4 mg), when co-administered with psychostimulants, was evaluated for 8 weeks, in children and adolescents aged 6-17 years with a diagnosis of ADHD, with a sub-optimal response to stimulants (n=455). Patients were started at the 1 mg INTUNIV® dose level and were titrated weekly over a 5-week dose-optimization period to an optimal INTUNIV® 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 INTUNIV® 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). Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® given in combination with a psychostimulant compared to placebo given with a psychostimulant for Study 3, for both morning and evening INTUNIV® dosing (see Table 17). Nearly two-thirds (64.2%) of patients reached optimal doses in the 0.05-0.12 mg/kg/day range. Studies 4, 5 And 6: Flexible-Dose INTUNIV® 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 INTUNIV® (1 mg, 2 mg, 3 mg, and 4 mg) was evaluated for 8 weeks in children aged 6-12 years (n=340). Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline score at endpoint on the ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 8). Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® compared to placebo in both AM and PM dosing groups of INTUNIV® (see Table 17). Study 5 (312 study) was a 15-week, double-blind, randomized, placebo-controlled, dose-optimization study conducted in adolescents aged 13-17 years (n=314) to evaluate the efficacy and safety of INTUNIV® (1-7 mg/day; optimized dose range of 0.05-0.12 mg/kg/day) in the treatment of ADHD as measured by the ADHD Rating Scale-IV (ADHD-RS-IV). Patients receiving INTUNIV® showed statistically significantly greater improvement on the ADHD-RS-IV total score compared with patients receiving placebo (see Table 17). Study 6 (316 study) was a 12-week (for children aged 6-12) or 15-week (for adolescents aged 13-17), randomized, double-blind, parallel-group, placebo- and active-reference, dose-optimization study conducted in pediatric patients (children and adolescents aged 6-17 years old inclusive) (n=337) to assess the efficacy and safety of once-daily dosing (children: 1-4 mg/day, adolescents: 1-7 mg/day; optimized dose range of 0.05 to 0.12 mg/kg/day) in the treatment of ADHD. INTUNIV® was statistically superior to placebo on symptoms of ADHD in patients 6-17 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 Bas eline (SE) Placebos ubtracted Difference (95% CI) Study 3† (6—17 years) INTUNIV® 1—4 mg AM‡ 37.6 (8.13) -20.3 (0.97) -4.5 (-7.5, -1.4) INTUNIV® 1—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—12 years) INTUNIV® 1—4 mg AM‡ 41.7 (6.39) -20.0 (1.23) -9.4 (-12.8, -6.0) INTUNIV® 1—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—17 years) INTUNIV® 1—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—17 years) INTUNIV® 1—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. *Difference (drug minus placebo) in least-squares mean change from baseline. †Treatment was given in combination with a psychostimulant. ‡Doses statistically significantly superior to placebo. Study 7: Long-Term Maintenance Of INTUNIV® 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, INTUNIV: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 INTUNIV® 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 6-17 (Study 7)

Find Lowest Prices on INTUNIV®  (guanfacine) Extended-release Tablets DESCRIPTION INTUNIV® 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 molecular formula is C9H9Cl2N3O•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 hypromellose, methacrylic acid copolymer, lactose, povidone, crospovidone, microcrystalline cellulose, fumaric acid, and glyceryl behenate. In addition, the 3-mg and 4-mg tablets also contain green pigment blend PB-1763.

INDICATIONS INTUNIV® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [see Clinical Studies]. DOSAGE AND ADMINISTRATION 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. Dose Selection Take INTUNIV® orally once daily, either in the morning or evening, at approximately the same time each day. Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week. In monotherapy clinical trials, there was dose- and exposure-related clinical improvement as well as risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). To balance the exposure-related potential benefits and risks, the recommended target dose range depending on clinical response and tolerability for INTUNIV® is 0.05-0.12 mg/kg/day (total daily dose between 1- 7 mg) (See Table 1). Table 1: Recommended Target Dose Range for Therapy with INTUNIV® Weight Target dose range (0.05 - 0.12 mg/kg/day) 25-33.9 kg 2-3 mg/day 34-41.4 kg 2-4 mg/day 41.5-49.4 kg 3-5 mg/day 49.5-58.4 kg 3-6 mg/day 58.5-91 kg 4-7 mg/day > 91 kg 5-7 mg/day Doses above 4 mg/day have not been evaluated in children (ages 6-12 years) and doses above 7 mg/day have not been evaluated in adolescents (ages 13-17 years) In the adjunctive trial which evaluated INTUNIV® treatment with psychostimulants, the majority of patients reached optimal doses in the 0.05-0.12 mg/kg/day range. Doses above 4 mg/day have not been studied in adjunctive trials. Switching From Immediate-Release Guanfacine to INTUNIV® If switching from immediate-release guanfacine, discontinue that treatment, and titrate with INTUNIV® following above recommended schedule. Do not substitute for immediate-release guanfacine tablets on a milligram-per-milligram basis, because of differing pharmacokinetic profiles. INTUNIV® has significantly reduced C (60% lower), bioavailability (43% lower), and a delayed Tmax (3 hours later) compared to those of the same dose of immediate-release guanfacine [see CLINICAL PHARMACOLOGY]. Maintenance Treatment Pharmacological treatment of ADHD may be needed for extended periods. Healthcare providers should periodically re-evaluate the long-term use of INTUNIV®, and adjust weight-based dosage as needed. The majority of children and adolescents reach optimal doses in the 0.05-0.12 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]. Discontinuation Of Treatment Following discontinuation of INTUNIV®, patients may experience increases in blood pressure and heart rate [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Patients/caregivers should be instructed not to discontinue INTUNIV® without consulting their health care provider. Monitor blood pressure and pulse when reducing the dose or discontinuing the drug. Taper the daily dose in decrements of no more than 1 mg every 3 to 7 days to avoid rebound hypertension. Missed Doses When reinitiating patients to the previous maintenance dose after two or more missed consecutive doses, consider titration based on patient tolerability. Dosage Adjustment With Concomitant Use Of Strong CYP3A4 Inhibitors Or Inducers Dosage adjustments for INTUNIV® are recommended with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole), or CYP3A4 inducers (e.g., carbamazepine) (Table 2) [see DRUG INTERACTIONS]. Table 2: INTUNIV® Dosage Adjustments for Patients Taking Concomitant CYP3A4 Inhibitors or Inducers Clinical Scenarios Starting INTUNIV® while currently on a CYP3A4 modulator Continuing INTUNIV® while adding a CYP3A4 modulator Continuing INTUNIV® while stopping a CYP3A4 modulator CYP3A4 Strong Inhibitors Decrease INTUNIV® dosage to half the recommended level. (see Table 1) Decrease INTUNIV® dosage to half the recommended level. (see Table 1) Increase INTUNIV® dosage to recommended level. (see Table 1) CYP3A4 Strong Inducers Consider increasing INTUNIV® dosage up to double the recommended level. (see Table 1) Consider increasing INTUNIV® dosage up to double the recommended level over 1 to 2 weeks. (see Table 1) Decrease INTUNIV® dosage to recommended level over 1 to 2 weeks. (see Table 1) HOW SUPPLIED Dosage Forms And Strengths 1 mg, 2 mg, 3 mg and 4 mg extended-release tablets Storage And Handling INTUNIV® is supplied in 1 mg, 2 mg, 3 mg, and 4 mg strength extended-release tablets in 100 count bottles. 1 mg 2 mg 3 mg 4 mg Color White/off- white White/off- white Green Green Shape Round Caplet Round Caplet Debossment (top/bottom) 503 / 1 mg 503 / 2 mg 503 / 3 mg 503 / 4 mg NDC number 54092-513-02 54092-515-02 54092-517-02 54092-519-02 Storage 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. Manufactured for Shire US Inc., 300 Shire Way, Lexington, MA 02421. Revised: Mar 2016

PATIENT INFORMATION INTUNIV®  (in-TOO-niv) (guanfacine) Extended-Release Tablets Read the Patient Information that comes with INTUNIV® 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 is INTUNIV® ? INTUNIV® is a prescription medicine used to treat the symptoms of attention deficit hyperactivity disorder (ADHD). INTUNIV® may be used alone or with ADHD stimulant medicines. INTUNIV® is not a central nervous system (CNS) stimulant. It is not known if INTUNIV® is safe and effective in children younger than 6 years of age. Who should not take INTUNIV® ? Do not take INTUNIV® if you are allergic to guanfacine or any of the ingredients in INTUNIV. See the end of this leaflet for a complete list of ingredients in INTUNIV. What should I tell my doctor before taking INTUNIV® ? Before you take INTUNIV®, 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 INTUNIV® 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 INTUNIV® passes into your breast milk. Talk to your doctor about the best way to feed your baby while taking INTUNIV®. Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. INTUNIV® may affect the way other medicines work, and other medicines may affect how INTUNIV® works. 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 INTUNIV® ? Take INTUNIV® exactly as your doctor tells you. Your doctor may change your dose. Do not change your dose of INTUNIV® without talking to your doctor. Do not stop taking INTUNIV® without talking to your doctor. Try not to miss your dose of INTUNIV®. If you miss a dose of INTUNIV®, 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 INTUNIV® with a lower dose. Do not take a double dose to make up for a missed dose. INTUNIV® 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 INTUNIV® and when to take your ADHD stimulant medication. INTUNIV® should be swallowed whole with a small amount of water, milk, or other liquid. Do not crush, chew, or break INTUNIV®. Tell your doctor if you cannot swallow INTUNIV® whole. Do not take INTUNIV® with a high-fat meal. Your doctor will check your blood pressure and heart rate while you take INTUNIV®. If you take too much INTUNIV®, 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 INTUNIV® ? Do not drive, operate heavy machinery, or do other dangerous activities until you know how INTUNIV® affects you. INTUNIV® can slow your thinking and motor skills. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking INTUNIV® until you talk with your doctor. INTUNIV® 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 INTUNIV. What are the possible side effects of INTUNIV® ? INTUNIV® may cause serious side effects including: low blood pressure low heart rate fainting sleepiness withdrawal symptoms of increased heart rate and high blood pressure after suddenly stopping INTUNIV® (which may be accompanied by headaches, feeling confused, nervousness, agitation, and tremors). Get medical help right away, if you have any of the symptoms listed above. The most common side effects of INTUNIV® 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 INTUNIV®. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store INTUNIV® ? Store INTUNIV® between 68°F to 77°F (20°C to 25°C) Keep INTUNIV® and all medicines out of the reach of children. General Information about the safe and effective use INTUNIV® Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use INTUNIV® for a condition for which it was not prescribed. Do not give INTUNIV® 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 INTUNIV®. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about INTUNIV® that is written for health professionals. For more information, go to www.INTUNIV.com or call 1-800-828-2088. What are the ingredients in INTUNIV® ? Active ingredient: guanfacine hydrochloride Inactive ingredients : hypromellose, methacrylic acid copolymer, lactose, povidone, crospovidone, microcrystalline cellulose, fumaric acid, and glycerol behenate. In addition, the 3 mg and 4 mg tablets also contain green pigment blend PB-1763. This Patient Information has been approved by the U.S. Food and Drug Administration.

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

SIDE EFFECTS The following serious adverse reactions are described elsewhere in the labeling: Hypotension, bradycardia, and syncope [see WARNINGS AND PRECAUTIONS] Sedation and somnolence [see WARNINGS AND PRECAUTIONS] Cardiac conduction abnormalities [see WARNINGS AND PRECAUTIONS] Blood Pressure and Heart Rate Increase upon Discontinuation [see WARNINGS AND PRECAUTIONS] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect clinical trial exposure to INTUNIV® in 2,825 patients. This includes 2,330 patients from completed studies in children and adolescents, ages 6 to 17 years and 495 patients in completed studies in adult healthy volunteers. The mean duration of exposure of 446 patients that previously participated in two 2-year, open-label long-term studies was approximately 10 months. Fixed Dose Trials Table 3: Percentage of Patients Experiencing Most Common ( ≥ 5% and at least twice the rate for placebo) Adverse Reactions in Fixed Dos e Studies 1 and 2 Adverse Reaction Term Placebo (N=149) INTUNIV® (mg) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of INTUNIV® (N=513) Somnolence† 11% 28% 30% 38% 51% 38% Fatigue 3% 10% 13% 17% 15% 14% Hypotension‡ 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. †The somnolence term includes somnolence, sedation, and hypersomnia. ‡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 INTUNIV® and > rate than in placebo) in Fixed Dose Studies 1 and 2 Adverse Reaction Term Placebo (N=149) INTUNIV® mg) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of INTUNIV® (N=513) n (%) n (%) n (%) n (%) n (%) n (%) Total patients 4 (3%) 2 (3%) 10 (7%) 15 (10%) 27 (18%) 54 (11%) Somnolence† 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. †The somnolence term includes somnolence, sedation, and hypersomnia. Table 5: Other Common Adverse Reactions ( ≥ 2% for all doses of INTUNIV® and > rate than in placebo) in Fixed Dose Studies 1 and 2 Adverse Reaction Term Placebo (N=149) INTUNIV® (mg) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of INTUNIV® (N=513) Headache 19% 26% 25% 16% 28% 23% Abdominal Pain† 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‡ 0% 0% 0% 3% 4% 2% Enuresis§ 1% 0% 1% 3% 2% 2% Affect Lability¶ 1% 2% 1% 3% 1% 2% Adverse reactions ≥ 2% for all doses of INTUNIV® and > rate in placebo in any dose group but did not meet this criteria in all doses combined: insomnia (insomnia, initial insomnia, middle insomnia, terminal insomnia, sleep disorder), vomiting, diarrhea, abdominal/stomach discomfort (abdominal discomfort, epigastric discomfort, stomach discomfort), rash (rash, rash generalized, rash papular), dyspepsia, increased weight, bradycardia (bradycardia, sinus bradycardia), asthma (asthma, bronchospasm, wheezing), agitation, anxiety (anxiety, nervousness), sinus arrhythmia, blood pressure increased (blood pressure increased, blood pressure diastolic increased), and first degree atrioventricular block. *The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. †The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. ‡The nightmare term includes abnormal dreams, nightmare, and sleep terror. §The enuresis term includes enuresis, nocturia, and urinary incontinence. ¶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 Dos e Study 4 Adverse Reaction Term Placebo (N=112) INTUNIV® AM (N=107) PM (N=114) All Doses of INTUNIV® (N=221) Somnolence* 15% 57% 54% 56% Abdominal Pain† 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‡ 0% 6% 4% 5% Decreased Appetite 3% 6% 3% 4% Enuresis§ 1% 2% 5% 4% *The somnolence term includes somnolence, sedation, and hypersomnia. †The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness ‡The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). §The enuresis term includes enuresis, nocturia, and urinary incontinence. Table 7: Adverse Reactions Leading to Discontinuation ( ≥ 2% for all doses of INTUNIV® and > rate than in placebo) in Monotherapy Flexible Dos e Study 4 Adverse Reaction Term Placebo (N=112) INTUNIV® AM (N=107) PM (N=114) All Doses of INTUNIV® (N=221) n (%) n (%) n (%) n (%) Total patients 0 (0%) 8 (7%) 7 (6%) 15 (7%) Somnolence* 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 *The somnolence term includes somnolence, sedation, and hypersomnia. Table 8: Other Common Adverse Reactions ( ≥ 2% for all doses of INTUNIV® and > rate than in placebo) in the Monotherapy Flexible Dos e Study 4 Adverse Reaction Term Placebo (N=112) INTUNIV® AM (N=107) PM (N=114) All Doses of INTUNIV® (N=221) Headache 11% 18% 16% 17% Insomnia* 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 INTUNIV® and > rate in placebo in any dose group but did not meet this criteria in all doses combined: affect lability (affect lability, mood swings), increased weight, syncope/loss of consciousness (loss of consciousness, presyncope, syncope), dyspepsia, tachycardia (tachycardia, sinus tachycardia), and bradycardia (bradycardia, sinus bradycardia). *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 INTUNIV® (N=157) Somnolence* 23% 54% Insomnia† 6% 13% Hypotension‡ 3% 9% Dry Mouth 0% 8% Postural Dizziness 2% 5% Bradycardia§ 0% 5% *The somnolence term includes somnolence, sedation, and hypersomnia. †The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. ‡The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). §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 INTUNIV® and > rate than in placebo) in the Monotherapy Flexible Dose Study 5 Adverse Reaction Term Placebo (N=155) INTUNIV® All Doses of INTUNIV® (N=157) Headache 18% 27% Fatigue 12% 22% Dizziness 10% 16% Decreased Appetite 14% 15% Abdominal Pain* 8% 12% Irritability 4% 7% Anxiety† 3% 5% Rash‡ 1% 3% Constipation 0% 3% Increased Weight 2% 3% Abdominal/Stomach Discomfort§ 1% 2% Pruritus 1% 2% Adverse reactions ≥ 2% for all doses of INTUNIV® and > rate in placebo in any dose group but did not meet this criteria in all doses combined: nausea, diarrhea, vomiting, and depression (depressed mood, depression, depressive symptom). *The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. †The anxiety term includes anxiety and nervousness. ‡The rash term includes rash, rash generalized, and rash papular. §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 Adverse Reaction Term Placebo+ stimulant (N=153) INTUNIV® + stimulant AM (N=150) PM (N=152) All Doses (N=302) Somnolence* 7% 18% 18% 18% Insomnia† 6% 10% 14% 12% Abdominal Pain‡ 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% *The somnolence term includes somnolence, sedation, and hypersomnia. †The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. ‡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 INTUNIV® and > rate than in placebo) in the Short-Term Adjunctive Study 3 Adverse Reaction Term Placebo (N=153) INTUNIV® + stimulant AM (N=150) PM (N=152) All Doses of INTUNIV® (N=302) Headache 13% 21% 21% 21% Diarrhea 1% 4% 3% 4% Hypotension* 0% 4% 2% 3% Constipation 0% 2% 3% 2% Affect Lability† 1% 3% 2% 2% Dry Mouth 0% 1% 3% 2% Bradycardia‡ 0% 1% 3% 2% Postural Dizziness 0% 1% 3% 2% Rash§ 1% 1% 2% 2% Nightmare¶ 1% 2% 1% 2% Tachycardia# 1% 2% 1% 2% Adverse reactions ≥ 2% for all doses of INTUNIV® and > rate in placebo in any dose group but did not meet this criteria in all doses combined: irritability, vomiting, asthma (asthma, bronchospasm, wheezing), and enuresis (enuresis, nocturia, urinary incontinence). *The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased. †The affect lability term includes affect lability and mood swings. ‡The bradycardia term includes bradycardia and sinus bradycardia. §The rash term includes rash, rash generalized, and rash papular. ¶The nightmare term includes abnormal dreams, nightmare, and sleep terror. #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 INTUNIV® group and 3% of the placebo group. This includes orthostatic hypotension, which was reported for 1% of the INTUNIV® group and none in the placebo group. These findings were generally similar in the monotherapy flexible dose trials (Studies 4 and 5). In the adjunctive trial, hypotension (3%) and bradycardia (2%) were observed in patients treated with INTUNIV® as compared to none in the placebo group. In long-term, open-label studies, (mean exposure of approximately 10 months), maximum decreases in systolic and diastolic blood pressure occurred in the first month of therapy. Decreases were less pronounced over time. Syncope occurred in 1% of pediatric patients in the clinical program. The majority of these cases occurred in the long-term, open-label studies. Discontinuation Of Treatment Blood pressure and pulse may increase following discontinuation of INTUNIV®. In postmarketing experience, hypertensive encephalopathy has been very rarely reported upon abrupt discontinuation of INTUNIV® [see Postmarketing Experience]. In a maintenance of efficacy study in children and adolescents [see Clinical Studies], increases in mean systolic and diastolic blood pressure, of approximately 3 mmHg and 1 mmHg respectively, above original baseline were observed upon discontinuation of INTUNIV®. The increases in blood pressure were observed in some individuals at the end of the follow up period which ranged between 3 and 26 weeks post final dose. Mean increases in pulse of approximately 1.5 bpm were observed at approximately 2 weeks after the last dose of INTUNIV® and then decreased to baseline 4 weeks later. 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. Effects On Height, Weight, And Body Mass Index (BMI) Patients taking INTUNIV® demonstrated similar growth compared to normative data. Patients taking INTUNIV® had a mean increase in weight of 0.5 kg compared to those receiving placebo over a comparable treatment period. Patients receiving INTUNIV® for at least 12 months in open-label studies gained an average of 8 kg in weight and 8 cm (3 in) in height. The height, weight, and BMI percentile remained stable in patients at 12 months in the long-term studies compared to when they began receiving INTUNIV®. Other Adverse Reactions Observed In Clinical Studies Table 13 includes additional adverse reactions observed in short-term, placebo-controlled and longterm, 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 Postmarketing Experience The following adverse reactions have been identified during post-approval use of  uanfacine. 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, 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: impotence Respiratory System: dyspnea Skin and Appendages: alopecia, dermatitis, exfoliative dermatitis, pruritus, rash Special Senses: alterations in taste DRUG INTERACTIONS Table 14 contains clinically important drug interactions with INTUNIV® [see CLINICAL PHARMACOLOGY]. Table 14: Clinically Important Drug Interactions : Effect of other Drugs on INTUNIV® Concomitant Drug Name or Drug Class Clinical Rationale and Magnitude of Drug Interaction Clinical Recommendation CYP3A4 inhibitors, e.g., ketoconazole Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a 200% increase in exposure Consider dose reduction [see DOSAGE AND ADMINISTRATION] CYP3A4 inducers, e.g., rifampin Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a 60% decrease in exposure Consider dose increase [see DOSAGE AND ADMINISTRATION] Drug Abuse And Dependence Controlled Substance INTUNIV® is not a controlled substance and has no known potential for abuse or dependence.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypotension, Bradycardia, And Syncope Treatment with INTUNIV® can cause dose-dependent decreases in blood pressure and heart rate. Decreases were less pronounced over time of treatment. Orthostatic hypotension and syncope have been reported [see ADVERSE REACTIONS]. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Titrate INTUNIV® slowly in patients with a history of hypotension, and those with underlying conditions that may be worsened by hypotension and bradycardia; e.g., heart block, bradycardia, cardiovascular disease, vascular disease, cerebrovascular disease, or chronic renal failure. In patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, advise patients to avoid becoming dehydrated or overheated. Monitor blood pressure and heart rate, and adjust dosages accordingly in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Sedation And Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies [see ADVERSE REACTIONS]. Before using INTUNIV® with other centrally active depressants, consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with INTUNIV®. Advise patients to avoid use with alcohol. Cardiac Conduction Abnormalities The sympatholytic action of INTUNIV® may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. Titrate INTUNIV® slowly and monitor vital signs frequently in patients with cardiac conduction abnormalities or patients concomitantly treated with other sympatholytic drugs. Blood Pressure And Heart Rate Increase Upon Discontinuation Blood pressure and pulse may increase following discontinuation of INTUNIV®. In postmarketing experience, hypertensive encephalopathy has been very rarely reported upon abrupt discontinuation of INTUNIV® [see ADVERSE REACTIONS]. To minimize the risk of an increase in blood pressure upon discontinuation, the total daily dose of INTUNIV® should be tapered in decrements of no more than 1 mg every 3 to 7 days [see DOSAGE AND ADMINISTRATION]. Blood pressure and pulse should be monitored when reducing the dose or discontinuing INTUNIV®. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION). Dosing And Administration Instruct patients to swallow INTUNIV® 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 INTUNIV® together with a high-fat meal, since this can raise blood levels of INTUNIV®. Instruct the parent or caregiver to supervise the child or adolescent taking INTUNIV® and to keep the bottle of tablets out of reach of children. Advise patients not to abruptly discontinue INTUNIV®. Instruct patients on how to properly taper the dose because clinically significant blood pressure increases can occur [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. 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 INTUNIV® [see WARNINGS AND PRECAUTIONS]. 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]. Advise patients to avoid use with alcohol. Nonclinical Toxicology 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 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 basis. Use In Specific Populations Pregnancy Pregnancy Category B Risk Summary There are no adequate and well-controlled studies of INTUNIV® 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/m² 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. 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 INTUNIV® is administered to a nursing woman. Observe human milk-fed infants for sedation and somnolence. Pediatric Use Safety and efficacy of INTUNIV® in pediatric patients less than 6 years of age have not been established. The efficacy of INTUNIV® 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 6-17 who met DSM-IV criteria for ADHD [see ADVERSE REACTIONS and Clinical Studies]. 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/m² 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/m² basis. These findings were not observed with guanfacine alone at 1 mg/kg/day or methylphenidate alone at 50 mg/kg/day. Geriatric Use The safety and efficacy of INTUNIV® in geriatric patients have not been established. Renal Impairment It may be necessary to reduce the dosage in patients with significant impairment of renal function [see CLINICAL PHARMACOLOGY]. Hepatic Impairment It may be necessary to reduce the dosage in patients with significant impairment of hepatic function [see CLINICAL PHARMACOLOGY].