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, USP 1 mg are white to off-white, round, biconvex tablets, engraved "APO" on one side, "GU1" on the other side.

Guanfacine extended-release tablets, USP 2 mg are white to off-white, oval shaped, biconvex tablets, engraved "APO" on one side, "GUA 2" on the other side.

Guanfacine extended-release tablets, USP 3 mg are green, round, biconvex tablets, engraved "APO" on one side, "GU3" on the other side.

Guanfacine extended-release tablets, USP 4 mg are green, oval shaped, biconvex tablets, engraved "APO" on one side, "GUA 4" on the other side.

Guanfacine extended-release tablets are contraindicated in patients with a history of a hypersensitivity reaction to guanfacine extended-release tablets or its inactive ingredients, or other products containing guanfacine. Rash and pruritus have been reported.

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)]

Table 14 contains clinically important drug interactions with guanfacine extended-release tablets [see Clinical Pharmacology (12.3)].

Symptoms

Postmarketing reports of guanfacine overdosage indicate that hypotension, drowsiness, lethargy, and bradycardia have been observed following overdose. Initial hypertension may develop early and may be followed by hypotension. Similar symptoms have been described in voluntary reports to the American Association of Poison Control Center’s National Poison Data System. Miosis of the pupils may be noted on examination. No fatal overdoses of guanfacine have been reported in published literature.

Treatment

Consult a Certified Poison Control Center by calling 1-800-222-1222 for up-to-date guidance and advice.

Management of guanfacine extended-release tablets overdose should include monitoring for and the treatment of initial hypertension, if that occurs, as well as hypotension, bradycardia, lethargy and respiratory depression. Children and adolescents who develop lethargy should be observed for the development of more serious toxicity including coma, bradycardia and hypotension for up to 24 hours, due to the possibility of delayed onset hypotension.

Guanfacine extended-release tablets, USP are a once-daily, extended-release formulation of guanfacine hydrochloride 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 g/mol. The chemical structure is:

Guanfacine hydrochloride, USP is a white to off-white 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 hydrochloride, USP equivalent to 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine base. The tablets also contain anhydrous lactose, colloidal silicon dioxide, fumaric acid, hypromellose and magnesium stearate. In addition, the 3-mg and 4-mg tablets also contain FD&C Blue #2 and ferric oxide yellow.

Dissolution test pending.

Efficacy of guanfacine extended-release tablets 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 Guanfacine extended-release tablets Monotherapy

Study 1 (301 study) was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with guanfacine extended-release tablets (2 mg, 3 mg and 4 mg) was evaluated for 5 weeks (n=345) in children and adolescents aged 6 to 17 years. Study 2 (304 study) was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with guanfacine extended-release tablets (1 mg, 2 mg, 3 mg and 4 mg) was evaluated for 6 weeks (n=324) in children and adolescents aged 6 to 17 years. In both studies, randomized patients in 2 mg, 3 mg and 4 mg dose groups were titrated to their target fixed dose, and continued on the same dose until a dose tapering phase started. The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. Patients who weighed less than 25 kg were not included in either study. 

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 guanfacine extended-release tablets 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 guanfacine extended-release tablets randomized treatment groups in both studies, as well as the 1 mg guanfacine extended-release tablets 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 to 0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range 0.05 to 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 to 12 vs. 13 to 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 to 12 age subgroup. Due to the relatively small proportion of adolescent patients (ages 13 to 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 guanfacine extended-release tablets 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 to 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 3: Flexible-dose Guanfacine Extended-Release Tablets as Adjunctive Therapy to Psychostimulants

Study 3 (313 study) was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily optimized dosing (morning or evening) with guanfacine extended-release tablets (1 mg, 2 mg, 3 mg and 4 mg), when co-administered with psychostimulants, was evaluated for 8 weeks, in children and adolescents aged 6 to 17 years with a diagnosis of ADHD, with a sub-optimal response to stimulants (n=455). Patients were started at the 1 mg guanfacine extended-release tablets dose level and were titrated weekly over a 5-week dose-optimization period to an optimal guanfacine extended-release tablets dose not to exceed 4 mg/day based on tolerability and clinical response. The dose was then maintained for a 3-week dose maintenance period before entry to 1 week of dose tapering. Patients took guanfacine extended-release tablets either in the morning or the evening while maintaining their current dose of psychostimulant treatment given each morning. Allowable psychostimulants in the study were ADDERALL XR®, VYVANSE®, CONCERTA®,  FOCALIN XR®, RITALIN LA®, METADATE CD® or FDA-approved generic equivalents. 

Symptoms of ADHD were evaluated on a weekly basis by clinicians using the ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week prior to dose tapering for which a valid score was obtained (up to Week 8).

Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for guanfacine extended-release tablets given in combination with a psychostimulant compared to placebo given with a psychostimulant for Study 3, for both morning and evening guanfacine extended-release tablets dosing (see Table 17). Nearly two-thirds (64.2%) of patients reached optimal doses in the 0.05 to 0.12 mg/kg/day range. 

Studies 4, 5 and 6: Flexible-dose Guanfacine Extended-Release Tablets Monotherapy

Study 4 (314 study) was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily dosing (morning or evening) with guanfacine extended-release tablets (1 mg, 2 mg, 3 mg, and 4 mg) was evaluated for 8 weeks in children aged 6 to 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 guanfacine extended-release tablets compared to placebo in both AM and PM dosing groups of guanfacine extended-release tablets (see Table 17).

Study 5 (312 study) was a 15-week, double-blind, randomized, placebo-controlled, dose-optimization study conducted in adolescents aged 13 to 17 years (n=314) to evaluate the efficacy and safety of guanfacine extended-release tablets (1 to 7 mg/day; optimized dose range of 0.05 to 0.12 mg/kg/day) in the treatment of ADHD as measured by the ADHD Rating Scale-IV (ADHD-RS-IV). Patients receiving guanfacine extended-release tablets 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 to 12) or 15-week (for adolescents aged 13 to 17), randomized, double-blind, parallel-group, placebo- and active-reference, dose-optimization study conducted in pediatric patients (children and adolescents aged 6 to 17 years old inclusive) (n=337) to assess the efficacy and safety of once-daily dosing (children: 1 to 4 mg/day, adolescents: 1 to 7 mg/day; optimized dose range of 0.05 to 0.12 mg/kg/day) in the treatment of ADHD. Guanfacine extended-release tablets were statistically superior to placebo on symptoms of ADHD in patients 6 to 17 years as measured by change from baseline in ADHD-RS-IV total scores (see Table 17).

Table 17: Flexible-Dose studies

Study 7: Long-Term Maintenance of Guanfacine Extended-Release Tablets Efficacy

Study 7 (315 study) was a double-blind, placebo-controlled, randomized withdrawal trial in pediatric patients aged 6 to 17 years with DSM-IV-TR diagnosis of ADHD. The study consisted of an open-label phase, including a 7-week dose optimization period to titrate patients to an optimal dose (maximum 4 mg/day for children and 7 mg/day for adolescents; optimized dose range: 0.05 to 0.12 mg/kg/day) and a 6-week dose maintenance period. There were 526 patients included in the open-label phase. Among those, 315 patients who met response criteria in the open-label phase were then randomized (1:1, guanfacine extended-release tablets:placebo) in a 26-week, double-blind, randomized withdrawal phase. The response criteria were defined by ≥30% reduction in ADHD-RS-IV total score and a Clinical Global Impression-Improvement (CGI-I) score of 1 or 2 during the open-label phase. A statistically significantly lower proportion of treatment failures occurred among guanfacine extended-release tablets patients compared to placebo at the end of the randomized withdrawal period (Figure 4). Treatment failure was defined as a ≥50% increase (worsening) in ADHD-RS-IV total score and a ≥2-point increase in Clinical Global Impression-Severity (CGI-S) score. Patients who met the treatment failure criteria on two consecutive visits or discontinued for any reason were classified as treatment failure.

Figure 4. Kaplan-Meier Estimation of Proportion of Patients with Treatment Failure for Children and Adolescents Ages 6-17 (Study 7)

Guanfacine extended-release tablets, USP 1 mg are white to off-white, round, biconvex tablets, engraved “APO” on one side, “GU1” on the other side. They are supplied as follows:

Bottles of 100s (NDC 60505-3927-1)

Guanfacine extended-release tablets, USP 2 mg are white to off-white, oval shaped, biconvex tablets, engraved “APO” on one side, “GUA 2” on the other side. They are supplied as follows:

Bottles of 100s (NDC 60505-3928-1)

Guanfacine extended-release tablets, USP 3 mg are green, round, biconvex tablets, engraved “APO” on one side, “GU3” on the other side. They are supplied as follows:

Bottles of 100s (NDC 60505-3929-1)

Guanfacine extended-release tablets, USP 4 mg are green, oval shaped, biconvex tablets, engraved “APO” on one side, “GUA 4” on the other side. They are supplied as follows:

Bottles of 100s (NDC 60505-3930-1)

Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Protect from moisture.

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 tablets. Instruct the parent or caregiver to supervise the child or adolescent taking guanfacine extended-release tablets and to keep the bottle of tablets out of reach of children. 

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.

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to guanfacine extended-release tablets during pregnancy [see Use in Specific Populations (8.1)].  

Lactation 

Advise breastfeeding mothers to monitor infants exposed to guanfacine through breastmilk for sedation, lethargy and poor feeding [see Use in Specific Populations (8.2)].

All registered trademarks in this document are the property of their respective owners.

Dispense with Patient Information available at www1.apotex.com/products/us

APOTEX INC.

Guanfacine Extended-Release Tablets, USP

1 mg, 2 mg, 3 mg and 4 mg

Guanfacine Extended-Release Tablets, USP 

(gwahn-fa-seen)

Patient Information available at www1.apotex.com/products/us

Read the Patient Information that comes with guanfacine extended-release tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

What are guanfacine extended-release tablets?

Guanfacine extended-release tablets are a prescription medicine used to treat the symptoms of attention deficit hyperactivity disorder (ADHD). Guanfacine extended-release tablets may be used alone or with ADHD stimulant medicines.

Guanfacine extended-release tablets are not a central nervous system (CNS) stimulant.

It is not known if guanfacine extended-release tablets are safe and effective in children younger than 6 years of age.

Who should not take guanfacine extended-release tablets?

Do not take guanfacine extended-release tablets if you are allergic to guanfacine or any of the ingredients in guanfacine extended-release tablets. See the end of this leaflet for a complete list of ingredients in guanfacine extended-release tablets.

What should I tell my doctor before taking guanfacine extended-release tablets?

Before you take guanfacine extended-release tablets, tell your doctor if you:

• have heart problems or a low heart rate
• have fainted
• have low or high blood pressure
• have liver or kidney problems
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if guanfacine extended-release tablets will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
• There is a pregnancy registry for females who are exposed to ADHD medications, including guanfacine extended-release tablets, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to guanfacine extended-release tablets and their baby. If you or your child becomes pregnant during treatment with guanfacine extended-release tablets, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD medications at 1-866-961-2388.
• are breastfeeding or plan to breastfeed. It is not known if guanfacine extended-release tablets passes into your breast milk. Talk to your doctor about the best way to feed your baby while taking guanfacine extended-release tablets.

Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Guanfacine extended-release tablets may affect the way other medicines work, and other medicines may affect how guanfacine extended-release tablets work.

Especially tell your doctor if you take:

• ketoconazole
• medicines that can affect enzyme metabolism
• high blood pressure medicine
• sedatives
• benzodiazepines
• barbiturates
• antipsychotics
  

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I take guanfacine extended-release tablets?

• Take guanfacine extended-release tablets exactly as your doctor tells you.
• Your doctor may change your dose. Do not change your dose of guanfacine extended-release tablets without talking to your doctor.
• Do not stop taking guanfacine extended-release tablets without talking to your doctor.
• Try not to miss your dose of guanfacine extended-release tablets. If you miss a dose of guanfacine extended-release tablets, take the next dose at your regular time. If you miss 2 or more doses, talk to your doctor, as you may need to restart guanfacine extended-release tablets with a lower dose.
• Do not take a double dose to make up for a missed dose.
• Guanfacine extended-release tablets should be taken 1 time a day in the morning or in the evening, either alone or in combination with an ADHD stimulant medicine that your doctor may prescribe. Your doctor will tell you when to take guanfacine extended-release tablets and when to take your ADHD stimulant medication.
• Guanfacine extended-release tablets should be swallowed whole with a small amount of water, milk, or other liquid.
• Do not crush, chew, or break guanfacine extended-release tablets. Tell your doctor if you cannot swallow guanfacine extended-release tablets whole.
• Do not take guanfacine extended-release tablets with a high-fat meal.
• Your doctor will check your blood pressure and heart rate while you take guanfacine extended-release tablets.
• If you take too much guanfacine extended-release tablets, call your local Poison Control Center at 1-800-222-1222 or go to the nearest emergency room right away.

What should I avoid while taking guanfacine extended-release tablets?

• Do not drive, operate heavy machinery, or do other dangerous activities until you know how guanfacine extended-release tablets affect you. Guanfacine extended-release tablets can slow your thinking and motor skills.
• Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking guanfacine extended-release tablets until you talk with your doctor. Guanfacine extended-release tablets taken with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not become dehydrated or overheated. This may increase your chance of having low blood pressure or fainting while taking guanfacine extended-release tablets.
• Do not suddenly stop guanfacine extended-release tablets. Tell your healthcare provider if you have been vomiting and cannot take guanfacine extended-release tablets, you may be at risk for rebound hypertension.

What are the possible side effects of guanfacine extended-release tablets?

Guanfacine extended-release tablets may cause serious side effects including:

• low blood pressure
• low heart rate
• fainting
• sleepiness
• increased blood pressure and heart rate after suddenly stopping guanfacine extended-release tablets (rebound hypertension). Suddenly stopping guanfacine extended-release tablets can cause increased blood pressure and heart rate and other withdrawal symptoms such as headache, confusion, nervousness, agitation, and tremors. If these symptoms continue to get worse and are left untreated, it could lead to a very serious condition including very high blood pressure, feeling very sleepy or tired, severe headache, vomiting, vision problems, seizures.

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of guanfacine extended-release tablets include:

• sleepiness
• tiredness
• trouble sleeping
• low blood pressure
• nausea
• stomach pain
• dizziness
• dry mouth
• irritability
• vomiting
• slow heart rate

Tell the doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of guanfacine extended-release tablets. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store guanfacine extended-release tablets?

• Store at 20°C to 25°C (68°F to 77°F). Protect from moisture.

Keep guanfacine extended-release tablets and all medicines out of the reach of children.

General Information about the safe and effective use of guanfacine extended-release tablets

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use guanfacine extended-release tablets for a condition for which it was not prescribed. Do not give guanfacine extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them.

This leaflet summarizes the most important information about guanfacine extended-release tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about guanfacine extended-release tablets that is written for health professionals.

For more information, go to www.apotex.com or call 1-800-706-5575

What are the ingredients in guanfacine extended-release tablets?

Active ingredient: guanfacine hydrochloride

Inactive ingredients: anhydrous lactose, colloidal silicon dioxide, fumaric acid, hypromellose and magnesium stearate.  In addition, the 3 mg and 4 mg tablets also contain FD&C Blue #2 and ferric oxide yellow.

This Patient Information has been approved by the U.S. Food and Drug Administration.

All registered trademarks in this document are the property of their respective owners.

APOTEX INC.

Guanfacine Extended-Release Tablets, USP

1 mg, 2 mg, 3 mg and 4 mg

Revised: November 2022

Rev. 13

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 1 MG LABEL

APOTEX CORP. NDC 60505-3927-1

Guanfacine Extended-Release Tablets

1 mg

Rx only

100 Tablets

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 2 MG LABEL

APOTEX CORP. NDC 60505-3928-1

Guanfacine Extended-Release Tablets

2 mg

Rx only

100 Tablets

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 3 MG LABEL

APOTEX CORP. NDC 60505-3929-1

Guanfacine Extended-Release Tablets

3 mg

Rx only

100 Tablets

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 4 MG LABEL

APOTEX CORP. NDC 60505-3930-1

Guanfacine Extended-Release Tablets

4 mg

Rx only

100 Tablets