GUANFACINE- guanfacine tablet, extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
GUANFACINE HYDROCHLORIDE (UNII: PML56A160O) (GUANFACINE - UNII:30OMY4G3MK)
Available from:
Bryant Ranch Prepack
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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 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. Pregnancy Category B Risk Summary There are no adequate and well-controlled studies of guanfacine 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 t
Product summary:
Product: 63629-8161 NDC: 63629-8161-1 30 TABLET, EXTENDED RELEASE in a BOTTLE Product: 63629-8203 NDC: 63629-8203-1 30 TABLET, EXTENDED RELEASE in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
63629-8161-1, 63629-8203-1

GUANFACINE- guanfacine tablet, extended release

Bryant Ranch Prepack

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use GUANFACINE EXTENDED-RELEASE

TABLETS safely and effectively. See full prescribing information for GUANFACINE EXTENDED-RELEASE

TABLETS.

GUANFACINE extended-release tablets, for oral use

Initial U.S. Approval: 1986

INDICATIONS AND USAGE

Guanfacine extended-release tablets are a central alpha

-adrenergic receptor agonist indicated for the treatment of

Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications (1,

14). (1)

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

Extended-release tablets: 1 mg, 2 mg, 3 mg and 4 mg (3) (3)

CONTRAINDICATIONS

History of hypersensitivity to guanfacine, its inactive ingredients, or other products containing guanfacine (4). (4)

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

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). (6)

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). (6)

To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-

Recommended dose: 1 mg to 4 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).

Hypotension, bradycardia, syncope: Titrate slowly and monitor vital signs frequently in patients at risk for

hypotension, heart block, bradycardia, syncope, cardiovascular disease, vascular disease, cerebrovascular disease or

chronic renal failure. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases,

and periodically while on therapy. Avoid concomitant use of drugs with additive effects unless clinically indicated.

Advise patients to avoid becoming dehydrated or overheated (5.1).

Sedation and somnolence: Occur commonly with guanfacine. Consider the potential for additive sedative effects with

CNS depressant drugs. Caution patients against operating heavy equipment or driving until they know how they

respond to guanfacine (5.2).

Cardiac Conduction Abnormalities: May worsen sinus node dysfunction and atrioventricular (AV) block, especially in

patients taking other sympatholytic drugs. Titrate slowly and monitor vital signs frequently (5.3).

Rebound Hypertension: Abrupt discontinuation of guanfacine can lead to clinically significant and persistent rebound

hypertension. Subsequent hypertensive encephalopathy was also reported. To minimize the risk of rebound

hypertension upon discontinuation, the total daily dose of guanfacine should be tapered in decrements of no more

than 1 mg every 3 to 7 days (5.4).

7984 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. (6)

DRUG INTERACTIONS

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 General Instruction for Use

2.2 Dose Selection

2.3 Switching from Immediate-Release Guanfacine to Guanfacine Extended-Release Tablets

2.4 Maintenance Treatment

2.5 Discontinuation of Treatment

2.6 Missed Doses

2.7 Dosage Adjustment with Concomitant Use of Strong and Moderate CYP3A4 Inhibitors or

Inducers

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hypotension, Bradycardia, and Syncope

5.2 Sedation and Somnolence

5.3 Cardiac Conduction Abnormalities

5.4 Rebound Hypertension

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

Strong and moderate CYP3A4 inhibitors increase guanfacine exposure. Decrease guanfacine to 50% of target dosage

when coadministered with strong 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).

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Guanfacine extended-release tablets are indicated for the treatment of Attention Deficit Hyperactivity

Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [see Clinical

Studies (14)].

2 DOSAGE AND ADMINISTRATION

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 -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 guanfacine extended-release tablets 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.

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.

Sections or subsections omitted from the full prescribing information are not listed.

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

(60% lower), bioavailability (43% lower), and a delayed T

(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.

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-releas e

tablets while

currently on a

CYP3A4

modulator

Continuing

guanfacine

extended-releas e

tablets while adding

a CYP3A4

modulator

Continuing

guanfacine

extended-

releas e

tablets while

stopping a

CYP3A4

modulator

CYP3A4

Strong

and

moderate

Inhibitors

Decreas e

guanfacine

extended-release

tablets dosage to

half the

recommended level.

(see Table 1)

Decreas e

guanfacine

extended-release

tablets dosage to

half the

recommended level.

(see Table 1)

Increas e

guanfacine

extended-

release

tablets

dosage to

recommended

level. (see

Table 1)

Cons iderincreas ing Cons iderincreas ing Decreas e

CYP3A4

Strong

and

moderate

Inducers

guanfacine

extended-release

tablets dosage up to

double the

recommended level.

(see Table 1)

guanfacine

extended-release

tablets dosage up to

double the

recommended level

over 1 to 2 weeks.

(see Table 1)

guanfacine

extended-

release

tablets

dosage to

recommended

level over 1

to 2 weeks.

(see Table 1)

3 DOSAGE FORMS AND STRENGTHS

1 mg, 2 mg, 3 mg and 4 mg extended-release tablets

4 CONTRAINDICATIONS

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.

5 WARNINGS AND PRECAUTIONS

5.1 Hypotension, Bradycardia, and Syncope

Treatment with guanfacine 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 (6.1)].

Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and

periodically while on therapy. Titrate guanfacine 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.

5.2 Sedation and Somnolence

Somnolence and sedation were commonly reported adverse reactions in clinical studies [see Adverse

Reactions (6.1)]. Before using guanfacine 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 guanfacine. Advise patients to avoid use with alcohol.

5.3 Cardiac Conduction Abnormalities

The sympatholytic action of guanfacine may worsen sinus node dysfunction and atrioventricular (AV)

block, especially in patients taking other sympatholytic drugs. Titrate guanfacine slowly and monitor

vital signs frequently in patients with cardiac conduction abnormalities or patients concomitantly treated

with other sympatholytic drugs.

5.4 Rebound Hypertension

In post marketing experience, abrupt discontinuation of guanfacine has resulted in clinically significant

and persistent rebound hypertension above baseline levels and increases in heart rate. Hypertensive

encephalopathy has also been reported in association with rebound hypertension with both guanfacine

and immediate release guanfacine [see Adverse Reactions (6.2)]. In these cases, high-dosage guanfacine

was discontinued; concomitant stimulant use was also reported, which may potentially increase

hypertensive response upon abrupt discontinuation of guanfacine. Children commonly have

gastrointestinal illnesses that lead to vomiting, and a resulting inability to take medications, so they may

be especially at risk for rebound hypertension.

To minimize the risk of rebound hypertension upon discontinuation, the total daily dose of guanfacine

should be tapered in decrements of no more than 1 mg every 3 to 7 days [see Dosage and Administration

(2.5)]. Blood pressure and heart rate should be monitored when reducing the dose or discontinuing

guanfacine. If abrupt discontinuation occurs (especially with concomitant stimulant use), patients should

be closely followed for rebound hypertension.

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

Hypotension, bradycardia, and syncope [see Warnings and Precautions (5.1)]

Sedation and somnolence [see Warnings and Precautions (5.2)]

Cardiac conduction abnormalities [see Warnings and Precautions (5.3)]

Rebound Hypertension [see Warnings and Precautions (5.4)]

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

Fatigue

Hypotension

Dizziness

Lethargy

Nausea

Dry mouth

*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)

4mg

(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

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

Abdominal Pain

Decreased Appetite

Irritability

Constipation

Nightmare

Enuresis

Affect Lability

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)

(N = 112)

(N = 107)

(N = 114)

221)

Somnolence

Abdominal Pain

Fatigue

Irritability

Nausea

Dizziness

Vomiting

Hypotension

Decreased Appetite

Enuresis

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

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

Insomnia

Diarrhea

Lethargy

Constipation

Dry Mouth

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

Insomnia

Hypotension

Dry Mouth

Postural Dizziness

Bradycardia

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

Fatigue

Dizziness

Decreased Appetite

Abdominal Pain

Irritability

Anxiety

Rash

Constipation

Increased Weight

Abdominal/Stomach Discomfort

Pruritus

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

Insomnia

Abdominal Pain

Fatigue

Dizziness

Decreased Appetite

Nausea

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

Diarrhea

Hypotension

Constipation

Affect Lability

Dry Mouth

Bradycardia

Postural Dizziness

Rash

Nightmare

Tachycardia

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: 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

7 DRUG INTERACTIONS

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)]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Risk Summary

There are no adequate and well-controlled studies of guanfacine in pregnant women. No fetal harm was

observed in rats and rabbits with administration of guanfacine at 4 and 2.7 times, respectively, the

maximum recommended human dose. Because animal studies are not always predictive of human

response, this drug should be used during pregnancy only if clearly needed.

Animal data

Reproduction studies conducted in rats have shown that guanfacine crosses the placenta. However,

administration of guanfacine to rats and rabbits at 4 and 2.7 times, respectively, the maximum

recommended human dose of 0.12 mg/kg/day on a mg/m basis resulted in no evidence of harm to the

fetus. Higher doses (13.5 times the maximum recommended human dose in both rabbits and rats) were

associated with reduced fetal survival and maternal toxicity.

8.3 Nursing Mothers

It is not known whether guanfacine is excreted in human milk; however, guanfacine is excreted in rat

milk. Because many drugs are excreted in human milk, caution should be exercised when guanfacine is

administered to a nursing woman. Observe human milk-fed infants for sedation and somnolence.

8.4 Pediatric Use

Safety and efficacy of guanfacine in pediatric patients less than 6 years of age have not been

established. The efficacy of guanfacine was studied for the treatment of ADHD in five controlled

monotherapy clinical trials (up to 15 weeks in duration), one randomized withdrawal study one

controlled adjunctive trial with psychostimulants (8 weeks in duration) in children and adolescents ages

6 to 17 who met DSM-IV® criteria for ADHD [see Adverse Reactions (6) and Clinical Studies (14)].

Animal Data

In studies in juvenile rats, guanfacine alone produced a slight delay in sexual maturation in males and

females at 2 to 3 times the maximum recommended human dose (MRHD). Guanfacine in combination

with methylphenidate produced a slight delay in sexual maturation and decreased growth as measured by

a decrease in bone length in males at a dose of guanfacine comparable to the MRHD and a dose of

methylphenidate approximately 4 times the MRHD.

In a study where juvenile rats were treated with guanfacine alone from 7 to 59 days of age, development

was delayed as indicated by a slight delay in sexual maturation and decreased body weight gain in males

at 2 mg/kg/day and in females at 3 mg/kg/day. The No Adverse Effect Level (NOAEL) for delayed

sexual maturation was 1 mg/kg/day, which is equivalent to the MRHD of 4 mg/day, on a mg/m basis.

The effects on fertility were not evaluated in this study.

In a study where juvenile rats were treated with guanfacine in combination with methylphenidate from 7

to 59 days of age, a decrease in ulna bone length and a slight delay in sexual maturation were observed

in males given 1 mg/kg/day of guanfacine in combination with 50 mg/kg/day of methylphenidate. The

NOAELs for these findings were 0.3 mg/kg of guanfacine in combination with 16 mg/kg/day of

methylphenidate, which are equivalent to 0.3 and 1.4 times the MRHD of 4 mg/day and 54 mg/day for

guanfacine and methylphenidate, respectively, on a mg/m basis. These findings were not observed with

guanfacine alone at 1 mg/kg/day or methylphenidate alone at 50 mg/kg/day.

8.5 Geriatric Use

The safety and efficacy of guanfacine in geriatric patients have not been established.

8.6 Renal Impairment

It may be necessary to reduce the dosage in patients with significant impairment of renal function [see

Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

It may be necessary to reduce the dosage in patients with significant impairment of hepatic function [see

Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Guanfacine is not a controlled substance and has no known potential for abuse or dependence.

10 OVERDOSAGE

Symptoms

Postmarketing reports of guanfacine overdosage indicate that hypotension, drowsiness, lethargy, and

bradycardia have been observed following overdose. Initial hypertension may develop early and may be

followed by hypotension. Similar symptoms have been described in voluntary reports to the American

Association of Poison Control Center’s National Poison Data System. Miosis of the pupils may be

noted on examination. No fatal overdoses of guanfacine have been reported in published literature.

Treatment

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

advice.

Management of guanfacine 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.

11 DESCRIPTION

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 H Cl

N OHCl

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

behenate, 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.

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

Guanfacine is a selective central alpha

-adrenergic receptor agonist in that it has a 15 to 20 times

higher affinity for this receptor subtype than for the alpha

or alpha

subtypes.

Guanfacine is a known antihypertensive agent. By stimulating central alpha

-adrenergic receptors,

guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood

vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate.

In a thorough QT study, the administration of two dose levels of immediate-release guanfacine (4 mg

and 8 mg) produced concentrations approximately 2 to 4 times the concentrations observed with the

maximum recommended dose of guanfacine of 0.12 mg/kg. Guanfacine was not shown to prolong the

QTc interval to any clinically relevant extent.

12.3 Pharmacokinetics

Absorption and Distribution

Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug

concentration. After oral administration of guanfacine the time to peak plasma concentration is

approximately 5 hours in children and adolescents with ADHD.

Immediate-release guanfacine and extended-release guanfacine 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 extended-release guanfacine compared to immediate-release guanfacine. Therefore,

the relative bioavailability of extended-release guanfacine to immediate-release guanfacine is 58%.

The mean pharmacokinetic parameters in adults following the administration of extended-release

guanfacine 1 mg once daily and immediate-release guanfacine 1 mg once daily are summarized in Table

Table 15: Comparison of Pharmacokinetics: Extended-release Guanfacine vs. Immediate release

Guanfacine in Adults

Parameter

Extended-release guanfacine 1 mg once

daily

(n = 52)

Immediate-releas e

guanfacine

1 mg once daily

(n = 12)

(ng/mL)

1 ± 0.3

2.5 ± 0.6

(ng.h/mL)

32 ± 9

56 ± 15

6 (4 to 8)

3 (1.5 to 4)

18 ± 4

16 ± 3

Note: Values are mean +/- SD, except for t

which is median (range)

Figure 1: Comparison of Pharmacokinetics: Extended-release Guanfacine vs. Immediate-release

Guanfacine in Adults

0-∞

0-∞

Exposure to guanfacine was higher in children (ages 6 to 12) compared to adolescents (ages 13 to 17)

and adults. After oral administration of multiple doses of guanfacine 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 to 12)

and adolescents (ages 13 to 17), respectively. These differences are probably attributable to the lower

body weight of children compared to adolescents and adults.

The pharmacokinetics were affected by intake of food when a single dose of guanfacine 4 mg was

administered with a high-fat breakfast. The mean exposure increased (C

~75% and AUC ~40%)

compared to dosing in a fasted state.

Dose Proportionality

Following administration of guanfacine in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, C

and AUC

of guanfacine were proportional to dose.

Metabolism and Elimination

In vitro studies with human liver microsomes and recombinant CYP’s demonstrated that guanfacine was

primarily metabolized by CYP3A4. In pooled human hepatic microsomes, guanfacine did not inhibit the

activities of the major cytochrome P450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9,

CYP2C19, CYP2D6 or CYP3A4/5); guanfacine is also not an inducer of CYP3A, CYP1A2 and

CYP2B6. Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5

inducers/inhibitors.

Guanfacine inhibits MATE1 and OCT1, but does not inhibit BSEP, MRP2, OATP1B1, OATP1B3,

OAT1, OAT3, OCT2, or MATE2K. Guanfacine is a substrate of OCT1 and OCT2, but not BCRP,

OATP1B1, OATP1B3, OAT1, OAT3, MATE1, or MATE2. Concomitant administration of guanfacine

with OCT1 substrates might potentially increase the exposure of these OCT1 substrates.

Studies in Specific Populations

Renal Impairment

The impact of renal impairment on the pharmacokinetics of guanfacine in children was not assessed. In

0-∞

adult patients with impaired renal function, the cumulative urinary excretion of guanfacine and the renal

clearance diminished as renal function decreased. In patients on hemodialysis, the dialysis clearance

was about 15% of the total clearance. The low dialysis clearance suggests that the hepatic elimination

(metabolism) increases as renal function decreases.

Hepatic Impairment

The impact of hepatic impairment on PK of guanfacine in children was not assessed. Guanfacine in

adults is cleared both by the liver and the kidney, and approximately 50% of the clearance of guanfacine

is hepatic [see Hepatic Impairment (8.7)].

Drug Interaction Studies

Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be affected

significantly by CYP3A4 inhibitors or inducers (Figure 2).

Figure 2: Effect of Other Drugs on the Pharmacokinetics (PK) of Guanfacine

Guanfacine does not significantly affect exposures of methylphenidate and lisdexamfetamine when

coadministered (Figure 3).

Figure 3: Effect of Guanfacine on the Pharmacokinetics (PK) of Other Drugs

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice or 102 weeks in rats

at doses up to 6.8 times the maximum recommended human dose of 0.12 mg/kg/day on a mg/m 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.

14 CLINICAL STUDIES

Efficacy of guanfacine in the treatment of ADHD was established in children and adolescents (6 to 17

years) in:

Studies 1 and 2: Fixed-dose Guanfacine 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 (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 (1

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).

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 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 randomized treatment groups in

both studies, as well as the 1 mg guanfacine 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 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

Number

(Age

Range)

Treatment

Group

Primary Efficacy Measure: ADHD-RS-IV Total Score

Mean Baseline

Score (SD)

LS Mean Change

from Baseline (SE)

Placebo-s ubtracted

Difference

(95% CI)

Study 1

(6 to 17

years)

guanfacine 2

guanfacine 3

guanfacine 4

Placebo

36.1 (9.99)

36.8 (8.72)

38.4 (9.21)

38.1 (9.34)

-15.9 (1.37)

-16 (1.38)

-18.5 (1.39)

-8.5 (1.42)

-7.4 (-11.3, -3.5)

-7.5 (-11.4, -3.6)

-10 (-13.9, -6.1)

Study 2

(6 to 17

years)

guanfacine 1

mg*^

guanfacine 2

guanfacine 3

guanfacine 4

41.7 (7.81)

39.9 (8.74)

39.1 (9.22)

40.6 (8.57)

39.3 (8.85)

-19.4 (1.69)

-18.1 (1.60)

-20 (1.64)

-20.6 (1.60)

-12.7 (1.60)

-6.8 (-11.3, -2.2)

-5.4 (-9.9, -0.9)

-7.3 (-11.8, -2.8)

-7.9 (-12.3, -3.4)

a

Placebo

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence

interval.

a Difference (drug minus placebo) in least-squares mean change from baseline.

* Doses statistically significantly superior to placebo.

^ The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg.

Study 3: Flexible-dose Guanfacine 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 (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 dose level and were titrated weekly over a 5-week

dose-optimization period to an optimal guanfacine 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 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 given in combination with a psychostimulant compared to placebo given with a

psychostimulant for Study 3, for both morning and evening guanfacine 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 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 (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 compared to placebo in both AM and PM dosing groups of guanfacine (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

guanfacine (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 guanfacine 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. Guanfacine 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 Baseline (SE)

Placebo-s ubtracted

Difference (95% CI)

Study 3

(6 to 17 years)

Guanfacine 1 to 4 mg

Guanfacine 1 to 4 mg

Placebo

37.6 (8.13)

37 (7.65)

37.7 (7.75)

-20.3 (0.97)

-21.2 (0.97)

-15.9 (0.96)

-4.5 (-7.5, -1.4)

-5.3 (-8.3, -2.3)

Study 4

(6 to 12 years)

Guanfacine 1 to 4 mg

Guanfacine 1 to 4 mg

PM Placebo

41.7 (6.39)

41.6 (6.66)

42.9 (6.29)

-20 (1.23)

-20.4 (1.19)

-10.6 (1.20)

-9.4 (-12.8, -6)

-9.8 (-13.1, -6.4)

Study 5 (13 to 17

years)

Guanfacine 1 to 7

Placebo

-6.03 (-8.87, -3.19)

Study 6 (6 to 17

years)

Guanfacine 1 to 7

Placebo

-8.88 (-11.94, -5.81)

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence

interval.

Treatment was given in combination with a psychostimulant.

Difference (drug minus placebo) in least-squares mean change from baseline.

Doses statistically significantly superior to placebo.

Study 7: Long-Term Maintenance of guanfacine 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: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 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.

b

39.9 (5.57)

40.0 (6.11)

-24.6 (1.06)

-18.5 (1.08)

43.1 (5.47)

43.2 (5.60)

-23.89 (1.15)

-15.01 (1.16)

Figure 4. Kaplan-Meier Estimation of Proportion of Patients with Treatment Failure for Children

and Adolescents Ages 6-17 (Study 7)

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 63629-8161

NDC: 63629-8161-1 30 TABLET, EXTENDED RELEASE in a BOTTLE

Product: 63629-8203

NDC: 63629-8203-1 30 TABLET, EXTENDED RELEASE in a BOTTLE

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Dosing and Administration

Instruct patients to swallow guanfacine extended-release tablets whole with water, milk or other liquid.

Tablets should not be crushed, chewed or broken prior to administration because this may increase the

rate of release of the active drug. Patients should not take guanfacine extended-release tablets together

with a high-fat meal, since this can raise blood levels of guanfacine extended-release 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.

All brand names listed are the registered trademarks of their respective owners.

Manufactured by:

Ohm Laboratories Inc.

New Brunswick, NJ 08901

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

Patient Information

Guanfacine (GWAHN fa seen) Extended-release Tablets

Rx only

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.

are breastfeeding or plan to breastfeed. It is not known if guanfacine 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

June 2019 FDA-07

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 tabletscan 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 guanfacine extended-release tablets between 68° to 77° F (20° to 25° C).

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

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

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information

Leaflet. Do not use guanfacine extended-release tablets for a condition for which it was not prescribed.

Do not give guanfacine extended-release tablets to other people, even if they have the same symptoms

that you have. It may harm them.

This leaflet summarizes the most important information about guanfacine extended-release tablets. If

you would like more information, talk with your doctor. You can ask your pharmacist or doctor for

information about guanfacine extended-release tablets that is written for health professionals.

For more information, call 1-800-818-4555.

Guanfacine

What are the ingredients in guanfacine extended-release tablets?

Active ingredient: guanfacine hydrochloride, USP

Inactive ingredients: colloidal silicon dioxide, fumaric acid, glyceryl behenate, 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.

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

Manufactured by:

Ohm Laboratories Inc.

New Brunswick, NJ 08901

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

June 2019 FDA-05

Guanfacine

GUANFACINE

guanfacine tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 36 29 -8 16 1(NDC:6 330 4-9 24)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

GUANFACINE HYDRO CHLO RIDE (UNII: PML56 A16 0 O) (GUANFACINE - UNII:30 OMY4G3MK)

GUANFACINE

1 mg

Inactive Ingredients

Ingredient Name

Stre ng th

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

FUMARIC ACID (UNII: 8 8 XHZ13131)

METHACRYLIC ACID - ETHYL ACRYLATE CO PO LYMER ( 1:1) TYPE A (UNII: NX76 LV5T8 J)

GLYCERYL DIBEHENATE (UNII: R8 WTH25YS2)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

PO VIDO NE, UNSPECIFIED (UNII: FZ9 8 9 GH9 4E)

Product Characteristics

Color

white (white to o ff white)

S core

no sco re

S hap e

ROUND

S iz e

8 mm

Flavor

Imprint Code

RJ70

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 36 29 -8 16 1-1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/11/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 56 8 9

0 8 /17/20 18

GUANFACINE

guanfacine tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 36 29 -8 20 3(NDC:6 330 4-9 25)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

GUANFACINE HYDRO CHLO RIDE (UNII: PML56 A16 0 O) (GUANFACINE - UNII:30 OMY4G3MK)

GUANFACINE

2 mg

Inactive Ingredients

Ingredient Name

Stre ng th

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

FUMARIC ACID (UNII: 8 8 XHZ13131)

METHACRYLIC ACID - ETHYL ACRYLATE CO PO LYMER ( 1:1) TYPE A (UNII: NX76 LV5T8 J)

GLYCERYL DIBEHENATE (UNII: R8 WTH25YS2)

Bryant Ranch Prepack

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

PO VIDO NE, UNSPECIFIED (UNII: FZ9 8 9 GH9 4E)

Product Characteristics

Color

white (white to o ff white)

S core

no sco re

S hap e

OVAL

S iz e

14mm

Flavor

Imprint Code

RJ71

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 36 29 -8 20 3-1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/31/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 56 8 9

0 8 /17/20 18

Labeler -

Bryant Ranch Prepack (171714327)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Bryant Ranch Prepack

171714327

REPACK(6 36 29 -8 20 3, 6 36 29 -8 16 1) , RELABEL(6 36 29 -8 16 1, 6 36 29 -8 20 3)

Revised: 8/2019

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