Guanfacine

Name: Guanfacine

What special precautions should I follow?

Before taking guanfacine,

  • tell your doctor and pharmacist if you are allergic to guanfacine, any other medications, or any of the ingredients in guanfacine tablets or extended-release tablets. Ask your pharmacist for a list of the ingredients.
  • you should know that guanfacine is the active ingredient in guanfacine tablets and guanfacine extended-release tablets. Do not take both of these products at the same time.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: antidepressants; antihistamines; barbiturates such as phenobarbital (Luminal); carbamazepine (Carbatrol, Epitol, Equetro, Tegretol); clarithromycin (Biaxin, in PrevPac); indinavir (Crixivan); itraconazole (Onmel, Sporanox); ketoconazole (Nizoral); medications for anxiety, high blood pressure, mental illness, nausea, or seizures; nefazodone; nelfinavir (Viracept); phenytoin (Dilantin, Phenytek); pioglitazone (Actos, in Actoplus Met, in Duetact, in Oseni); rifabutin (Mycobutin); rifampin (Rifadin, in Rifamate, in Rifater, Rimactane); ritonavir (Norvir, in Kaletra); sedatives; sleeping pills; tranquilizers; and valproic acid (Depakene). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor what herbal products you are taking, especially St. John's wort.
  • tell your doctor if you have ever fainted, or if you have recently had a heart attack; and if you have or have ever had a stroke; low blood pressure; a slow heart rate; bipolar disorder (manic depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods); or heart, kidney or liver disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking guanfacine, call your doctor.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking guanfacine.
  • you should know that guanfacine may make you drowsy or dizzy. Do not drive a car or operate machinery until you know how this medication affects you.
  • ask your doctor about the safe use of alcoholic beverages while you are taking guanfacine. Alcohol can make the side effects from guanfacine worse.
  • you should know that guanfacine may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. This is more common when you first start taking guanfacine. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
  • you should know that you may faint if you become dehydrated or overheated during your treatment with guanfacine. Be sure to drink plenty of liquids and stay cool while you are taking this medication.
  • you should know that guanfacine should be used as part of a total treatment program for ADHD, which may include counseling and special education. Make sure to follow all of your doctor's and/or therapist's instructions.

What other information should I know?

Keep all appointments with your doctor. Your blood pressure and heart rate should be checked regularly to determine your response to guanfacine.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Side effects

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

  • Hypotension, bradycardia, and syncope [see WARNINGS AND PRECAUTIONS]
  • Sedation and somnolence [see WARNINGS AND PRECAUTIONS]
  • Cardiac conduction abnormalities [see WARNINGS AND PRECAUTIONS]
  • Blood Pressure and Heart Rate Increase upon Discontinuation [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect clinical trial exposure to INTUNIV® in 2,825 patients. This includes 2,330 patients from completed studies in children and adolescents, ages 6 to 17 years and 495 patients in completed studies in adult healthy volunteers.

The mean duration of exposure of 446 patients that previously participated in two 2-year, open-label long-term studies was approximately 10 months.

Fixed Dose Trials

Table 3: Percentage of Patients Experiencing Most Common ( ≥ 5% and at least twice the rate for placebo) Adverse Reactions in Fixed Dos e Studies 1 and 2

Adverse Reaction Term Placebo
(N=149)
INTUNIV® (mg)
1mg*
(N=61)
2mg
(N=150)
3mg
(N=151)
4mg
(N=151)
All Doses of INTUNIV® (N=513)
Somnolence† 11% 28% 30% 38% 51% 38%
Fatigue 3% 10% 13% 17% 15% 14%
Hypotension‡ 3% 8% 5% 7% 8% 7%
Dizziness 4% 5% 3% 7% 10% 6%
Lethargy 3% 2% 3% 8% 7% 6%
Nausea 2% 7% 5% 5% 6% 6%
Dry mouth 1% 0% 1% 6% 7% 4%
*The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg.
†The somnolence term includes somnolence, sedation, and hypersomnia.
‡The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased).

Table 4: Adverse Reactions Leading to Discontinuation ( ≥ 2% for all doses of INTUNIV® and > rate than in placebo) in Fixed Dose Studies 1 and 2

Adverse Reaction Term Placebo
(N=149)
INTUNIV® mg)
1mg*
(N=61)
2mg
(N=150)
3mg
(N=151)
4mg
(N=151)
All Doses of INTUNIV®
(N=513)
  n (%) n (%) n (%) n (%) n (%) n (%)
Total patients 4 (3%) 2 (3%) 10 (7%) 15 (10%) 27 (18%) 54 (11%)
Somnolence† 1 (1%) 2 (3%) 5 (3%) 6 (4%) 17 (11%) 30 (6%)
Fatigue 0 (0%) 0 (0%) 2 (1%) 2 (1%) 4 (3%) 8 (2%)
Adverse reactions leading to discontinuation in ≥ 2% in any dose group but did not meet this criteria in all doses combined: hypotension (hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased), headache, and dizziness.
*The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg.
†The somnolence term includes somnolence, sedation, and hypersomnia.

Table 5: Other Common Adverse Reactions ( ≥ 2% for all doses of INTUNIV® and > rate than in placebo) in Fixed Dose Studies 1 and 2

Adverse Reaction Term Placebo
(N=149)
INTUNIV® (mg)
1mg*
(N=61)
2mg
(N=150)
3mg
(N=151)
4mg
(N=151)
All Doses of INTUNIV®
(N=513)
Headache 19% 26% 25% 16% 28% 23%
Abdominal Pain† 9% 10% 7% 11% 15% 11%
Decreased Appetite 4% 5% 4% 9% 6% 6%
Irritability 4% 5% 8% 3% 7% 6%
Constipation 1% 2% 2% 3% 4% 3%
Nightmare‡ 0% 0% 0% 3% 4% 2%
Enuresis§ 1% 0% 1% 3% 2% 2%
Affect Lability¶ 1% 2% 1% 3% 1% 2%
Adverse reactions ≥ 2% for all doses of INTUNIV® and > rate in placebo in any dose group but did not meet this criteria in all doses combined: insomnia (insomnia, initial insomnia, middle insomnia, terminal insomnia, sleep disorder), vomiting, diarrhea, abdominal/stomach discomfort (abdominal discomfort, epigastric discomfort, stomach discomfort), rash (rash, rash generalized, rash papular), dyspepsia, increased weight, bradycardia (bradycardia, sinus bradycardia), asthma (asthma, bronchospasm, wheezing), agitation, anxiety (anxiety, nervousness), sinus arrhythmia, blood pressure increased (blood pressure increased, blood pressure diastolic increased), and first degree atrioventricular block.
*The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg.
†The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness.
‡The nightmare term includes abnormal dreams, nightmare, and sleep terror.
§The enuresis term includes enuresis, nocturia, and urinary incontinence.
¶The affect lability term includes affect lability and mood swings.

Monotherapy Flexible Dose Trials

Table 6: Percentage of Patients Experiencing Most Common ( ≥ 5% and at least twice the rate for placebo) Adverse Reactions in the Monotherapy Flexible Dos e Study 4

Adverse Reaction Term Placebo
(N=112)
INTUNIV®
AM
(N=107)
PM
(N=114)
All Doses of INTUNIV®
(N=221)
Somnolence* 15% 57% 54% 56%
Abdominal Pain† 7% 8% 19% 14%
Fatigue 3% 10% 11% 11%
Irritability 3% 7% 7% 7%
Nausea 1% 6% 5% 5%
Dizziness 3% 6% 4% 5%
Vomiting 2% 7% 4% 5%
Hypotension‡ 0% 6% 4% 5%
Decreased Appetite 3% 6% 3% 4%
Enuresis§ 1% 2% 5% 4%
*The somnolence term includes somnolence, sedation, and hypersomnia.
†The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness
‡The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased).
§The enuresis term includes enuresis, nocturia, and urinary incontinence.

Table 7: Adverse Reactions Leading to Discontinuation ( ≥ 2% for all doses of INTUNIV® and > rate than in placebo) in Monotherapy Flexible Dos e Study 4

Adverse Reaction Term Placebo
(N=112)
INTUNIV®
AM
(N=107)
PM
(N=114)
All Doses of INTUNIV®
(N=221)
  n (%) n (%) n (%) n (%)
Total patients 0 (0%) 8 (7%) 7 (6%) 15 (7%)
Somnolence* 0 (0%) 4 (4%) 3 (3%) 7 (3%)
Adverse reactions leading to discontinuation in ≥ 2% in any dose group but did not meet this criteria in all doses combined: fatigue
*The somnolence term includes somnolence, sedation, and hypersomnia.

Table 8: Other Common Adverse Reactions ( ≥ 2% for all doses of INTUNIV® and > rate than in placebo) in the Monotherapy Flexible Dos e Study 4

Adverse Reaction Term Placebo
(N=112)
INTUNIV®
AM
(N=107)
PM
(N=114)
All Doses of INTUNIV®
(N=221)
Headache 11% 18% 16% 17%
Insomnia* 6% 8% 6% 7%
Diarrhea 4% 4% 6% 5%
Lethargy 0% 4% 3% 3%
Constipation 2% 2% 4% 3%
Dry Mouth 1% 3% 3% 3%
Adverse reactions ≥ 2% for all doses of INTUNIV® and > rate in placebo in any dose group but did not meet this criteria in all doses combined: affect lability (affect lability, mood swings), increased weight, syncope/loss of consciousness (loss of consciousness, presyncope, syncope), dyspepsia, tachycardia (tachycardia, sinus tachycardia), and bradycardia (bradycardia, sinus bradycardia).
*The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder.

Table 9: Percentage of Patients Experiencing Most Common ( ≥ 5% and at least twice the rate for placebo) Adverse Reactions in the Monotherapy Flexible Dose Study 5

Adverse Reaction Term Placebo
(N=155)
All Doses of INTUNIV®
(N=157)
Somnolence* 23% 54%
Insomnia† 6% 13%
Hypotension‡ 3% 9%
Dry Mouth 0% 8%
Postural Dizziness 2% 5%
Bradycardia§ 0% 5%
*The somnolence term includes somnolence, sedation, and hypersomnia.
†The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder.
‡The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased).
§The bradycardia term includes bradycardia and sinus bradycardia.

There were no specific adverse reactions ≥ 2% in any treatment group that led to discontinuation in the monotherapy flexible dose study (Study 5).

Table 10: Other Common Adverse Reactions ( ≥ 2% for all doses of INTUNIV® and > rate than in placebo) in the Monotherapy Flexible Dose Study 5

Adverse Reaction Term Placebo
(N=155)
INTUNIV® All Doses of INTUNIV®
(N=157)
Headache 18% 27%
Fatigue 12% 22%
Dizziness 10% 16%
Decreased Appetite 14% 15%
Abdominal Pain* 8% 12%
Irritability 4% 7%
Anxiety† 3% 5%
Rash‡ 1% 3%
Constipation 0% 3%
Increased Weight 2% 3%
Abdominal/Stomach Discomfort§ 1% 2%
Pruritus 1% 2%
Adverse reactions ≥ 2% for all doses of INTUNIV® and > rate in placebo in any dose group but did not meet this criteria in all doses combined: nausea, diarrhea, vomiting, and depression (depressed mood, depression, depressive symptom).
*The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness.
†The anxiety term includes anxiety and nervousness.
‡The rash term includes rash, rash generalized, and rash papular.
§The abdominal/stomach discomfort term includes abdominal discomfort, epigastric discomfort, and stomach discomfort.

Adjunctive Trial

Table 11: Percentage of Patients Experiencing Most Common ( ≥ 5% and at least twice the rate for placebo) Adverse Reactions in the Short-Term Adjunctive Study 3

Adverse Reaction Term Placebo+ stimulant
(N=153)
INTUNIV® + stimulant
AM
(N=150)
PM
(N=152)
All Doses
(N=302)
Somnolence* 7% 18% 18% 18%
Insomnia† 6% 10% 14% 12%
Abdominal Pain‡ 3% 8% 12% 10%
Fatigue 3% 12% 7% 10%
Dizziness 4% 10% 5% 8%
Decreased Appetite 4% 7% 8% 7%
Nausea 3% 3% 7% 5%
*The somnolence term includes somnolence, sedation, and hypersomnia.
†The insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder.
‡The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness.

There were no specific adverse reactions ≥ 2% in any treatment group that led to discontinuation in the short-term adjunctive study (Study 3).

Table 12: Other Common Adverse Reactions ( ≥ 2% for all doses of INTUNIV® and > rate than in placebo) in the Short-Term Adjunctive Study 3

Adverse Reaction Term Placebo
(N=153)
INTUNIV® + stimulant
AM
(N=150)
PM
(N=152)
All Doses of INTUNIV®
(N=302)
Headache 13% 21% 21% 21%
Diarrhea 1% 4% 3% 4%
Hypotension* 0% 4% 2% 3%
Constipation 0% 2% 3% 2%
Affect Lability† 1% 3% 2% 2%
Dry Mouth 0% 1% 3% 2%
Bradycardia‡ 0% 1% 3% 2%
Postural Dizziness 0% 1% 3% 2%
Rash§ 1% 1% 2% 2%
Nightmare¶ 1% 2% 1% 2%
Tachycardia# 1% 2% 1% 2%
Adverse reactions ≥ 2% for all doses of INTUNIV® and > rate in placebo in any dose group but did not meet this criteria in all doses combined: irritability, vomiting, asthma (asthma, bronchospasm, wheezing), and enuresis (enuresis, nocturia, urinary incontinence).
*The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased.
†The affect lability term includes affect lability and mood swings.
‡The bradycardia term includes bradycardia and sinus bradycardia.
§The rash term includes rash, rash generalized, and rash papular.
¶The nightmare term includes abnormal dreams, nightmare, and sleep terror.
#The tachycardia term includes tachycardia and sinus tachycardia.

Effects On Blood Pressure And Heart Rate

In the monotherapy pediatric, short-term, controlled trials (Studies 1 and 2), the maximum mean changes from baseline in seated systolic blood pressure, diastolic blood pressure, and pulse were -5.4 mmHg, -3.4 mmHg, and -5.5 bpm, respectively, for all doses combined (generally one week after reaching target doses). For the respective fixed doses 1 mg/day, 2 mg/day, 3 mg/day or 4 mg/day the maximum mean changes in seated systolic blood pressure were -4.3 mmHg, -5.5 mmHg, -5.4 mmHg and -8.2 mmHg. For these respective fixed doses the maximum mean changes in seated diastolic blood pressure were -3.4 mmHg, -3.3 mmHg, -4.4 mmHg and -5.4 mmHg. For these respective fixed doses the maximum mean changes in seated pulse were -4.8 bpm, -3.1 bpm, -6.5 bpm and -8.6 bpm. Decreases in blood pressure and heart rate were usually modest and asymptomatic; however, hypotension and bradycardia can occur. Hypotension was reported as an adverse reaction for 7% of the INTUNIV® group and 3% of the placebo group. This includes orthostatic hypotension, which was reported for 1% of the INTUNIV® group and none in the placebo group. These findings were generally similar in the monotherapy flexible dose trials (Studies 4 and 5). In the adjunctive trial, hypotension (3%) and bradycardia (2%) were observed in patients treated with INTUNIV® as compared to none in the placebo group. In long-term, open-label studies, (mean exposure of approximately 10 months), maximum decreases in systolic and diastolic blood pressure occurred in the first month of therapy. Decreases were less pronounced over time. Syncope occurred in 1% of pediatric patients in the clinical program. The majority of these cases occurred in the long-term, open-label studies.

Discontinuation Of Treatment

Blood pressure and pulse may increase following discontinuation of INTUNIV®. In postmarketing experience, hypertensive encephalopathy has been very rarely reported upon abrupt discontinuation of INTUNIV® [see Postmarketing Experience]. In a maintenance of efficacy study in children and adolescents [see Clinical Studies], increases in mean systolic and diastolic blood pressure, of approximately 3 mmHg and 1 mmHg respectively, above original baseline were observed upon discontinuation of INTUNIV®. The increases in blood pressure were observed in some individuals at the end of the follow up period which ranged between 3 and 26 weeks post final dose. Mean increases in pulse of approximately 1.5 bpm were observed at approximately 2 weeks after the last dose of INTUNIV® and then decreased to baseline 4 weeks later. In this study, the increases in blood pressure and pulse were not considered serious or associated with adverse events. However, individuals may have larger increases than reflected by the mean changes.

Effects On Height, Weight, And Body Mass Index (BMI)

Patients taking INTUNIV® demonstrated similar growth compared to normative data. Patients taking INTUNIV® had a mean increase in weight of 0.5 kg compared to those receiving placebo over a comparable treatment period. Patients receiving INTUNIV® for at least 12 months in open-label studies gained an average of 8 kg in weight and 8 cm (3 in) in height. The height, weight, and BMI percentile remained stable in patients at 12 months in the long-term studies compared to when they began receiving INTUNIV®.

Other Adverse Reactions Observed In Clinical Studies

Table 13 includes additional adverse reactions observed in short-term, placebo-controlled and longterm, open-label clinical studies not included elsewhere in section 6.1, listed by organ system.

Table 13: Other adverse reactions observed in clinical studies

Body System Adverse Reaction
Cardiac Atrioventricular block
General Asthenia, chest pain
Immune System Disorders Hypersensitivity
Investigations Increased alanine amino transferase
Nervous system Convulsion
Renal Increased urinary frequency
Vascular Hypertension, pallor

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of  uanfacine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Less frequent, possibly guanfacine-related events observed in the post-marketing study and/or reported spontaneously, not included in section 6.1, include:

General: edema, malaise, tremor

Cardiovascular: palpitations, tachycardia, hypertensive encephalopathy

Central Nervous System: paresthesias, vertigo

Eye Disorders: blurred vision

Musculo-Skeletal System: arthralgia, leg cramps, leg pain, myalgia

Psychiatric: confusion, hallucinations

Reproductive System, Male: impotence

Respiratory System: dyspnea

Skin and Appendages: alopecia, dermatitis, exfoliative dermatitis, pruritus, rash

Special Senses: alterations in taste

Clinical pharmacology

Mechanism Of Action

Guanfacine is a central alpha -adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) stimulant. The mechanism of action of guanfacine in ADHD is not known.

Pharmacodynamics

Guanfacine is a selective central alpha2A -adrenergic receptor agonist in that it has a 15-20 times higher affinity for this receptor subtype than for the alpha2B or alpha2C subtypes.

Guanfacine is a known antihypertensive agent. By stimulating central alpha2A -adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate.

In a thorough QT study, the administration of two dose levels of immediate-release guanfacine (4 mg and 8 mg) produced concentrations approximately 2 to 4 times the concentrations observed with the maximum recommended dose of INTUNIV® of 0.12 mg/kg. Guanfacine was not shown to prolong the QTc interval to any clinically relevant extent.

Pharmacokinetics

Absorption And Distribution

Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration. After oral administration of INTUNIV® the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD.

Immediate-release guanfacine and INTUNIV® have different pharmacokinetic characteristics; dose substitution on a milligram per milligram basis will result in differences in exposure.

A comparison across studies suggests that the C is 60% lower and AUC 43% lower, respectively, for INTUNIV® compared to immediate-release guanfacine. Therefore, the relative bioavailability of INTUNIV® to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of INTUNIV® 1 mg once daily and immediate-release guanfacine 1mg once daily are summarized in Table 15.

Table 15: Comparison of Pharmacokinetics : INTUNIV® vs. Immediate release Guanfacine in Adults

Parameter INTUNIV® 1 mg once daily
(n=52)
Immediate-release guanfacine 1 mg once daily
(n=12)
Cmax (ng/mL) 1.0 ± 0.3 2.5 ± 0.6
AUC0-∞ (ng•h/mL) 32 ± 9 56 ± 15
tmax (h) 6.0 (4.0 - 8.0) 3.0 (1.5-4.0)
t½ (h) 18 ± 4 16 ± 3
Note: Values are mean +/- SD, except for t which is median (range)

Figure 1: Comparison of Pharmacokinetics : INTUNIV® vs. Immediate-release guanfacine in Adults

Exposure to guanfacine was higher in children (ages 6-12) compared to adolescents (ages 13-17) and adults. After oral administration of multiple doses of INTUNIV® 4 mg, the C was 10 ng/mL compared to 7 ng/mL and the AUC was 162 ng·h/mL compared to 116 ng·h/mL in children (ages 6-12) and adolescents (ages 13-17), respectively. These differences are probably attributable to the lower body weight of children compared to adolescents and adults.

The pharmacokinetics were affected by intake of food when a single dose of INTUNIV® 4 mg was administered with a high-fat breakfast. The mean exposure increased (Cmax ~75% and AUC ~40%) compared to dosing in a fasted state.

Dose Proportionality

Following administration of INTUNIV® in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, Cmax and AUC0-∞ of guanfacine were proportional to dose.

Metabolism And Elimination

In vitro studies with human liver microsomes and recombinant CYP's demonstrated that guanfacine was primarily metabolized by CYP3A4. In pooled human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5). Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors.

Studies In Specific Populations

Renal Impairment

The impact of renal impairment on the pharmacokinetics of guanfacine in children was not assessed. In adult patients with impaired renal function, the cumulative urinary excretion of guanfacine and the renal clearance diminished as renal function decreased. In patients on hemodialysis, the dialysis clearance was about 15% of the total clearance. The low dialysis clearance suggests that the hepatic elimination (metabolism) increases as renal function decreases.

Hepatic Impairment

The impact of hepatic impairment on PK of guanfacine in children was not assessed. Guanfacine in adults is cleared both by the liver and the kidney, and approximately 50% of the clearance of guanfacine is hepatic [see Hepatic Impairment].

Drug Interaction Studies

Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be affected significantly by CYP3A4 inhibitors or inducers (Figure 2).

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

Guanfacine does not significantly affect exposures of methylphenidate and lisdexamfetamine when coadministered (Figure 3).

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

Clinical Studies

Efficacy of INTUNIV® in the treatment of ADHD was established in children and adolescents (6 to 17 years) in:

  • Five short-term, placebo-controlled monotherapy trials (Studies 1, 2, 4, 5, and 6).
  • One short-term, placebo-controlled adjunctive trial with psychostimulants (Study 3).
  • One long-term, placebo-controlled monotherapy maintenance trial (Study 7).
Studies 1 And 2: Fixed-Dose INTUNIV® Monotherapy

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

Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 5 in Study 1 and up to Week 6 in Study 2).

The mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® compared to placebo for Studies 1 and 2. Placebo-adjusted changes from baseline were statistically significant for each of the 2 mg, 3 mg, and 4 mg INTUNIV® randomized treatment groups in both studies, as well as the 1 mg INTUNIV® treatment group that was included only in Study 2 (see Table 16).

Dose-responsive efficacy was evident, particularly when data were examined on a weight-adjusted (mg/kg) basis. When evaluated over the dose range of 0.01-0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg/day. Doses up to 0.12 mg/kg/day were shown to provide additional benefit.

In the monotherapy trials (Studies 1 and 2), subgroup analyses were performed to identify any differences in response based on gender or age (6-12 vs. 13-17). Analyses of the primary outcome did not suggest any differential responsiveness on the basis of gender. Analyses by age revealed a statistically significant treatment effect only in the 6-12 age subgroup. Due to the relatively small proportion of adolescent patients (ages 13-17) enrolled into these studies (approximately 25%), these data may not have been sufficient to demonstrate efficacy in the adolescent patients. In these studies, patients were randomized to a fixed dose of INTUNIV® rather than optimized by body weight. Therefore, some adolescent patients were randomized to a dose that might have resulted in relatively lower plasma guanfacine concentrations compared to the younger patients. Over half (55%) of the adolescent patients received doses of 0.01-0.04 mg/kg. In studies in which systematic pharmacokinetic data were obtained, there was a strong inverse correlation between body weight and plasma guanfacine concentrations.

Table 16: Fixed dose Studies

Study Number (Age Range) Treatment Group Primary Efficacy Measure: ADHD-RS-IV Total Score
  Mean Baseline Score (SD) LS Mean Change from Bas eline (SE) Placebos ubtracted Difference (95% CI)
Study 1 (6—17 years) INTUNIV® 2 mg† 36.1 (9.99) -15.9 (1.37) -7.4
(-11.3, -3.5)
INTUNIV® 3 mg† 36.8 (8.72) -16.0 (1.38) -7.5
(-11.4, -3.6)
INTUNIV® 4 mg† 38.4 (9.21) -18.5 (1.39) -10.0
(-13.9, -6.1)
Placebo 38.1 (9.34) -8.5 (1.42) --
Study 2 (6—17 years) INTUNIV® 1 mg†‡ 41.7 (7.81) -19.4 (1.69) -6.8
(-11.3, -2.2)
INTUNIV® 2 mg† 39.9 (8.74) -18.1 (1.60) -5.4
(-9.9, -0.9)
INTUNIV® 3 mg† 39.1 (9.22) -20.0 (1.64) -7.3
(-11.8, -2.8)
INTUNIV® 4 mg† 40.6 (8.57) -20.6 (1.60) -7.9
(-12.3, -3.4)
Placebo 39.3 (8.85) -12.7 (1.60) --
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
*Difference (drug minus placebo) in least-squares mean change from baseline.
†Doses statistically significantly superior to placebo.
‡The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg.

Study 3: Flexible-Dose INTUNIV® as Adjunctive Therapy To Psychostimulants

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

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

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

Studies 4, 5 And 6: Flexible-Dose INTUNIV® Monotherapy

Study 4 (314 study) was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily dosing (morning or evening) with INTUNIV® (1 mg, 2 mg, 3 mg, and 4 mg) was evaluated for 8 weeks in children aged 6-12 years (n=340).

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

Mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV® compared to placebo in both AM and PM dosing groups of INTUNIV® (see Table 17).

Study 5 (312 study) was a 15-week, double-blind, randomized, placebo-controlled, dose-optimization study conducted in adolescents aged 13-17 years (n=314) to evaluate the efficacy and safety of INTUNIV® (1-7 mg/day; optimized dose range of 0.05-0.12 mg/kg/day) in the treatment of ADHD as measured by the ADHD Rating Scale-IV (ADHD-RS-IV). Patients receiving INTUNIV® showed statistically significantly greater improvement on the ADHD-RS-IV total score compared with patients receiving placebo (see Table 17).

Study 6 (316 study) was a 12-week (for children aged 6-12) or 15-week (for adolescents aged 13-17), randomized, double-blind, parallel-group, placebo- and active-reference, dose-optimization study conducted in pediatric patients (children and adolescents aged 6-17 years old inclusive) (n=337) to assess the efficacy and safety of once-daily dosing (children: 1-4 mg/day, adolescents: 1-7 mg/day; optimized dose range of 0.05 to 0.12 mg/kg/day) in the treatment of ADHD. INTUNIV® was statistically superior to placebo on symptoms of ADHD in patients 6-17 years as measured by change from baseline in ADHD-RS-IV total scores (see Table 17).

Table 17: Flexible-Dose studies

Study Number (Age Range) Treatment Group Primary Efficacy Measure: ADHD-RS-IV Total Score
Mean Baseline Score (SD) LS Mean Change from Bas eline (SE) Placebos ubtracted Difference (95% CI)
Study 3† (6—17 years) INTUNIV® 1—4 mg AM‡ 37.6 (8.13) -20.3 (0.97) -4.5 (-7.5, -1.4)
INTUNIV® 1—4 mg
PM‡
37.0 (7.65) -21.2 (0.97) -5.3 (-8.3, -2.3)
Placebo 37.7 (7.75) -15.9 (0.96) --
Study 4 (6—12 years) INTUNIV® 1—4 mg AM‡ 41.7 (6.39) -20.0 (1.23) -9.4 (-12.8, -6.0)
INTUNIV® 1—4 mg PM‡ 41.6 (6.66) -20.4 (1.19) -9.8 (-13.1, -6.4)
Placebo 42.9 (6.29) -10.6 (1.20) ---
Study 5 (13—17 years) INTUNIV® 1—7 mg‡ 39.9 (5.57) -24.6 (1.06) -6.03 (-8.87, -3.19)
Placebo 40.0 (6.11) -18.5 (1.08) --
Study 6 (6—17 years) INTUNIV® 1—7 mg‡ 43.1 (5.47) -23.89 (1.15) -8.88 (-11.94, -5.81)
Placebo 43.2 (5.60) -15.01 (1.16) -
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
*Difference (drug minus placebo) in least-squares mean change from baseline.
†Treatment was given in combination with a psychostimulant.
‡Doses statistically significantly superior to placebo.

Study 7: Long-Term Maintenance Of INTUNIV® Efficacy

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

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

Guanfacine Overview

Guanfacine tablets are a prescription medication used alone or with other medications to treat high blood pressure. Guanfacine extended-release tablets are used to treat the symptoms of attention deficit hyperactivity disorder (ADHD) in children.

Guanfacine belongs to a group of drugs called centrally acting alpha 2A -adrenergic receptor agonists. Guanfacine treats high blood pressure by decreasing heart rate and relaxing the blood vessels so that blood can flow more easily through the body. Guanfacine extended-release tablets may treat ADHD by affecting the part of the brain that controls attention and impulsivity.
 Guanfacine comes as a tablet and as an extended-release tablet. The tablet is usually taken once daily at bedtime. The extended-release tablet is usually taken once daily. Swallow the extended-release tablets whole. Do not chew, crush or break them.
 Common side effects include dry mouth, weakness and headache. Guanfacine can cause drowsiness. Do not drive or operate heavy machinery until you know how it affects you.

Guanfacine Drug Class

Guanfacine is part of the drug class:

  • Imidazoline receptor agonists

Guanfacine Interactions

Guanfacine may affect the way other medicines work, and other medicines may affect how guanfacine works. Especially tell your doctor if you take:

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

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

Guanfacine Food Interactions

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of guanfacine there are no specific foods that you must exclude from your diet when receiving guanfacine.

What is guanfacine (intuniv, tenex)?

Guanfacine reduces nerve impulses in your heart and blood vessels. Guanfacine works by relaxing blood vessels, which lowers blood pressure and improves blood flow.

Guanfacine is used to treat high blood pressure (hypertension). It is sometimes given together with other blood pressure medications.

Guanfacine is also used to treat attention deficit hyperactivity disorder (ADHD) in children who are at least 6 years old.

Guanfacine may also be used for purposes not listed in this medication guide.

What should I discuss with my healthcare provider before taking guanfacine?

You should not use this medication if you are allergic to guanfacine.

To make sure you can safely take guanfacine, tell your doctor if you have any of these other conditions:

  • heart disease or heart block;

  • coronary artery disease or a history of stroke;

  • low blood pressure;

  • kidney disease;

  • liver disease; or

  • if you have recently had a heart attack.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether guanfacine passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Call your doctor for instructions if you miss more than 2 doses in a row.

Guanfacine dosing information

Usual Adult Dose for Hypertension:

Initial dose: 1 mg orally once a day at bedtime; may increase to 2 mg once a day if satisfactory result not achieved after 3 to 4 weeks.

Comments: Adverse reactions increase significantly with doses above 3 mg/day.

Usual Pediatric Dose for Attention Deficit Disorder:

6 YEARS TO LESS THAN 18 YEARS:
Initial dose: 1 mg orally once a day, either in the morning or evening, at approximately the same time each day; may adjust in increments of no more than 1 mg/week.

Recommended target dose: 0.05 to 0.12 mg/kg/day (total daily dose between 1 and 7 mg) once a day, depending on clinical response and tolerability

Maximum dose: 6 to 12 years: Doses above 4 mg/day have not been evaluated; 13 to 17 years: Doses above 7 mg/day have not been evaluated.

Comments: Attention Deficit Hyperactivity Disorder (ADHD) may require treatment for an extended period of time; healthcare providers should periodically reevaluate treatment and adjust dose as needed.

Use: Treatment of ADHD as monotherapy and as adjunctive therapy to stimulant medications.

Usual Pediatric Dose for Hypertension:

12 YEARS OR OLDER:
Initial dose: 1 mg orally once a day at bedtime; may increase to 2 mg once a day if satisfactory result not achieved after 3 to 4 weeks.

Comments: Adverse reactions increase significantly with doses above 3 mg/day.

Cautions for Guanfacine

Contraindications

  • Known hypersensitivity to the drug.1

Warnings/Precautions

Sensitivity Reactions

Rash

Skin rash with exfoliation reported.1 Although causal relationship to guanfacine not established, discontinue drug if rash occurs and appropriately monitor patient.1

General Precautions

Withdrawal Effects

Risk of symptoms of nervousness and anxiety and, less commonly, rebound hypertension, if drug is stopped abruptly.1 Occurs less commonly than with clonidine;1 2 3 incidence may be about 3%.2

Following abrupt discontinuance of guanfacine, BP usually returns to pretreatment levels slowly (within 2–4 days) without ill effects.1 3 When rebound hypertension occurs, onset typically is 2–4 days after discontinuance of the drug (which is later than observed with clonidine hydrochloride).1

Cardiovascular Effects

Like other antihypertensive agents, use with caution in patients with severe coronary insufficiency, recent acute MI, or cerebrovascular disease.1

Nervous System Effects

Risk of dose-related sedation/drowsiness, especially during initial therapy.1 Performance of activities requiring mental alertness and physical coordination (operating machinery, driving a motor vehicle) may be impaired.1

Specific Populations

Pregnancy

Category B.1

Not recommended for the treatment of acute hypertension associated with toxemia of pregnancy.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use caution.1

Pediatric Use

Safety and efficacy for management of hypertension not established in children <12 years of age; use not recommended.1

Safe use for the management of ADHD in children has not been established, but clinical studies currently are under way to determine safety and efficacy.9 10

Mania and aggressive behavioral changes reported in pediatric patients with ADHD receiving the drug;1 all patients had medical or family risk factors for bipolar disorder.1 All patients recovered following discontinuance of the drug.1

Geriatric Use

Clinical trial data for patients ≥65 years of age insufficient to determine whether geriatric patients respond differently than younger adults. 1 Other experience suggests that response is similar to that in younger adults.1

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1

Hepatic Impairment

Like other antihypertensive agents, use guanfacine with caution in patients with chronic hepatic failure.1

Renal Impairment

Like other antihypertensive agents, use with caution in patients with chronic renal failure.1

Common Adverse Effects

Dry mouth,1 4 5 somnolence,1 3 4 5 dizziness,1 4 5 constipation,1 fatigue,1 4 5 asthenia,1 5 impotence,1 4 5 headache.1 4 5

Advice to Patients

  • Importance of advising patients not to discontinue therapy abruptly because of the risk of withdrawal symptoms (e.g., nervousness, anxiety) and, less commonly, rebound hypertension.1 (See Withdrawal Effects under Cautions.)

  • Importance of advising patients to exercise caution when operating dangerous machinery or driving motor vehicles until it is known that the drug is not causing untoward dizziness or drowsiness.1

  • Importance of advising patients of the potential for decreased tolerance for alcohol and other CNS depressants.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

guanfacine Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common
  • Blurred vision
  • confusion
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • sweating
  • unusual tiredness or weakness
Less common
  • Chest pain or discomfort
  • cough
  • difficulty with breathing
  • fast, slow, or irregular heartbeat
  • increased need to urinate
  • lightheadedness, dizziness, or fainting
  • mental depression
  • noisy breathing
  • passing urine more often
  • pounding heartbeat
  • tightness in the chest

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose
  • Dizziness (extreme) or faintness
  • unusual tiredness or weakness (severe)

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Constipation
  • dizziness
  • drowsiness
  • dryness of the mouth
  • headache
  • irritability
  • nausea
  • sleepiness or unusual drowsiness
  • unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
  • upper abdominal or stomach pain
  • vomiting
  • weight gain
Less common
  • Acid or sour stomach
  • belching
  • decreased appetite
  • decreased sexual ability
  • dry, itching, or burning eyes
  • heartburn
  • indigestion
  • lack or loss of strength
  • paleness of the skin
  • stomach discomfort, upset, or pain
  • trouble with sleeping

After you stop using guanfacine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

  • Anxiety or tenseness
  • increased salivation
  • nervousness or restlessness
  • shaking or trembling of the hands and fingers
  • stomach cramps
  • sweating

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

Description

Guanfacine hydrochloride, USP is a centrally acting antihypertensive with α2 -adrenoceptor agonist properties in tablet form for oral administration.

The chemical name of Guanfacine hydrochloride, USP is N-amidino-2-(2,6-dichlorophenyl) acetamide hydrochloride and its molecular weight is 282.56. Its structural formula is:

Guanfacine hydrochloride, USP is a white to off-white powder; sparingly soluble in water and alcohol and slightly soluble in acetone.

Each tablet, for oral administration, contains Guanfacine hydrochloride, USP equivalent to 1 mg or 2 mg Guanfacine. In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, and stearic acid.

Precautions

GENERAL

Like other antihypertensive agents, Guanfacine hydrochloride should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, or chronic renal or hepatic failure.

Sedation

Guanfacine, like other orally active central α2-adrenergic agonists, causes sedation or drowsiness, especially when beginning therapy. These symptoms are dose-related (see ADVERSE REACTIONS). When Guanfacine is used with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), the potential for additive sedative effects should be considered.

<content styleCode="bold">Rebound</content>Rebound

Abrupt cessation of therapy with orally active central α2-adrenergic agonists may be associated with increases (from depressed on-therapy levels) in plasma and urinary catecholamines, symptoms of “nervousness and anxiety” and, less commonly, increases in blood pressure to levels significantly greater than those prior to therapy.

Information for Patients

Patients who receive Guanfacine should be advised to exercise caution when operating dangerous machinery or driving motor vehicles until it is determined that they do not become drowsy or dizzy from the medication. Patients should be warned that their tolerance for alcohol and other CNS depressants may be diminished. Patients should be advised not to discontinue therapy abruptly.

<content styleCode="bold">Laboratory Tests</content>Laboratory Tests

In clinical trials, no clinically relevant laboratory test abnormalities were identified as causally related to drug during short-term treatment with Guanfacine hydrochloride.

<content styleCode="bold">Drug Interactions</content>Drug Interactions

The potential for increased sedation when Guanfacine is given with other CNS-depressant drugs should be appreciated.

The administration of Guanfacine concomitantly with a known microsomal enzyme inducer (phenobarbital or phenytoin) to two patients with renal impairment reportedly resulted in significant reductions in elimination half-life and plasma concentration. In such cases, therefore, more frequent dosing may be required to achieve or maintain the desired hypotensive response. Further, if Guanfacine is to be discontinued in such patients, careful tapering of the dosage may be necessary in order to avoid rebound phenomena (see Rebound above).

Anticoagulants

Ten patients who were stabilized on oral anticoagulants were given Guanfacine, 1 to 2 mg/day, for 4 weeks. No changes were observed in the degree of anticoagulation.

In several well-controlled studies, Guanfacine was administered together with diuretics with no drug interactions reported. In the long-term safety studies, Guanfacine was given concomitantly with many drugs without evidence of any interactions. The principal drugs given (number of patients in parentheses) were: cardiac glycosides (115), sedatives and hypnotics (103), coronary vasodilators (52), oral hypoglycemics (45), cough and cold preparations (45), NSAIDs (38), antihyperlipidemics (29), antigout drugs (24), oral contraceptives (18), bronchodilators (13), insulin (10) and beta blockers (10).

Drug/Laboratory Test Interactions

No laboratory test abnormalities related to the use of Guanfacine hydrochloride have been identified.

<content styleCode="bold">Carcinogenesis, Mutagenesis, Impairment of Fertility</content>Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenic effect was observed in studies of 78 weeks in mice at doses more than 150 times the maximum recommended human dose and 102 weeks in rats at doses more than 100 times the maximum recommended human dose. In a variety of test models, Guanfacine was not mutagenic.

No adverse effects were observed in fertility studies in male and female rats.

<content styleCode="bold">Pregnancy Category B</content>Pregnancy Category B

Administration of Guanfacine to rats at 70 times the maximum recommended human dose and to rabbits at 20 times the maximum recommended human dose resulted in no evidence of harm to the fetus. Higher doses (100 and 200 times the maximum recommended human dose in rabbits and rats respectively) were associated with reduced fetal survival and maternal toxicity. Rat experiments have shown that Guanfacine crosses the placenta.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

<content styleCode="bold">Labor and Delivery</content>Labor and Delivery

Guanfacine hydrochloride is not recommended in the treatment of acute hypertension associated with toxemia of pregnancy. There is no information available on the effects of Guanfacine on the course of labor and delivery.

<content styleCode="bold">Nursing Mothers</content>Nursing Mothers

It is not known whether Guanfacine hydrochloride is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Guanfacine is administered to a nursing woman. Experiments with rats have shown that Guanfacine is excreted in the milk.

<content styleCode="bold">Pediatric Use</content>Pediatric Use

Safety and effectiveness in children under 12 years of age have not been demonstrated. Therefore, the use of Guanfacine in this age group is not recommended. There have been spontaneous postmarketing reports of mania and aggressive behavioral changes in pediatric patients with attention-deficit hyperactivity disorder (ADHD) receiving Guanfacine. The reported cases were from a single center. All patients had medical or family risk factors for bipolar disorder. All patients recovered upon discontinuation of Guanfacine HCl. Hallucinations have been reported in pediatric patients receiving Guanfacine for treatment of attention-deficit hyperactivity disorder.

<content styleCode="bold">Geriatric Use</content>Geriatric Use

Clinical studies of Guanfacine did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

<content styleCode="bold">Drug Interactions</content>Drug Interactions

The potential for increased sedation when Guanfacine is given with other CNS-depressant drugs should be appreciated.

The administration of Guanfacine concomitantly with a known microsomal enzyme inducer (phenobarbital or phenytoin) to two patients with renal impairment reportedly resulted in significant reductions in elimination half-life and plasma concentration. In such cases, therefore, more frequent dosing may be required to achieve or maintain the desired hypotensive response. Further, if Guanfacine is to be discontinued in such patients, careful tapering of the dosage may be necessary in order to avoid rebound phenomena (see Rebound above).

Anticoagulants

Ten patients who were stabilized on oral anticoagulants were given Guanfacine, 1 to 2 mg/day, for 4 weeks. No changes were observed in the degree of anticoagulation.

In several well-controlled studies, Guanfacine was administered together with diuretics with no drug interactions reported. In the long-term safety studies, Guanfacine was given concomitantly with many drugs without evidence of any interactions. The principal drugs given (number of patients in parentheses) were: cardiac glycosides (115), sedatives and hypnotics (103), coronary vasodilators (52), oral hypoglycemics (45), cough and cold preparations (45), NSAIDs (38), antihyperlipidemics (29), antigout drugs (24), oral contraceptives (18), bronchodilators (13), insulin (10) and beta blockers (10).

Drug/Laboratory Test Interactions

No laboratory test abnormalities related to the use of Guanfacine hydrochloride have been identified.

Off Label Uses

Tourette syndrome (children and adolescents)

Data from a meta-analysis and 2 small, randomized double-blind controlled trials support the use of guanfacine in the treatment Tourette syndrome and chronic tic disorders in children and adolescents (including those with comorbid attention deficit hyperactivity disorder [ADHD]). Additional trials may be necessary to further define the role of guanfacine in this condition. Based on the European Society for the Study of Tourette Syndrome (ESSTS) and the Tourette Canada guidelines, drug therapy, including guanfacine, is effective and recommended for the management of Tourette syndrome to improve quality of life with tics that are painful or distressing, interfere with daily functioning, or cause sustained social or emotional problems. Similarly, according to an American Academy of Child and Adolescent Psychiatry (AACAP) practice parameter for the treatment of children and adolescents with tic disorders, drug therapy, including guanfacine, is effective and recommended for the management of moderate to severe tics that severely impair quality of life in patients with chronic tic disorders, including Tourette syndrome. Because of its preferable adverse effect profile compared with antipsychotics, guanfacine is considered a first-line option for reducing tics and ADHD symptoms in patients with Tourette syndrome and comorbid ADHD.

Adverse Reactions

>10%:

Central nervous system: Drowsiness (10% to 57%; dose-related), headache (4% to 28%), fatigue (5% to 22%), dizziness (4% to 16%; dose-related), insomnia (2% to 13%),

Gastrointestinal: Xerostomia (3% to 54%; dose-related), abdominal pain (≤8% to 19%; dose-related), decreased appetite (5% to 15%), constipation (2% to 15%; dose-related)

1% to 10%:

Cardiovascular: Hypotension (≤1% to 9%; dose-related; includes orthostatic), bradycardia (2% to 5%), atrioventricular block (≥2%), sinus arrhythmia (≥2%), syncope (1% to ≥2%)

Central nervous system: Irritability (5% to 8%), lethargy (3% to 8%), anxiety (2% to 5%), nightmares (3% to 4%), emotional lability (children and adolescents 6 to 17 years: 2% to 3%), agitation (≥2%), depression (≥2%)

Dermatologic: Skin rash (2% to 3%), pruritus (2%)

Endocrine & metabolic: Weight gain (≤2% to 3%)

Gastrointestinal: Nausea (≤5% to 7%), vomiting (2% to 7%), diarrhea (2% to 6%), dyspepsia (≥2%), stomach pain (≥2%)

Genitourinary: Impotence (≤3% to 7%), urinary incontinence (2% to 5%)

Neuromuscular & skeletal: Weakness (≤2% to 7%)

Respiratory: Asthma (≥2%)

Miscellaneous: Fever (8%; Biederman 2008)

Frequency not defined:

Cardiovascular: Chest pain, hypertension

Central nervous system: Convulsions

Dermatologic: Pallor

Genitourinary: Urinary frequency

Hepatic: Increased serum ALT

Hypersensitivity: Hypersensitivity reaction

<1% (Limited to important or life-threatening): Alopecia, amnesia, cardiac fibrillation, cerebrovascular accident, dermatitis, dysphagia, exacerbation of cardiac disease (sinus node dysfunction, atrioventricular block), exfoliative dermatitis, hallucination, hypertensive encephalopathy (with abrupt discontinuation), hypokinesia, iritis, mania (immediate release; children), myocardial infarction, nocturia, palpitations, paresis, Raynaud phenomenon, rebound hypertension, renal failure, tachycardia, visual disturbance

In Summary

Commonly reported side effects of guanfacine include: asthenia, constipation, drowsiness, decreased blood pressure, dizziness, fatigue, hypotension, sedation, and xerostomia. Other side effects include: impotence, and nausea. See below for a comprehensive list of adverse effects.

For Healthcare Professionals

Applies to guanfacine: oral tablet, oral tablet extended release

General

The most common adverse reactions were dry mouth, somnolence, headache, fatigue, dizziness, abdominal pain, constipation, appetite decreased, and sedation.[Ref]

Gastrointestinal

Very common (10% or more): Dry mouth (up to 54%), abdominal pain (up to 15%), constipation (up to 15%)
Common (1% to 10%): Vomiting, diarrhea, nausea, abdominal/stomach discomfort
Uncommon (0.1% to 1%): Dyspepsia[Ref]

Nervous system

Very common (10% or more): Somnolence (up to 40.6%), headache (up to 28%), dizziness (up to 16%), sedation (10.2%)
Common (1% to 10%): Lethargy, convulsion, dizziness postural, syncope
Rare (less than 0.1%): Hypersomnia
Postmarketing reports: Tremor, paresthesias, vertigo, taste alteration[Ref]

Other

Very common (10% or more): Fatigue (up to 22%)
Common (1% to 10%): Asthenia
Uncommon (0.1% to 1%): Chest pain
Rare (less than 0.1%): Malaise[Ref]

Metabolic

Very common (10% or more): Appetite decreased (up to 15%)
Common (1% to 10%): Weight increased
Frequency not reported: Body mass index increased
Postmarketing reports: Edema

Psychiatric

Common (1% to 10%): Insomnia, depression, anxiety, affect lability, middle insomnia, nightmare, irritability
Uncommon (0.1% to 1%): Agitation, hallucination
Postmarketing reports: Confusion[Ref]

Cardiovascular

Common (1% to 10%): Hypotension, bradycardia, orthostatic hypotension, tachycardia
Uncommon (0.1% to 1%): Pallor, atrioventricular block first degree, sinus arrhythmia, blood pressure increased, heart rate decreased
Rare (less than 0.1%): Hypertension
Frequency not reported: QTc prolongation
Postmarketing reports: Palpitations

Genitourinary

Common (1% to 10%): Impotence, enuresis
Uncommon (0.1% to 1%): Pollakiuria
Frequency not reported: Urinary frequency increased[Ref]

Dermatologic

Common (1% to 10%): Rash, pruritus
Postmarketing reports: Alopecia, dermatitis, exfoliative dermatitis

Respiratory

Uncommon (0.1% to 1%): Asthma
Postmarketing reports: Dyspnea

Hepatic

Uncommon (0.1% to 1%): ALT increased

Immunologic

Uncommon (0.1% to 1%): Hypersensitivity

Musculoskeletal

Postmarketing reports: Arthralgia, leg cramps, leg pain, myalgia

Ocular

Postmarketing reports: Blurred vision

Some side effects of guanfacine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Renal Dose Adjustments

Dose adjustment(s) may be required; however, no specific guidelines have been suggested. Caution recommended.

Precautions

Safety and efficacy have not been established in hypertensive patients younger than 12 years; safety and efficacy have not been established in Attention Deficit Hyperactivity Disorder (ADHD) patients younger than 6 years.

Consult WARNINGS section for additional precautions.

Response and Effectiveness

Peak plasma concentrations occur within one to four hours of a single dose (average time to peak is 2.6 hours). The effect of guanfacine lasts approximately 24 hours.

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Administrative Information

LactMed Record Number

631

Last Revision Date

20150310

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.

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