Guanfacine Extended-Release (Page 2 of 7)

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Hypotension, Bradycardia, and Syncope

Treatment with guanfacine extended-release tablets 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 extended-release tablets 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 extended-release tablets 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 extended-release tablets . Advise patients to avoid use with alcohol.

5.3 Cardiac Conduction Abnormalities

The sympatholytic action of guanfacine extended-release tablets may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. Titrate guanfacine extended-release tablets 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 extended-release tablets 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 extended-release tablets 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 extended-release tablets 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 extended-release tablets. 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) ]

To report SUSPECTED ADVERSE REACTIONS, contact TWi Pharmaceuticals, Inc. 1-844-518-2989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

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

The data described below reflect clinical trial exposure to guanfacine extended-release tablets 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
*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).
Guanfacine Extended-Release Tablets (mg)
Adverse Reaction Term Placebo (N=149) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of guanfacine extended-release tablets (N=513)
Somnolence a 11% 28% 30% 38% 51% 38%
Fatigue 3% 10% 13% 17% 15% 14%
Hypotension b 3% 8% 5% 7% 8% 7%
Dizziness 4% 5% 3% 7% 10% 6%
Lethargy 3% 2% 3% 8% 7% 6%
Nausea 2% 7% 5% 5% 6% 6%
Dry mouth 1% 0% 1% 6% 7% 4%
Table 4: Adverse Reactions Leading to Discontinuation (≥ 2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in Fixed Dose Studies 1 and 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.
Guanfacine Extended-Release Tablets (mg)
Adverse Reaction Term Placebo (N=149) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of guanfacine extended-release tablets (N=513)
n (%) n (%) n (%) n (%) n (%) n (%)
Total patients 4 (3%) 2 (3%) 10 (7%) 15 (10%) 27 (18%) 54 (11%)
Somnolence a 1 (1%) 2 (3%) 5 (3%) 6 (4%) 17 (11%) 30 (6%)
Fatigue 0 (0%) 0 (0%) 2 (1%) 2 (1%) 4 (3%) 8 (2%)
Table 5: Other Common Adverse Reactions (≥ 2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in Fixed Dose Studies 1 and 2
Adverse reactions ≥ 2% for all doses of guanfacine extended-release tablets 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.
Guanfacine Extended-Release Tablets (mg)
Adverse Reaction Term Placebo (N=149) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of guanfacine extended-release tablets (N=513)
Headache 19% 26% 25% 16% 28% 23%
Abdominal Pain a 9% 10% 7% 11% 15% 11%
Decreased Appetite 4% 5% 4% 9% 6% 6%
Irritability 4% 5% 8% 3% 7% 6%
Constipation 1% 2% 2% 3% 4% 3%
Nightmare b 0% 0% 0% 3% 4% 2%
Enuresis c 1% 0% 1% 3% 2% 2%
Affect Lability d 1% 2% 1% 3% 1% 2%

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
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.
Guanfacine Extended-Release Tablets
Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of guanfacine extended-release tablets (N=221)
Somnolence a 15% 57% 54% 56%
Abdominal Pain b 7% 8% 19% 14%
Fatigue 3% 10% 11% 11%
Irritability 3% 7% 7% 7%
Nausea 1% 6% 5% 5%
Dizziness 3% 6% 4% 5%
Vomiting 2% 7% 4% 5%
Hypotension c 0% 6% 4% 5%
Decreased Appetite 3% 6% 3% 4%
Enursis d 1% 2% 5% 4%
Table 7: Adverse Reactions Leading to Discontinuation (≥ 2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in Monotherapy Flexible Dose Studies 4
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.
Guanfacine Extended-Release Tablets
Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of guanfacine extended-release tablets (N=221)
n (%) n (%) n (%) n (%)
Total patients 0 (0%) 8 (7%) 7 (6%) 15 (7%)
Somnolence a 0 (0%) 4 (4%) 3 (3%) 7 (3%)
Table 8: Other Common Adverse Reactions (≥2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in the Monotherapy Flexible Dose Study 4
Adverse reactions ≥ 2% for all doses of guanfacine extended-release tablets and > rate in placebo in any dose group but did not meet this criteria inall doses combined: affect lability (affect lability, mood swings), increased weight, syncope/loss of consciousness (loss ofconsciousness, 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.
Guanfacine Extended-Release Tablets
Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of guanfacine extended-release tablets (N=221)
Headache 11% 18% 16% 17%
Insomnia a 6% 8% 6% 7%
Diarrhea 4% 4% 6% 5%
Lethargy 0% 4% 3% 3%
Constipation 2% 2% 4% 3%
Dry Mouth 1% 3% 3% 3%
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
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.
Adverse Reaction Term Placebo (N=155) All Doses of guanfacine extended-release tablets (N=157)
Somnolence a 23% 54%
Insomnia b 6% 13%
Hypotension c 3% 9%
Dry Mouth 0% 8%
Postural Dizziness 2% 5%
Bradycardia d 0% 5%

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

Table 10: Other Common Adverse Reactions (≥ 2% for all doses of guanfacine extended-release tablets and > rate than in placebo) in the Monotherapy Flexible Dose Study 5
Adverse reactions ≥ 2% for all doses of guanfacine extended-release tablets 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.
Guanfacine Extended-Release Tablets
Adverse Reaction Term Placebo (N=155) All Doses of guanfacine extended-release tablets (N=157)
Headache 18% 27%
Fatigue 12% 22%
Dizziness 10% 16%
Decreased Appetite 14% 15%
Abdominal Pain a 8% 12%
Irritability 4% 7%
Anxiety b 3% 5%
Rash c 1% 3%
Constipation 0% 3%
Increased Weight 2% 3%
Abdominal/Stomach Discomfort d 1% 2%
Pruritus 1% 2%

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
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.
Guanfacine Extended-Release Tablets + stimulant
Adverse Reaction Term Placebo+stimulant (N=153) AM (N=150) PM (N=152) All Doses (N=302)
Somnolence a 7% 18% 18% 18%
Insomnia b 6% 10% 14% 12%
Abdominal Pain c 3% 8% 12% 10%
Fatigue 3% 12% 7% 10%
Dizziness 4% 10% 5% 8%
Decreased Appetite 4% 7% 8% 7%
Nausea 3% 3% 7% 5%

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 extended-release tablets and > rate than in placebo) in the Short-Term Adjunctive Study 3
Adverse reactions ≥ 2% for all doses of guanfacine extended-release tablets 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.
Guanfacine Extended-Release Tablets + stimulant
Adverse Reaction Term Placebo (N=153) AM (N=150) PM (N=152) All Doses of Guanfacine Extended-Release Tablets (N=302)
Headache 13% 21% 21% 21%
Diarrhea 1% 4% 3% 4%
Hypotension a 0% 4% 2% 3%
Constipation 0% 2% 3% 2%
Affect Lability b 1% 3% 2% 2%
Dry Mouth 0% 1% 3% 2%
Bradycardia c 0% 1% 3% 2%
Postural Dizziness 0% 1% 3% 2%
Rash d 1% 1% 2% 2%
Nightmare e 1% 2% 1% 2%
Tachycardia f 1% 2% 1% 2%

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 -4.8bpm, -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 extended-release tabletsgroup and 3% of the placebo group. This includes orthostatic hypotension, which was reported for 1% of the guanfacine extended-release tablets 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 extended-release tablets 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 extended-release tablets. 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 extended-release tablets. 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 extended-release tablets, 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 extended-release tablets demonstrated similar growth compared to normative data. Patients taking guanfacine extended-release tablets had a mean increase in weight of 0.5 kg compared to those receiving placebo over a comparable treatment period. Patients receiving guanfacine extended-release tablets for at least 12 months in open-label studies gained an average of 8 kg inweight 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 extended-release tablets.

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

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