Guanfacine Hydrochloride: Package Insert and Label Information (Page 2 of 3)

ADVERSE REACTIONS

Adverse reactions noted with guanfacine hydrochloride are similar to those of other drugs of the central α 2 -adrenoreceptor agonist class: dry mouth, sedation (somnolence), weakness (asthenia), dizziness, constipation, and impotence. While the reactions are common, most are mild and tend to disappear on continued dosing.

Skin rash with exfoliation has been reported in a few cases; although clear cause and effect relationships to guanfacine could not be established, should a rash occur, guanfacine should be discontinued and the patient monitored appropriately.

In the dose-response monotherapy study described under CLINICAL PHARMACOLOGY, the frequency of the most commonly observed adverse reactions showed a dose relationship from 0.5 to 3 mg as follows:

Adverse Reaction Placebo n=59 0.5 mg n=60 1 mg n=61 2 mg n=60 3 mg n=59
Dry Mouth 0% 10% 10% 42% 54%
Somnolence 8% 5% 10% 13% 39%
Asthenia 0% 2% 3% 7% 3%
Dizziness 8% 12% 2% 8% 15%
Headache 8% 8% 13% 7% 3%
Impotence 0% 0% 0% 7% 3%
Constipation 0% 2% 0% 5% 15%
Fatigue 2% 2% 5% 8% 10%

The percent of patients who dropped out because of adverse reactions are shown below for each dosage group.

Placebo 0.5 mg 1 mg 2 mg 3 mg
Percent Dropouts 0% 2% 5% 13% 32%

The most common reasons for dropouts among patients who received guanfacine were dry mouth, somnolence, dizziness, fatigue, weakness and constipation.

In the 12-week, placebo-controlled, dose-response study of guanfacine administered with 25 mg chlorthalidone at bedtime, the frequency of the most commonly observed adverse reactions showed a clear dose relationship from 0.5 to 3 mg as follows:

Adverse Reactions Placebo n=73 0.5 mg n=72 1 mg n=72 2 mg n=72 3 mg n=72
Dry Mouth 5 (7%) 4 (5%) 6 (8%) 8 (11%) 20 (28%)
Somnolence 1 (1%) 3 (4%) 0 (0%) 1 (1%) 10 (14%)
Asthenia 0 (0%) 2 (3%) 0 (0%) 2 (2%) 7 (10%)
Dizziness 2 (2%) 1 (1%) 3 (4%) 6 (8%) 3 (4%)
Headache 3 (4%) 4 (3%) 3 (4%) 1 (1%) 2 (2%)
Impotence 1 (0%) 1 (0%) 0 (0%) 1 (1%) 3 (4%)
Constipation 0 (0%) 1 (0%) 0 (0%) 1 (1%) 1 (1%)
Fatigue 3 (3%) 0 (0%) 2 (3%) 5 (6%) 3 (4%)

There were 41 premature terminations because of adverse reactions in this study. The percent of patients who dropped out and the dose at which the dropout occurred were as follows:

Dose Placebo 0.5 mg 1 mg 2 mg 3 mg
Percent Dropouts 6.9% 4.2% 3.2% 6.9% 8.3%

Reasons for dropouts among patients who received guanfacine were: somnolence, headache, weakness, dry mouth, dizziness, impotence, insomnia, constipation, syncope, urinary incontinence, conjunctivitis, paresthesia and dermatitis.

In a second 12-week placebo-controlled combination therapy study in which the dose could be adjusted upward to 3 mg per day in 1 mg increments at 3-week intervals, i.e., a setting more similar to ordinary clinical use, the most commonly recorded reactions were: dry mouth, 47%; constipation, 16%; fatigue, 12%; somnolence, 10%; asthenia, 6%; dizziness, 6%; headache, 4%; and insomnia, 4%.

Reasons for dropouts among patients who received guanfacine were: somnolence, dry mouth, dizziness, impotence, constipation, confusion, depression and palpitations.

In the clonidine/guanfacine comparison described in CLINICAL PHARMACOLOGY, the most common adverse reactions noted were as follows:

Adverse Reactions Guanfacine (n=279) Clonidine (n=278)
Dry Mouth 30 % 37%
Somnolence 21% 35%
Dizziness 11% 8%
Constipation 10% 5%
Fatigue 9% 8%
Headache 4% 4%
Insomnia 4% 3%

Adverse reactions occurring in 3% or less of patients in the three controlled trials of guanfacine hydrochloride with a diuretic were:

• Cardiovascular: bradycardia, palpitations, substernal pain

• Gastrointestinal: abdominal pain, diarrhea, dyspepsia, dysphagia, nausea

• CNS: amnesia, confusion, depression, insomnia, libido decrease

• ENT disorders: rhinitis, taste perversion, tinnitus

• Eye disorders: conjunctivitis, iritis, vision disturbance

• Musculoskeletal: leg cramps, hypokinesia

• Respiratory: dyspnea

• Dermatologic: dermatitis, pruritus, purpura, sweating

• Urogenital: testicular disorder, urinary incontinence

• Other: malaise, paresthesia, paresis

Adverse reaction reports tend to decrease over time. In an open-label trial of one year’s duration, 580 hypertensive subjects were given guanfacine, titrated to achieve goal blood pressure, alone (51%), with diuretic (38%), with beta blocker (3%), with diuretic plus beta blocker (6%), or with diuretic plus vasodilator (2%). The mean daily dose of guanfacine reached was 4.7 mg.

Adverse Reaction Incidence of adverse reactions at any time during the study Incidence of adverse reactions at end of one year
n=580 n=580
Dry Mouth 60% 15%
Drowsiness 33% 6%
Dizziness 15% 1%
Constipation 14% 3%
Weakness 5% 1%
Headache 4% 0.2%
Insomnia 5% 0%

There were 52 (8.9%) dropouts due to adverse effects in this 1-year trial. The causes were: dry mouth (n = 20), weakness (n = 12), constipation (n = 7), somnolence (n = 3), nausea (n = 3), orthostatic hypotension (n = 2), insomnia (n = 1), rash (n = 1), nightmares (n = 1), headache (n = 1) and depression (n = 1).

Postmarketing Experience

An open-label postmarketing study involving 21,718 patients was conducted to assess the safety of guanfacine hydrochloride 1 mg/day given at bedtime for 28 days. Guanfacine was administered with or without other antihypertensive agents. Adverse events reported in the postmarketing study at an incidence greater than 1% included dry mouth, dizziness, somnolence, fatigue, headache and nausea. The most commonly reported adverse events in this study were the same as those observed in controlled clinical trials.

Less frequent, possibly guanfacine-related events observed in the postmarketing study and/or reported spontaneously include:

• Body as a Whole: asthenia, chest pain, edema, malaise, tremor

• Cardiovascular: bradycardia, palpitations, syncope, tachycardia

• Central Nervous System: paresthesias, vertigo

• Eye Disorders: blurred vision

• Gastrointestinal System: abdominal pain, constipation, diarrhea, dyspepsia

• Liver and Biliary System: abnormal liver function tests

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

• Psychiatric: agitation, anxiety, confusion, depression, insomnia, nervousness

• Reproductive System, Male: impotence

• Respiratory System: dyspnea

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

• Special Senses: alterations in taste

• Urinary System: nocturia, urinary frequency

Rare, serious disorders with no definitive cause and effect relationship to guanfacine have been reported spontaneously and/or in the postmarketing study. These events include acute renal failure, cardiac fibrillation, cerebrovascular accident, congestive heart failure, heart block, and myocardial infarction.

To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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