1 ). 1 ). To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. gov/medwatch. 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 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% *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 Extended-Release Tablets and >rate than in placebo) in Fixed Dose Studies 1 and 2 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%) 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 Extended-Release Tablets and >rate than in placebo) in Fixed Dose Studies 1 and 2 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% 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.
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 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% Enuresis d 1% 2% 5% 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.
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 Study 4 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%) 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 Extended-Release Tablets and >rate than in placebo) in the Monotherapy Flexible Dose Study 4 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% 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: 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 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% 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 Extended-Release Tablets and >rate than in placebo) in the Monotherapy Flexible Dose Study 5 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% 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.
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 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% 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 Extended-Release Tablets and >rate than in placebo) in the Short-Term Adjunctive Study 3 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% 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.
5 bpm, respectively, for all doses combined (generally one week after reaching target doses). 2 mmHg. 4 mmHg. 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 tablets group 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. 2 )]. Effects on Height, Weight, and Body Mass Index (BMI) Patients taking guanfacine extended-release tablets demonstrated similar growth compared to normative data.
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 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 extended-release tablets. 1, listed by organ system. 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. 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