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Intuniv

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Intuniv

Side Effects
Interactions

SIDE EFFECTS

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

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 2,299 patients. This includes 1,804 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

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)
Somnolencea 11% 28% 30% 38% 51% 38%
Fatigue 3% 10% 13% 17% 15% 14%
Hypotensionb 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 INTUNIV and > rate in placebo) in Fixed Dose Studies 1 and 2

Adverse Reaction Term Placebo
(N=149)
n (%)
INTUNIV® (mg)
1mg*
(N=61)
n (%)
2mg
(N=150)
n (%)
3mg
(N=151)
n (%)
4mg
(N=151)
n (%)
All Doses of INTUNIV®
(N=513)
n (%)
Total patients 4 (3%) 2 (3%) 10 (7%) 15 (10%) 27 (18%) 54 (11%)
Somnolencea 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 INTUNIV and > rate 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 Paina 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%
Nightmareb 0% 0% 0% 3% 4% 2%
Enuresisc 1% 0% 1% 3% 2% 2%
Affect Labilityd 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.
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

Adverse Reaction Term Placebo
(N=112)
INTUNIV®
AM
(N=107)
PM
(N=114)
All Doses of INTUNIV®
(N=221)
Somnolencea 15% 57% 54% 56%
Abdominal Painb 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%
Hypotensionc 0% 6% 4% 5%
Decreased Appetite 3% 6% 3% 4%
Enuresisd 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 INTUNIV and > rate in placebo) in Monotherapy Flexible Dose Study 4

Adverse Reaction Term Placebo
(N=112)
n (%)
INTUNIV®
AM
(N=107)
n (%)
PM
(N=114)
n (%)
All Doses of INTUNIV®
(N=221)
n (%)
Total patients 0 (0%) 8 (7%) 7 (6%) 15 (7%)
Somnolencea 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 INTUNIV and > rate in placebo) in the Monotherapy Flexible Dose 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%
Insomniaa 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).
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 forplacebo) Adverse Reactions in the Monotherapy Flexible Dose Study 5

Adverse Reaction Term Placebo
(N=155)
All Doses of INTUNIV®
(N=157)
Somnolencea 23% 54%
Insomniab 6% 13%
Hypotensionc 3% 9%
Dry Mouth 0% 8%
Postural Dizziness 2% 5%
Bradycardiad 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 INTUNIV and > rate 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 Paina 8% 12%
Irritability 4% 7%
Anxietyb 3% 5%
Rashc 1% 3%
Constipation 0% 3%
Increased Weight 2% 3%
Abdominal/Stomach Discomfortd 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).
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

Adverse Reaction Term Placebo+ stimulant
(N=153)
INTUNIV® + stimulant
AM
(N=150)
PM
(N=152)
All Doses
(N=302)
Somnolencea 7% 18% 18% 18%
Insomniab 6% 10% 14% 12%
Abdominal Painc 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 INTUNIV and > rate 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%
Hypotensiona 0% 4% 2% 3%
Constipation 0% 2% 3% 2%
Affect Labilityb 1% 3% 2% 2%
Dry Mouth 0% 1% 3% 2%
Bradycardiac 0% 1% 3% 2%
Postural Dizziness 0% 1% 3% 2%
Rashd 1% 1% 2% 2%
Nightmaree 1% 2% 1% 2%
T achycardiaf 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).
a The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased.
b The affect lability term includes affect lability and mood swings.
c The bradycardia term includes bradycardia and sinus bradycardia.
d The rash term includes rash, rash generalized, and rash papular.
e The nightmare term includes abnormal dreams, nightmare, and sleep terror.
f The tachycardia term includes tachycardia and sinus tachycardia.

Effects on Blood Pressure and Heart Rate

In the monotherapy pediatric, short-term, controlled trials (Studies 1 and 2), the maximum mean changes from baseline in seated systolic blood pressure, diastolic blood pressure, and pulse were -5.4 mmHg, -3.4 mmHg, and -5.5 bpm, respectively, for all doses combined (generally one week after reaching target doses). For the respective fixed doses 1 mg/day, 2 mg/day, 3 mg/day or 4 mg/day the maximum mean changes in seated systolic blood pressure were -4.3 mmHg, -5.5 mmHg, -5.4 mmHg and -8.2 mmHg. For these respective fixed doses the maximum mean changes in seated diastolic blood pressure were -3.4 mmHg, -3.3 mmHg, -4.4 mmHg and -5.4 mmHg. For these respective fixed doses the maximum mean changes in seated pulse were 4.8 bpm, -3.1 bpm, -6.5 bpm and -8.6 bpm. Decreases in blood pressure and heart rate were usually modest and asymptomatic; however, hypotension and bradycardia can occur. Hypotension was reported as an adverse reaction for 7% of the 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.

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 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

Post-marketing Experience

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

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

General: edema, malaise, tremor

Cardiovascular: palpitations, tachycardia

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

Read the Intuniv (guanfacine) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Table 14 contains clinically important drug interactions with INTUNIV® [see CLINICAL PHARMACOLOGY].

Table 14: Clinically Important Drug Interactions: Effect of other Drugs on INTUNIV®

Concomitant Drug Name or Drug Class Clinical Rationale and Magnitude of Drug Interaction Clinical Recommendation
CYP3A4 inhibitors, e.g.,ketoconazole Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a 200% increase in exposure Consider dose reduction [see DOSAGE AND ADMINISTRATION]
CYP3A4 inducers, e.g., rifampin Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a 60% decrease in exposure Consider dose increase [see DOSAGE AND ADMINISTRATION]

Drug Abuse And Dependence

Controlled Substance

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

Read the Intuniv Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 12/4/2014
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions
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