Data from FDA - Curated by EPG Health - Last updated 01 April 2018

Indication(s)

1 INDICATIONS AND USAGE INTUNIV® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [see Clinical Studies (14)]. INTUNIV ® is a central alpha2A-adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications (1,14).

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Advisory information

contraindications
4 CONTRAINDICATIONS INTUNIV is contraindicated in patients with a history of a hypersensitivity reaction to INTUNIV or its inactive ingredients, or other products containing guanfacine. Rash and pruritus have been reported. History of hypersensitivity to INTUNIV ® , its inactive ingredients, or other products containing guanfacine (4).
Adverse reactions
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)] Most common adverse reactions (≥5% and at least twice placebo rate) in fixed-dose monotherapy ADHD trials in children and adolescents (6 to 17 years): hypotension, somnolence, fatigue, nausea, and lethargy (6.1) Flexible dose-optimization ADHD trials in children (6 to 12 years) and adolescents (13 to 17 years): somnolence, hypotension, abdominal pain, insomnia, fatigue, dizziness, dry mouth, irritability, nausea, vomiting, and bradycardia (6.1). Adjunctive treatment to psychostimulant ADHD trial in children and adolescents (6 to 17 years): somnolence, fatigue, insomnia, dizziness, and abdominal pain (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Shire US Inc. at 1-800-828-2088 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 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 Dose Studies 1 and 2 INTUNIV® (mg) Adverse Reaction Term Placebo (N=149) 1mgThe lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of INTUNIV® (N=513) SomnolenceThe somnolence term includes somnolence, sedation, and hypersomnia. 11% 28% 30% 38% 51% 38% Fatigue 3% 10% 13% 17% 15% 14% HypotensionThe hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). 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 INTUNIV and >rate than in placebo) in Fixed Dose Studies 1 and 2 INTUNIV® (mg) Adverse Reaction Term Placebo (N=149) 1mgThe lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of INTUNIV® (N=513) n (%) n (%) n (%) n (%) n (%) n (%) 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. Total patients 4 (3%) 2 (3%) 10 (7%) 15 (10%) 27 (18%) 54 (11%) SomnolenceThe somnolence term includes somnolence, sedation, and hypersomnia. 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 INTUNIV and >rate than in placebo) in Fixed Dose Studies 1 and 2 INTUNIV® (mg) Adverse Reaction Term Placebo (N=149) 1mgThe lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of INTUNIV® (N=513) 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. Headache 19% 26% 25% 16% 28% 23% Abdominal PainThe abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. 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% NightmareThe nightmare term includes abnormal dreams, nightmare, and sleep terror. 0% 0% 0% 3% 4% 2% EnuresisThe enuresis term includes enuresis, nocturia, and urinary incontinence. 1% 0% 1% 3% 2% 2% Affect LabilityThe affect lability term includes affect lability and mood swings. 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 INTUNIV® Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of INTUNIV® (N=221) SomnolenceThe somnolence term includes somnolence, sedation, and hypersomnia. 15% 57% 54% 56% Abdominal PainThe abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness 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% HypotensionThe hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). 0% 6% 4% 5% Decreased Appetite 3% 6% 3% 4% EnuresisThe enuresis term includes enuresis, nocturia, and urinary incontinence. 1% 2% 5% 4% Table 7: Adverse Reactions Leading to Discontinuation (≥2% for all doses of INTUNIV and >rate than in placebo) in Monotherapy Flexible Dose Study 4 INTUNIV® Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of INTUNIV® (N=221) n (%) n (%) n (%) n (%) Adverse reactions leading to discontinuation in ≥2% in any dose group but did not meet this criteria in all doses combined: fatigue Total patients 0 (0%) 8 (7%) 7 (6%) 15 (7%) SomnolenceThe somnolence term includes somnolence, sedation, and hypersomnia. 0 (0%) 4 (4%) 3 (3%) 7 (3%) Table 8: Other Common Adverse Reactions (≥2% for all doses of INTUNIV and >rate than in placebo) in the Monotherapy Flexible Dose Study 4 INTUNIV® Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of INTUNIV® (N=221) 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). Headache 11% 18% 16% 17% InsomniaThe insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. 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 Adverse Reaction Term Placebo (N=155) All Doses of INTUNIV® (N=157) SomnolenceThe somnolence term includes somnolence, sedation, and hypersomnia. 23% 54% InsomniaThe insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. 6% 13% HypotensionThe hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). 3% 9% Dry Mouth 0% 8% Postural Dizziness 2% 5% BradycardiaThe bradycardia term includes bradycardia and sinus bradycardia. 0% 5% 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 INTUNIV® Adverse Reaction Term Placebo (N=155) All Doses of INTUNIV® (N=157) 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). Headache 18% 27% Fatigue 12% 22% Dizziness 10% 16% Decreased Appetite 14% 15% Abdominal PainThe abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. 8% 12% Irritability 4% 7% AnxietyThe anxiety term includes anxiety and nervousness. 3% 5% RashThe rash term includes rash, rash generalized, and rash papular. 1% 3% Constipation 0% 3% Increased Weight 2% 3% Abdominal/Stomach DiscomfortThe abdominal/stomach discomfort term includes abdominal discomfort, epigastric discomfort, and stomach discomfort. 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 INTUNIV® + stimulant Adverse Reaction Term Placebo+ stimulant (N=153) AM (N=150) PM (N=152) All Doses (N=302) SomnolenceThe somnolence term includes somnolence, sedation, and hypersomnia. 7% 18% 18% 18% InsomniaThe insomnia term includes insomnia, initial insomnia, middle insomnia, terminal insomnia, and sleep disorder. 6% 10% 14% 12% Abdominal PainThe abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. 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 INTUNIV and >rate than in placebo) in the Short-Term Adjunctive Study 3 INTUNIV® + stimulant Adverse Reaction Term Placebo (N=153) AM (N=150) PM (N=152) All Doses of INTUNIV® (N=302) 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). Headache 13% 21% 21% 21% Diarrhea 1% 4% 3% 4% HypotensionThe hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased. 0% 4% 2% 3% Constipation 0% 2% 3% 2% Affect LabilityThe affect lability term includes affect lability and mood swings. 1% 3% 2% 2% Dry Mouth 0% 1% 3% 2% BradycardiaThe bradycardia term includes bradycardia and sinus bradycardia. 0% 1% 3% 2% Postural Dizziness 0% 1% 3% 2% RashThe rash term includes rash, rash generalized, and rash papular. 1% 1% 2% 2% NightmareThe nightmare term includes abnormal dreams, nightmare, and sleep terror. 1% 2% 1% 2% TachycardiaThe tachycardia term includes tachycardia and sinus tachycardia. 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 -4.8 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 above baseline values following discontinuation of INTUNIV®. 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 INTUNIV+. 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 INTUNIV®, 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 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 6.2 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. 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, 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

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended dose: 1 mg to 7 mg (0.05-0.12 mg/kg target weight based dose range) once daily in the morning or evening based on clinical response and tolerability (2.2). Begin at a dose of 1 mg once daily and adjust in increments of no more than 1 mg/week (2.2). Do not crush, chew or break tablets before swallowing (2.1). Do not administer with high-fat meals, because of increased exposure (2.1). Do not substitute for immediate-release guanfacine tablets on a mg-per-mg basis, because of differing pharmacokinetic profiles (2.3). If switching from immediate-release guanfacine, discontinue that treatment and titrate with INTUNIV ® as directed (2.3). When discontinuing, taper the dose in decrements of no more than 1 mg every 3 to 7 days to avoid rebound hypertension (2.5). 2.1 General Instruction for Use Swallow tablets whole. Do not crush, chew, or break tablets because this will increase the rate of guanfacine release. Do not administer with high fat meals, due to increased exposure. 2.2 Dose Selection Take INTUNIV orally once daily, either in the morning or evening, at approximately the same time each day. Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week. In monotherapy clinical trials, there was dose- and exposure-related clinical improvement as well as risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). To balance the exposure-related potential benefits and risks, the recommended target dose range depending on clinical response and tolerability for INTUNIV® is 0.05-0.12 mg/kg/day (total daily dose between 1-7 mg) (See Table 1). Table 1: Recommended Target Dose Range for Therapy with INTUNIV® Weight Target dose range (0.05 - 0.12 mg/kg/day) Doses above 4 mg/day have not been evaluated in children (ages 6-12 years) and doses above 7 mg/day have not been evaluated in adolescents (ages 13-17 years) 25-33.9 kg 2-3 mg/day 34-41.4 kg 2-4 mg/day 41.5-49.4 kg 3-5 mg/day 49.5-58.4 kg 3-6 mg/day 58.5-91 kg 4-7 mg/day >91 kg 5-7 mg/day In the adjunctive trial which evaluated INTUNIV® treatment with psychostimulants, the majority of patients reached optimal doses in the 0.05-0.12 mg/kg/day range. Doses above 4 mg/day have not been studied in adjunctive trials. 2.3 Switching from Immediate-Release Guanfacine to INTUNIV® If switching from immediate-release guanfacine, discontinue that treatment, and titrate with INTUNIV® following above recommended schedule. Do not substitute for immediate-release guanfacine tablets on a milligram-per-milligram basis, because of differing pharmacokinetic profiles. INTUNIV® has significantly reduced Cmax (60% lower), bioavailability (43% lower), and a delayed Tmax (3 hours later) compared to those of the same dose of immediate-release guanfacine [see Clinical Pharmacology (12.3)]. 2.4 Maintenance Treatment Pharmacological treatment of ADHD may be needed for extended periods. Healthcare providers should periodically re-evaluate the long-term use of INTUNIV®, and adjust weight-based dosage as needed. The majority of children and adolescents reach optimal doses in the 0.05-0.12 mg/kg/day range. Doses above 4 mg/day have not been evaluated in children (ages 6-12 years) and above 7 mg/day have not been evaluated in adolescents (ages 13-17 years) [see Clinical Studies (14)]. 2.5 Discontinuation of Treatment Following discontinuation of INTUNIV®, patients may experience increases in blood pressure and heart rate [see Warnings and Precautions (5.4) and Adverse Reactions (6)]. Patients/caregivers should be instructed not to discontinue INTUNIV® without consulting their health care provider. Monitor blood pressure and pulse when reducing the dose or discontinuing the drug. Taper the daily dose in decrements of no more than 1 mg every 3 to 7 days to minimize the risk of rebound hypertension. 2.6 Missed Doses When reinitiating patients to the previous maintenance dose after two or more missed consecutive doses, consider titration based on patient tolerability. 2.7 Dosage Adjustment with Concomitant Use of Strong and Moderate CYP3A4 Inhibitors or Inducers Dosage adjustments for INTUNIV® are recommended with concomitant use of strong and moderate CYP3A4 inhibitors (e.g., ketoconazole) or CYP3A4 inducers (e.g., carbamazepine) (Table 2) [see Drug Interactions (7)]. Table 2: INTUNIV® Dosage Adjustments for Patients Taking Concomitant CYP3A4 Inhibitors or Inducers Clinical Scenarios Starting INTUNIV® while currently on a CYP3A4 modulator Continuing INTUNIV® while adding a CYP3A4 modulator Continuing INTUNIV® while stopping a CYP3A4 modulator CYP3A4 Strong and moderate Inhibitors Decrease INTUNIV® dosage to half the recommended level. (see Table 1) Decrease INTUNIV® dosage to half the recommended level. (see Table 1) Increase INTUNIV® dosage to recommended level. (see Table 1) CYP3A4 Strong and moderate Inducers Consider increasing INTUNIV® dosage up to double the recommended level. (see Table 1) Consider increasing INTUNIV® dosage up to double the recommended level over 1 to 2 weeks. (see Table 1) Decrease INTUNIV® dosage to recommended level over 1 to 2 weeks. (see Table 1)
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B Risk Summary There are no adequate and well-controlled studies of INTUNIV in pregnant women. No fetal harm was observed in rats and rabbits with administration of guanfacine at 4 and 2.7 times, respectively, the maximum recommended human dose. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Animal data Reproduction studies conducted in rats have shown that guanfacine crosses the placenta. However, administration of guanfacine to rats and rabbits at 4 and 2.7 times, respectively, the maximum recommended human dose of 0.12 mg/kg/day on a mg/m2 basis resulted in no evidence of harm to the fetus. Higher doses (13.5 times the maximum recommended human dose in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity. 8.3 Nursing Mothers It is not known whether guanfacine is excreted in human milk; however, guanfacine is excreted in rat milk. Because many drugs are excreted in human milk, caution should be exercised when INTUNIV® is administered to a nursing woman. Observe human milk-fed infants for sedation and somnolence. 8.4 Pediatric Use Safety and efficacy of INTUNIV® in pediatric patients less than 6 years of age have not been established. The efficacy of INTUNIV® was studied for the treatment of ADHD in five controlled monotherapy clinical trials (up to 15 weeks in duration), one randomized withdrawal study and one controlled adjunctive trial with psychostimulants (8 weeks in duration) in children and adolescents ages 6-17 who met DSM-IV® criteria for ADHD [see Adverse Reactions (6) and Clinical Studies (14)]. Animal Data In studies in juvenile rats, guanfacine alone produced a slight delay in sexual maturation in males and females at 2 to 3 times the maximum recommended human dose (MRHD). Guanfacine in combination with methylphenidate produced a slight delay in sexual maturation and decreased growth as measured by a decrease in bone length in males at a dose of guanfacine comparable to the MRHD and a dose of methylphenidate approximately 4 times the MRHD. In a study where juvenile rats were treated with guanfacine alone from 7 to 59 days of age, development was delayed as indicated by a slight delay in sexual maturation and decreased body weight gain in males at 2 mg/kg/day and in females at 3 mg/kg/day. The No Adverse Effect Level (NOAEL) for delayed sexual maturation was 1 mg/kg/day, which is equivalent to the MRHD of 4 mg/day, on a mg/m2 basis. The effects on fertility were not evaluated in this study. In a study where juvenile rats were treated with guanfacine in combination with methylphenidate from 7 to 59 days of age, a decrease in ulna bone length and a slight delay in sexual maturation were observed in males given 1 mg/kg/day of guanfacine in combination with 50 mg/kg/day of methylphenidate. The NOAELs for these findings were 0.3 mg/kg of guanfacine in combination with 16 mg/kg/day of methylphenidate, which are equivalent to 0.3 and 1.4 times the MRHD of 4 mg/day and 54 mg/day for guanfacine and methylphenidate, respectively, on a mg/m2 basis. These findings were not observed with guanfacine alone at 1 mg/kg/day or methylphenidate alone at 50 mg/kg/day. 8.5 Geriatric Use The safety and efficacy of INTUNIV® in geriatric patients have not been established. 8.6 Renal Impairment It may be necessary to reduce the dosage in patients with significant impairment of renal function [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment It may be necessary to reduce the dosage in patients with significant impairment of hepatic function [see Clinical Pharmacology (12.3)].
Pregnancy and lactation
8.3 Nursing Mothers It is not known whether guanfacine is excreted in human milk; however, guanfacine is excreted in rat milk. Because many drugs are excreted in human milk, caution should be exercised when INTUNIV® is administered to a nursing woman. Observe human milk-fed infants for sedation and somnolence.

Interactions

7 DRUG INTERACTIONS Table 14 contains clinically important drug interactions with INTUNIV® [see Clinical Pharmacology (12.3)]. 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 Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure Consider dose reduction [see Dosage and administration (2.7)] Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure Consider dose increase [see Dosage and administration (2.7)] Strong and moderate CYP3A4 inhibitors increase guanfacine exposure. Decrease INTUNIV ® to 50% of target dosage when coadministered with strong and moderate CYP3A4 inhibitors (2.7). Strong and moderate CYP3A4 inducers decrease guanfacine exposure. Based on patient response, consider titrating INTUNIV dosage up to double the target dosage over 1 to 2 weeks (2.7).

More information

Category Value
Authorisation number NDA022037
Agency product number PML56A160O
Orphan designation No
Product NDC 54092-519,54092-520,54092-513,54092-515,54092-517
Date Last Revised 12-03-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 862019
Storage and handling Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature.
Marketing authorisation holder Shire US Manufacturing Inc.