These highlights do not include all the information needed to use GUANFACINE EXTENDED-RELEASE TABLETS safely and effectively. See full prescribing information for GUANFACINE EXTENDED-RELEASE TABLETS. GUANFACINE extended-release tablets, for oral use Initial U.S. Approval: 1986
1 INDICATIONS AND USAGE
- Guanfacine extended-release tablets are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [ see CLINICAL STUDIES ( 14 ) ].
2 DOSAGE AND ADMINISTRATION
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
In the adjunctive trial which evaluated guanfacine extended-release tablets treatment with psychostimulants, the majority of patients reached optimal doses in the 0.05 to 0.12 mg/kg/day range. Doses above 4 mg/day have not been studied in adjunctive trials.
| Weight | Target dose range (0.05 to 0.12 mg/kg/day) |
| 25 to 33.9 kg | 2 to 3 mg/day |
| 34 to 41.4 kg | 2 to 4 mg/day |
| 41.5 to 49.4 kg | 3 to 5 mg/day |
| 49.5 to 58.4 kg | 3 to 6 mg/day |
| 58.5 to 91 kg | 4 to 7 mg/day |
| >91 kg | 5 to 7 mg/day |
- Take guanfacine extended-release tablets 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.
2.3 Switching from Immediate-Release Guanfacine to Guanfacine Extended-Release Tablets
- If switching from immediate-release guanfacine, discontinue that treatment, and titrate with guanfacine extended-release tablets following above recommended schedule.
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 guanfacine extended-release tablets, and adjust weight-based dosage as needed. The majority of children and adolescents reach optimal doses in the 0.05 to 0.12 mg/kg/day range. Doses above 4 mg/day have not been evaluated in children (ages 6 to 12 years) and above 7 mg/day have not been evaluated in adolescents (ages 13 to 17 years) [see CLINICAL STUDIES ( 14 ) ] .
2.5 Discontinuation of Treatment
- Following discontinuation of guanfacine extended-release tablets, patients may experience increases in blood pressure and heart rate [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 ) ]. Patients/caregivers should be instructed not to discontinue guanfacine extended-release tablets 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
| Clinical Scenarios | |||
| Starting guanfacine extended-release tablets while currently on a CYP3A4 modulator | Continuing guanfacine extended-release tablets while adding a CYP3A4 modulator | Continuing guanfacine extended-release tablets while stopping a CYP3A4 modulator | |
| CYP3A4 Strong and moderate Inhibitors | Decrease guanfacine extended-release tablets dosage to half the recommended level. (see Table 1 ) | Decrease guanfacine extended-release tablets dosage to half the recommended level. (see Table 1 ) | Increase guanfacine extended-release tablets dosage to recommended level. (see Table 1 ) |
| CYP3A4 Strong and moderate Inducers | Consider increasing guanfacine extended-release tablets dosage up to double the recommended level. (see Table 1 ) | Consider increasing guanfacine extended-release tablets dosage up to double the recommended level over 1 to 2 weeks. (see Table 1 ) | Decrease guanfacine extended-release tablets dosage to recommended level over 1 to 2 weeks. (see Table 1 ) |
- Dosage adjustments for guanfacine extended-release tablets 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 ) ] .
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 ) ] .
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
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.
- The following serious adverse reactions are described elsewhere in the labeling:
6.1 Clinical Trials Experience
Fixed Dose Trials
Monotherapy Flexible Dose Trials
Adjunctive Trial
There were no specific adverse reactions ≥ 2% in any treatment group that led to discontinuation in the short-term adjunctive study (Study 3).
Effects on Blood Pressure and Heart Rate
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.
| 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% |
| 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%) |
| 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% |
| 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% |
| 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%) |
| 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 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% |
| 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% |
| 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% |
| 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% |
| 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 |
- 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.
6.2 Postmarketing Experience
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
- 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.
7 DRUG INTERACTIONS
Table 14 contains clinically important drug interactions with guanfacine extended-release tablets [see Clinical Pharmacology (12.3)] .
| 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)] |
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
Risk Summary
There are no adequate and well-controlled studies of guanfacine extended-release tablets 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/m 2basis 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 guanfacine extended-release tablets are administered to a nursing woman. Observe human milk-fed infants for sedation and somnolence.
8.4 Pediatric Use
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.
- Safety and efficacy of guanfacine extended-release tabletsin pediatric patients less than 6 years of age have not been established. The efficacy of guanfacine extended-release tablets 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 to 17 who met DSM-IV ® criteria for ADHD [see ADVERSE REACTIONS ( 6 ) and CLINICAL STUDIES ( 14 ) ] .
8.5 Geriatric Use
The safety and efficacy of guanfacine extended-release tablets 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 ) ] .
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
- Guanfacine extended-release tablets are not controlled substance and have no known potential for abuse or dependence.
10 OVERDOSAGE
Symptoms
Treatment
Management of guanfacine extended-release tablets overdose should include monitoring for and the treatment of initial hypertension, if that occurs, as well as hypotension, bradycardia, lethargy and respiratory depression. Children and adolescents who develop lethargy should be observed for the development of more serious toxicity including coma, bradycardia and hypotension for up to 24 hours, due to the possibility of delayed onset hypotension.
- Postmarketing reports of guanfacine overdosage indicate that hypotension, drowsiness, lethargy, and bradycardia have been observed following overdose. Initial hypertension may develop early and may be followed by hypotension. Similar symptoms have been described in voluntary reports to the American Association of Poison Control Center's National Poison Data System. Miosis of the pupils may be noted on examination. No fatal overdoses of guanfacine have been reported in published literature.
11 DESCRIPTION
- Guanfacine extended-release tablets are once-daily, extended-release formulation of guanfacine hydrochloride (HCl) in a matrix tablet formulation for oral administration only. The chemical designation is N-amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride. The molecular formula is C 9 H 9 Cl 2 N 3 O·HCl corresponding to a molecular weight of 282.55. The chemical structure is:
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
- Guanfacine is a central alpha 2A -adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) stimulant. The mechanism of action of guanfacine in ADHD is not known.
12.2 Pharmacodynamics
In a thorough QT study, the administration of two dose levels of immediate-release guanfacine (4 mg and 8 mg) produced concentrations approximately 2 to 4 times the concentrations observed with the maximum recommended dose of guanfacine extended-release tablets of 0.12 mg/kg. Guanfacine was not shown to prolong the QTc interval to any clinically relevant extent.
- Guanfacine is a selective central alpha 2A -adrenergic receptor agonist in that it has a 15 to 20 times higher affinity for this receptor subtype than for the alpha 2B or alpha 2C subtypes.
12.3 Pharmacokinetics
Absorption and Distribution
Immediate-release guanfacine and guanfacine extended-release tablets have different pharmacokinetic characteristics; dose substitution on a milligram per milligram basis will result in differences in exposure.
Figure 1: Comparison of Pharmacokinetics: Guanfacine Extended-Release Tablets vs. Immediate-release guanfacine in Adults
Exposure to guanfacine was higher in children (ages 6 to 12) compared to adolescents (ages 13 to 17) and adults. After oral administration of multiple doses of guanfacine extended-release tablets 4 mg, the C max was 10 ng/mL compared to 7 ng/mL and the AUC was 162 ng∙h/mL compared to 116 ng∙h/mL in children (ages 6 to 12) and adolescents (ages 13 to 17), respectively. These differences are probably attributable to the lower body weight of children compared to adolescents and adults.
The pharmacokinetics were affected by intake of food when a single dose of guanfacine extended-release tablets 4 mg was administered with a high-fat breakfast. The mean exposure increased (C max ~75% and AUC ~40%) compared to dosing in a fasted state.
Dose Proportionality
Following administration of guanfacine extended-release tablets in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, C max and AUC 0-∞ of guanfacine were proportional to dose.
Metabolism and Elimination
In vitro studies with human liver microsomes and recombinant CYP's demonstrated that guanfacine was primarily metabolized by CYP3A4. In pooled human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2,CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5); guanfacine is also not an inducer of CYP3A, CYP1A2 and CYP2B6. Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors.
Guanfacine inhibits MATE1 and OCT1, but does not inhibit BSEP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, or MATE2K. Guanfacine is a substrate of OCT1 and OCT2, but not BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, or MATE2. Concomitant administration of guanfacine with OCT1 substrates might potentially increase the exposure of these OCT1 substrates.
Studies in Specific Populations
Renal Impairment
Hepatic Impairment
Drug Interaction Studies
Figure 2: Effect of Other Drugs on the Pharmacokinetics (PK) of Guanfacine Extended-Release Tablets
Figure 3: Effect of Guanfacine Extended-Release Tablets on the Pharmacokinetics (PK) of Other Drugs
| Parameter | Guanfacine Extended-Release Tablets 1 mg once daily (n=52) | Immediate-release guanfacine 1 mg once daily (n=12) |
| C max (ng/mL) | 1.0 ± 0.3 | 2.5 ± 0.6 |
| AUC 0-∞ (ng∙h/mL) | 32 ± 9 | 56 ± 15 |
| t max (h) | 6.0 (4.0 - 8.0) | 3.0 (1.5-4.0) |
| t ½ (h) | 18 ± 4 | 16 ± 3 |
- Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration. After oral administration of guanfacine extended-release tablets the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenesis
14 CLINICAL STUDIES
Studies 1 and 2: Fixed-dose Guanfacine Extended-Release Tablets Monotherapy
Study 3: Flexible-dose Guanfacine Extended-Release Tablets as Adjunctive Therapy to Psychostimulants
Study 3 (313 study) was a double-blind, randomized, placebo-controlled, dose-optimization study, in which efficacy of once daily optimized dosing (morning or evening) with guanfacine extended-release tablets (1 mg, 2 mg, 3 mg and 4 mg), when co-administered with psychostimulants, was evaluated for 8 weeks, in children and adolescents aged 6 to 17 years with a diagnosis of ADHD, with a sub-optimal response to stimulants (n=455). Patients were started at the 1 mg guanfacine extended-release tablets dose level and were titrated weekly over a 5-week dose-optimization period to an optimal guanfacine extended-release tablets dose not to exceed 4 mg/day based on tolerability and clinical response. The dose was then maintained for a 3-week dose maintenance period before entry to 1 week of dose tapering. Patients took guanfacine extended-release tablets either in the morning or the evening while maintaining their current dose of psychostimulant treatment given each morning. Allowable psychostimulants in the study were ADDERALL XR ® , VYVANSE ® , CONCERTA ® , FOCALIN XR ® , RITALIN LA ® , METADATE CD ® or FDA-approved generic equivalents.
Studies 4, 5 and 6: Flexible-dose Guanfacine Extended-Release Tablets Monotherapy
Study 6 (316 study) was a 12-week (for children aged 6 to 12) or 15-week (for adolescents aged 13 to 17), randomized, double-blind, parallel-group, placebo- and active-reference, dose-optimization study conducted in pediatric patients (children and adolescents aged 6 to 17 years old inclusive) (n=337) to assess the efficacy and safety of once-daily dosing (children: 1 to 4 mg/day, adolescents: 1 to 7 mg/day; optimized dose range of 0.05 to 0.12 mg/kg/day) in the treatment of ADHD. Guanfacine extended-release tablets were statistically superior to placebo on symptoms of ADHD in patients 6 to 17 years as measured by change from baseline in ADHD-RS-IV total scores (see Table 17 ).
Study 7: Long-Term Maintenance of Guanfacine Extended-Release Tablets Efficacy
Study 7 (315 study) was a double-blind, placebo-controlled, randomized withdrawal trial in pediatric patients aged 6 to 17 years with DSM-IV-TR diagnosis of ADHD. The study consisted of an open-label phase, including a 7-week dose optimization period to titrate patients to an optimal dose (maximum 4 mg/day for children and 7 mg/day for adolescents; optimized dose range: 0.05 to 0.12 mg/kg/day) and a 6-week dose maintenance period. There were 526 patients included in the open-label phase. Among those, 315 patients who met response criteria in the open-label phase were then randomized (1:1, guanfacine extended-release tablets:placebo) in a 26-week, double-blind, randomized withdrawal phase. The response criteria were defined by ≥ 30% reduction in ADHD-RS-IV total score and a Clinical Global Impression-Improvement (CGI-I) score of 1 or 2 during the open-label phase. A statistically significantly lower proportion of treatment failures occurred among guanfacine extended-release tablets patients compared to placebo at the end of the randomized withdrawal period (Figure 4). Treatment failure was defined as a ≥ 50% increase (worsening) in ADHD-RS-IV total score and a ≥ 2-point increase in Clinical Global Impression-Severity (CGI-S) score. Patients who met the treatment failure criteria on two consecutive visits or discontinued for any reason were classified as treatment failure.
Figure 4. Kaplan-Meier Estimation of Proportion of Patients with Treatment Failure for Children and Adolescents Ages 6 to 17 (Study 7)
| Study Number•(Age Range) | Treatment Group | Primary Efficacy Measure: ADHD-RS-IV Total Score | ||
| Mean Baseline Score (SD) | LS Mean Change from Baseline (SE) | Placebo-subtracted Difference a (95% CI) | ||
| Study 1 (6 to 17 years) | Guanfacine Extended-Release Tablets 2 mg* | 36.1 (9.99) | -15.9 (1.37) | -7.4 (-11.3, -3.5) |
| Guanfacine Extended-Release Tablets 3 mg* | 36.8 (8.72) | -16.0 (1.38) | -7.5 (-11.4, -3.6) | |
| Guanfacine Extended-Release Tablets 4 mg* | 38.4 (9.21) | -18.5 (1.39) | -10.0 (-13.9, -6.1) | |
| Placebo | 38.1 (9.34) | -8.5 (1.42) | -- | |
| Study 2 (6 to 17 years) | Guanfacine Extended-Release Tablets 1 mg*^ | 41.7 (7.81) | -19.4 (1.69) | -6.8 (-11.3, -2.2) |
| Guanfacine Extended-Release Tablets 2 mg* | 39.9 (8.74) | -18.1 (1.60) | -5.4 (-9.9, -0.9) | |
| Guanfacine Extended-Release Tablets 3 mg* | 39.1 (9.22) | -20.0 (1.64) | -7.3 (-11.8, -2.8) | |
| Guanfacine Extended-Release Tablets 4 mg* | 40.6 (8.57) | -20.6 (1.60) | -7.9 (-12.3, -3.4) | |
| Placebo | 39.3 (8.85) | -12.7 (1.60) | -- |
| Study Number•(Age Range) | Treatment Group | Primary Efficacy Measure: ADHD-RS-IV Total Score | ||
| Mean Baseline Score (SD) | LS Mean Change from Baseline (SE) | Placebo-subtracted Difference b (95% CI) | ||
| • Study 3 a (6 to 17 years) | Guanfacine Extended-Release Tablets 1 to 4 mg AM* | 37.6 (8.13) | -20.3 (0.97) | -4.5 (-7.5, -1.4) |
| Guanfacine Extended-Release Tablets 1 to 4 mg PM* | 37.0 (7.65) | -21.2 (0.97) | -5.3 (-8.3, -2.3) | |
| Placebo | 37.7 (7.75) | -15.9 (0.96) | -- | |
| Study 4 (6 to 12 years) | Guanfacine Extended-Release Tablets 1 to 4 mg AM* | 41.7 (6.39) | -20.0 (1.23) | -9.4 (-12.8, -6.0) |
| Guanfacine Extended-Release Tablets 1 to 4 mg PM* | 41.6 (6.66) | -20.4 (1.19) | -9.8 (-13.1, -6.4) | |
| Placebo | 42.9 (6.29) | -10.6 (1.20) | -- | |
| Study 5 (13 to 17 years) | Guanfacine Extended-Release Tablets 1 to 7 mg* | 39.9 (5.57) | -24.6 (1.06) | -6.03 (-8.87, -3.19) |
| Placebo | 40.0 (6.11) | -18.5 (1.08) | -- | |
| Study 6 (6 to 17 years) | Guanfacine Extended-Release Tablets 1 to 7 mg* | 43.1 (5.47) | -23.89 (1.15) | -8.88 (-11.94, -5.81) |
| Placebo | 43.2 (5.60) | -15.01 (1.16) | -- |
- Efficacy of guanfacine extended-release tablets in the treatment of ADHD was established in children and adolescents (6 to 17 years) in:
16 HOW SUPPLIED/STORAGE AND HANDLING
Storage - Store at 20° to 25°C (68° to 77°F). [see USP Controlled Room Temperature].
| 1 mg | 2 mg | 3 mg | 4 mg | |
| Color | White | White | Blue | Blue |
| Shape | Round | Caplet | Round | Caplet |
| Debossment (top/bottom) | A533/ 1 mg | A534/ 2 mg | A536/ 3 mg | A538/ 4 mg |
| NDC number | 30 count: 71205-944-3060 count:71205-944-6090 count:71205-944-90 | 30 count: 71205-945-3060 count:71205-945-6090 count:71205-945-90 | 30 count: 71205-946-3060 count:71205-946-6090 count:71205-946-90 | 30 count: 71205-947-3060 count:71205-947-6090 count:71205-947-90 |
| 100 count:71205-944-00500 count: 71205-944-55 | 100 count:71205-945-00500 count: 71205-945-55 | 100 count:71205-946-00500 count: 71205-946-55 | 100 count:71205-947-00500 count: 71205-947-55 |
- Guanfacine extended-release tablets are supplied in 1 mg, 2 mg, 3 mg, and 4 mg strength extended-release tablets in 30, 60, 90, 100, and 500 count bottles.
17 PATIENT COUNSELING INFORMATION
Dosing and Administration
Adverse Reactions
- Advise the patient to read theFDA-approved patient labeling (Patient Information).
Patient Information
Guanfacine Extended-Release Tablets
(gwahn-fa-seen)
Read the Patient Information that comes with guanfacine extended-release tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.
What are guanfacine extended-release tablets?
Guanfacine extended-release tablets are prescription medicine used to treat the symptoms of attention deficit hyperactivity disorder (ADHD). Guanfacine extended-release tablets may be used alone or with ADHD stimulant medicines.
Guanfacine extended-release tablets are not central nervous system (CNS) stimulant.
It is not known if guanfacine extended-release tablets are safe and effective in children younger than 6 years of age.
Who should not take guanfacine extended-release tablets?
Do not take guanfacine extended-release tablets if you are allergic to guanfacine or any of the ingredients in guanfacine extended-release tablets. See the end of this leaflet for a complete list of ingredients in guanfacine extended-release tablets.
What should I tell my doctor before taking guanfacine extended-release tablets?
Before you take guanfacine extended-release tablets, tell your doctor if you:
Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Guanfacine extended-release tablets may affect the way other medicines work, and other medicines may affect how guanfacine extended-release tablets work.
Especially tell your doctor if you take:
Ask your doctor or pharmacist for a list of these medicines, if you are not sure.
Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.
How should I take guanfacine extended-release tablets?
What should I avoid while taking guanfacine extended-release tablets?
What are the possible side effects of guanfacine extended-release tablets?
Guanfacine extended-release tablets may cause serious side effects including:
Get medical help right away, if you have any of the symptoms listed above.
The most common side effects of guanfacine extended-release tablets include:
Tell the doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of guanfacine extended-release tablets. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to TWi Pharmaceuticals, inc. 1-844-518-2989 or FDA at 1-800-FDA-1088 or www. fda.gov/medwatch.
How should I store guanfacine extended-release tablets?
Keep guanfacine extended-release tablets and all medicines out of the reach of children.
General Information about the safe and effective use guanfacine extended-release tablets
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use guanfacine extended-release tablets for a condition for which it was not prescribed. Do not give guanfacine extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them.
This leaflet summarizes the most important information about guanfacine extended-release tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about guanfacine extended-release tablets that is written for health professionals.
What are the ingredients in guanfacine extended-release tablets?
Active ingredient: guanfacine hydrochloride
Inactive ingredients: microcrystalline cellulose, hypromellose, polyvinyl acetate, povidone, lactose monohydrate, magnesium stearate, sodium lauryl sulfate and silica. In addition, the 3 mg and 4 mg tablets also contain FD&C Blue #1.
This Patient Information has been approved by the U.S. Food and Drug Administration.
All other trademarks are the property of their respective owners.
Manufactured for: TWi Pharmaceuticals USA, Inc.Paramus, NJ 07652
Manufactured by:
TWi Pharmaceuticals, Inc.
Taoyuan City, 32063, Taiwan
Revised: 10/19
Repackaged and Relabeled by: Proficient Rx LPThousand Oaks, CA 91320
OS24979533
- •have heart problems or a low heart rate
- •have fainted
- •have low or high blood pressure
- •have liver or kidney problems
- •have any other medical conditions
- •are pregnant or plan to become pregnant. It is not known if guanfacine extended-release tablets will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
- •are breastfeeding or plan to breastfeed. It is not known if guanfacine extended-release tablets pass into your breast milk. Talk to your doctor about the best way to feed your baby while taking guanfacine extended-release tablets.
Package/Label Display Panel
- NDC 71205-945-30 Guanfacine Extended-Release Tablets 2 mg 30-count
Package/Label Display Panel
- NDC 71205-946-30 Guanfacine Extended-Release Tablets 3 mg 30-count
Package/Label Display Panel
- NDC 71205-947-30 Guanfacine Extended-Release Tablets 4 mg 30-count