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Uses
Guanfacine extended-release tablets are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications. The efficacy of guanfacine extended-release tabletswere studied for the treatment of ADHD in three controlled monotherapy clinical trials (up to 8 weeks in duration) 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 Clinical Studies (14)]. The effectiveness of guanfacine extended-release tablets for longer-term use (more than 8 weeks) has not been systematically evaluated in controlled trials.
History
There is currently no drug history available for this drug.
Other Information
Guanfacine is a 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 C9H9Cl2 N3O(HCl corresponding to a molecular weight of 282.55. The chemical structure is:
Guanfacine hydrochloride, USP is a white to off-white crystalline powder, sparingly soluble in water (approximately 1 mg/mL) and alcohol and slightly soluble in acetone. The only organic solvent in which it has relatively high solubility is methanol (greater than 30 mg/mL). Each tablet contains guanfacine hydrochloride, USP equivalent to 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine base. The tablets also contain colloidal silicon dioxide, crospovidone, fumaric acid, glyceryl behenate, hydroxypropyl cellulose, hypromellose, lactose monohydrate, microcrystalline cellulose, and povidone. In addition, the 1 mg and 2 mg tablets contain FD&C Yellow #6 Aluminum Lake and the 3 mg and 4 mg tablets contain D&C Yellow #10.
Sources
Guanfacine Manufacturers
- Avkare, Inc.
Guanfacine | Avkare, Inc.
2.1 General Instruction for UseSwallow 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 SelectionGuanfacine extended-release tablets should be taken once daily, either in the morning or evening, at approximately same time each day. Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week. Maintain the dose within the range of 1 mg to 4 mg once daily, depending on clinical response and tolerability, for both monotherapy and adjunctive therapy to a psychostimulant. Doses above 4 mg/day have not been systematically studied in controlled clinical studies [see Clinical Studies (14.1)].
Clinically relevant improvements were observed beginning at doses in the range 0.05 to 0.08 mg/kg once daily in both mono- and adjunctive therapy. Efficacy increased with increasing weight-adjusted dose (mg/kg). If well tolerated, doses up to 0.12 mg/kg once daily may provide additional benefit.
In clinical trials, there were dose-related and exposure-related risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). Thus, consideration should be given to dosing guanfacine extended-release on a mg/kg basis, in order to balance the exposure-related potential benefits and risks of treatment.
2.3 Switching from Immediate-Release Guanfacine to Guanfacine Extended-ReleaseIf switching from immediate-release guanfacine, discontinue that treatment, and titrate with guanfacine extended-release following above recommended schedule.
Do not substitute for immediate-release guanfacine tablets on a milligram-per-milligram basis, because of differing pharmacokinetic profiles. Guanfacine extended-release has a delayed Tmax, reduced Cmax and lower bioavailability compared to those of the same dose of immediate-release guanfacine [see Clinical Pharmacology (12.3)].
2.4 Maintenance TreatmentIt is generally agreed that pharmacological treatment of ADHD may be needed for extended period. The effectiveness of guanfacine extended-release for longer-term use (more than 9 weeks) has not been systematically evaluated in controlled trials. Therefore the physician electing to use guanfacine extended-release for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
2.5 DiscontinuationInfrequent, transient elevations in blood pressure above original baseline (i.e., rebound) have been reported to occur upon abrupt discontinuation of guanfacine. To minimize these effects, the dose should generally be tapered in decrements of no more than 1 mg every 3 to 7 days.
2.6 Missed DosesWhen reinitiating patients to the previous maintenance dose after two or more missed consecutive doses, physicians should consider titration based on patient tolerability.
2.7 Dose Adjustment with Concomitant Use of Strong CYP3A4 Inhibitors or InducersDosage adjustments for guanfacine extended-release are recommended with concomitant use of strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole), or CYP3A4 inducers (e.g., avasimibe, carbamazepine, phenytoin, rifampin, and St. John’s wort) (Table 1) [see Drug Interactions (7)].
Table 1: Dose Adjustments in Patients Taking Concomitant CYP3A4 Inhibitors or Inducers Scenarios Comedications Initiate guanfacine extended-release when taking comedications Continue guanfacine extended-release when adding a comedication Stop a comedication when continuing guanfacine extended-release Strong CYP3A4 Inhibitors Guanfacine extended-release dose should be limited to 2 mg/day Guanfacine extended-release dose should be decreased by half. Guanfacine extended-release dose should be doubled based on patient tolerability. The maximum dose should not exceed 4 mg/day Strong CYP3A4 Inducers Guanfacine extended-release dose may be titrated up to 8 mg/day. Consider faster titration (e.g. in increments of 2 mg/week) Consider increase guanfacine extended-release dose gradually in 1 to 2 weeks to 2 fold of the original dose based on patient tolerability. Guanfacine extended-release dose should be decreased by half in 1 to 2 weeks based on patient tolerability. The maximum dose should not exceed 4 mg/day - Teva Pharmaceuticals Usa Inc
Guanfacine | Teva Pharmaceuticals Usa Inc
2.1 General Instruction for UseSwallow 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 SelectionTake 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.
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 guanfacine extended-release tablets is 0.05 to 0.12 mg/kg/day (total daily dose between 1 to 7 mg (See Table 1).
Table 1: Recommended Target Dose Range for Therapy with Guanfacine Extended-Release Tablets
Weight
Target dose range (0.05 to 0.12 mg/kg/day)
25 to 33.9 kg2 to 3 mg/day
34 to 41.4 kg2 to 4 mg/day
41.5 to 49.4 kg3 to 5 mg/day
49.5 to 58.4 kg3 to 6 mg/day
58.5 to 91 kg4 to 7 mg/day
> 91 kg5 to 7 mg/day
Doses above 4 mg/day have not been evaluated in children (ages 6 to 12 years) and doses above 7 mg/day have not been evaluated in adolescents (ages 13 to 17 years)
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.
2.3 Switching From Immediate-Release Guanfacine to Guanfacine Extended-Release TabletsIf switching from immediate-release guanfacine, discontinue that treatment, and titrate with guanfacine extended-release tablets following above recommended schedule.
Do not substitute for immediate-release guanfacine tablets on a milligram-per-milligram basis, because of differing pharmacokinetic profiles. Guanfacine extended-release tablets have 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 TreatmentPharmacological 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 TreatmentFollowing discontinuation of guanfacine extended-release tablets, patients may experience increases in blood pressure and heart rate [see Adverse Reaction (6.1)]. Patients/caregivers should be instructed not to discontinue guanfacine extended-release tabletswithout 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 avoid rebound hypertension.
2.6 Missed DosesWhen 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 CYP3A4 Inhibitors or InducersDosage adjustments for guanfacine extended-release tablets are recommended with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole), or CYP3A4 inducers (e.g., carbamazepine) (Table 2) [see Drug Interactions (7)].
Table 2: Guanfacine Extended-Release Tablets Dosage Adjustments for Patients Taking Concomitant CYP3A4 Inhibitors or InducersClinical 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 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 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)
- Genpharm Inc.
Guanfacine | Genpharm Inc.
The recommended initial dose of guanfacine tablets when given alone or in combination with another antihypertensive drug is 1 mg daily given at bedtime to minimize somnolence. If after 3 to 4 weeks of therapy, 1 mg does not give a satisfactory result, a dose of 2 mg may be given, although most of the effect of guanfacine is seen at 1 mg (see CLINICAL PHARMACOLOGY). Higher daily doses have been used, but adverse reactions increase significantly with doses above 3 mg/day.
The frequency of rebound hypertension is low, but it can occur. When rebound occurs, it does so after 2 to 4 days, which is delayed compared with clonidine hydrochloride. This is consistent with the longer half-life of guanfacine. In most cases, after abrupt withdrawal of guanfacine, blood pressure returns to pretreatment levels slowly (within 2 to 4 days) without ill effects.
- Physicians Total Care, Inc.
Guanfacine | Physicians Total Care, Inc.
The recommended initial dose of guanfacine (as the hydrochloride) when given alone or in combination with another antihypertensive drug is 1 mg daily given at bedtime to minimize somnolence. If after 3 to 4 weeks of therapy 1 mg does not give a satisfactory result, a dose of 2 mg may be given, although most of the effect of guanfacine is seen at 1 mg (see CLINICAL PHARMACOLOGY). Higher daily doses have been used, but adverse reactions increase significantly with doses above 3 mg/day.
The frequency of rebound hypertension is low, but it can occur. When rebound occurs, it does so after 2 to 4 days, which is delayed compared with clonidine hydrochloride. This is consistent with the longer half-life of guanfacine. In most cases, after abrupt withdrawal of guanfacine, blood pressure returns to pretreatment levels slowly (within 2 to 4 days) without ill effects.
- Cardinal Health
Guanfacine | Cardinal Health
The recommended initial dose of guanfacine (as the hydrochloride) when given alone or in combination with another antihypertensive drug is 1 mg daily given at bedtime to minimize somnolence. If after 3 to 4 weeks of therapy 1 mg does not give a satisfactory result, a dose of 2 mg may be given, although most of the effect of guanfacine is seen at 1 mg (see CLINICAL PHARMACOLOGY). Higher daily doses have been used, but adverse reactions increase significantly with doses above 3 mg/day.
The frequency of rebound hypertension is low, but it can occur. When rebound occurs, it does so after 2 to 4 days, which is delayed compared with clonidine hydrochloride. This is consistent with the longer half-life of guanfacine. In most cases, after abrupt withdrawal of guanfacine, blood pressure returns to pretreatment levels slowly (within 2 to 4 days) without ill effects.
- Cardinal Health
Guanfacine | Cardinal Health
The recommended initial dose of guanfacine (as the hydrochloride) when given alone or in combination with another antihypertensive drug is 1 mg daily given at bedtime to minimize somnolence. If after 3 to 4 weeks of therapy, 1 mg does not give a satisfactory result, a dose of 2 mg may be given, although most of the effect of guanfacine is seen at 1 mg (seeCLINICAL PHARMACOLOGY). Higher daily doses have been used, but adverse reactions increase significantly with doses above 3 mg/day.
The frequency of rebound hypertension is low, but it can occur. When rebound occurs, it does so after 2-4 days, which is delayed compared with clonidine hydrochloride. This is consistent with the longer half-life of guanfacine. In most cases, after abrupt withdrawal of guanfacine, blood pressure returns to pretreatment levels slowly (within 2-4 days) without ill effects.
- Epic Pharma, Llc
Guanfacine | Epic Pharma, Llc
The recommended initial dose of guanfacine (as the hydrochloride) when given alone or in combination with another antihypertensive drug is 1 mg daily given at bedtime to minimize somnolence. If after 3 to 4 weeks of therapy, 1 mg does not give a satisfactory result, a dose of 2 mg may be given, although most of the effect of guanfacine is seen at 1 mg (see CLINICAL PHARMACOLOGY). Higher daily doses have been used, but adverse reactions increase significantly with doses above 3 mg/day.
The frequency of rebound hypertension is low, but it can occur. When rebound occurs, it does so after 2-4 days, which is delayed compared with clonidine hydrochloride. This is consistent with the longer half-life of guanfacine. In most cases, after abrupt withdrawal of guanfacine, blood pressure returns to pretreatment levels slowly (within 2-4 days) without ill effects.
- Golden State Medical Supply, Inc.
Guanfacine | Golden State Medical Supply, Inc.
The recommended initial dose of guanfacine (as the hydrochloride) when given alone or in combination with another antihypertensive drug is 1 mg daily given at bedtime to minimize somnolence. If after 3 to 4 weeks of therapy, 1 mg does not give a satisfactory result, a dose of 2 mg may be given, although most of the effect of guanfacine is seen at 1 mg (see CLINICAL PHARMACOLOGY). Higher daily doses have been used, but adverse reactions increase significantly with doses above 3 mg/day.
The frequency of rebound hypertension is low, but it can occur. When rebound occurs, it does so after 2-4 days, which is delayed compared with clonidine hydrochloride. This is consistent with the longer half-life of guanfacine. In most cases, after abrupt withdrawal of guanfacine, blood pressure returns to pretreatment levels slowly (within 2-4 days) without ill effects.
- Mylan Pharmaceuticals Inc.
Guanfacine | Harris Pharmaceutical, Inc.
Dosage and Administration in Adults:
Single Dose
Vaginal candidiasis: The recommended dosage of fluconazole for vaginal candidiasis is 150 mg as a single oral dose.
Multiple Dose
SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF FLUCONAZOLE IS THE SAME FOR ORAL (TABLETS AND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy.
The daily dose of fluconazole for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient’s response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse.
Oropharyngeal candidiasis: The recommended dosage of fluconazole for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: The recommended dosage of fluconazole for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms.
Systemic Candida infections: For systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used.
Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50 to 200 mg have been used in open, noncomparative studies of small numbers of patients.
Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10 to 12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of fluconazole for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily.
Prophylaxis in patients undergoing bone marrow transplantation: The recommended fluconazole daily dosage for the prevention of candidiasis in patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should start fluconazole prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per cu mm.
Dosage and Administration in Children:
The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients:
Pediatric Patients Adults 3 mg/kg 100 mg 6 mg/kg 200 mg 12* mg/kg 400 mg* Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended.
Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding fluconazole pharmacokinetics in full-term newborns is available.
Oropharyngeal candidiasis: The recommended dosage of fluconazole for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of fluconazole in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms.
Systemic Candida infections: For the treatment of candidemia and disseminated Candida infections, daily doses of 6 to 12 mg/kg/day have been used in an open, noncomparative study of a small number of children.
Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10 to 12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of fluconazole is 6 mg/kg once daily.
Dosage In Patients With Impaired Renal Function:
Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust single dose therapy for vaginal candidiasis because of impaired renal function. In patients with impaired renal function who will receive multiple doses of fluconazole, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table:
Creatinine Clearance (mL/min) Percent of Recommended Dose >50 100% ≤50 (no dialysis) 50% Regular dialysis 100% after each dialysisPatients on regular dialysis should receive 100% of the recommended dose after each dialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance.
These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition.
When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults:
Males: Weight (kg) × (140-age)
72 × serum creatinine (mg/100 mL)
Females: 0.85 × above value
Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children:
K × linear length or height (cm)
serum creatinine (mg/100 mL)
(Where K=0.55 for children older than 1 year and 0.45 for infants.)
Administration
Fluconazole tablets, USP are administered orally. Fluconazole tablets, USP can be taken with or without food.
- Carilion Materials Management
Guanfacine | Carilion Materials Management
The recommended initial dose of guanfacine (as the hydrochloride) when given alone or in combination with another antihypertensive drug is 1 mg daily given at bedtime to minimize somnolence. If after 3 to 4 weeks of therapy, 1 mg does not give a satisfactory result, a dose of 2 mg may be given, although most of the effect of guanfacine is seen at 1 mg (see ). Higher daily doses have been used, but adverse reactions increase significantly with doses above 3 mg/day. CLINICAL PHARMACOLOGY
The frequency of rebound hypertension is low, but it can occur. When rebound occurs, it does so after 2-4 days, which is delayed compared with clonidine hydrochloride. This is consistent with the longer half-life of guanfacine. In most cases, after abrupt withdrawal of guanfacine, blood pressure returns to pretreatment levels slowly (within 2-4 days) without ill effects.
- Actavis Pharma, Inc.
Guanfacine | Actavis Pharma, Inc.
The recommended initial dose of guanfacine hydrochloride when given alone or in combination with another antihypertensive drug is 1 mg daily given at bedtime to minimize somnolence. If after 3 to 4 weeks of therapy 1 mg does not give a satisfactory result, a dose of 2 mg may be given, although most of the effect of guanfacine is seen at 1 mg (see CLINICAL PHARMACOLOGY). Higher daily doses have been used, but adverse reactions increase significantly with doses above 3 mg/day.
The frequency of rebound hypertension is low, but it can occur. When rebound occurs, it does so after 2-4 days, which is delayed compared with clonidine hydrochloride. This is consistent with the longer half-life of guanfacine. In most cases, after abrupt withdrawal of guanfacine, blood pressure returns to pretreatment levels slowly (within 2-4 days) without ill effects.
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