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  • CLASSES

    ADHD Agents, Non-stimulant
    Centrally Acting Alpha Agonists

    DEA CLASS

    Rx

    DESCRIPTION

    Central acting alpha-2 adrenergic agonist
    Used for hypertension primarily in adult patients, also used for attention deficit hyperactivity disorder (ADHD) in pediatric patients
    Similar to clonidine but is more selective for alpha-2 adrenergic receptors and is longer acting, which allows for once daily dosing

    COMMON BRAND NAMES

    Intuniv, Tenex

    HOW SUPPLIED

    Guanfacine/Guanfacine Hydrochloride/Intuniv Oral Tab ER: 1mg, 2mg, 3mg, 4mg
    Guanfacine/Guanfacine Hydrochloride/Tenex Oral Tab: 1mg, 2mg

    DOSAGE & INDICATIONS

    For the treatment of hypertension.
    Oral dosage (immediate-release tablets)
    Adults and Adolescents

    Initially, 1 mg PO once daily at bedtime. If after 3 to 4 weeks of therapy results are not satisfactory, a dose of 2 mg PO once daily may be given, although most of the effect of guanfacine on blood pressure is seen at 1 mg/day. Higher daily doses have been used, but adverse reactions increase significantly with doses above 3 mg/day PO. Max: 3 to 4 mg PO once daily. If therapeutic response is inadequate, a second drug such as a thiazide diuretic may be added. Do not abruptly discontinue therapy.

    For the treatment of attention-deficit hyperactivity disorder (ADHD), as monotherapy or as adjunctive therapy to a psychostimulant.
    Oral dosage (extended-release tablets)
    Children and Adolescents 6 to 17 years

    1 mg PO once daily administered at the same time each day (morning or evening) initially. Titrate by no more than 1 mg/week based on clinical response and tolerability. TARGET DOSE RANGE: 0.05 to 0.12 mg/kg/day PO. ESTIMATED WEIGHT-BASED TARGET DOSES: Weight 25 to 33.9 kg = 2 to 3 mg/day PO; Weight 34 to 41.4 kg = 2 to 4 mg/day PO; Weight 41.5 to 49.4 kg = 3 to 5 mg/day PO; Weight 49.5 to 58.4 kg = 3 to 6 mg/day PO; Weight 58.5 to 91 kg = 4 to 7 mg/day PO. Weight more than 91 kg: 5 to 7 mg/day PO. AGE BASED MAXIMUM: Do not exceed 4 mg/day PO for children 6 to 12 years; do not exceed 7 mg/day PO for adolescents 13 to 17 years; doses more than 4 mg have not been studied in adjunctive trials. Periodically re-evaluate efficacy and adjust weight-based dosage as needed. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. DOSE CONVERSION: Do not substitute immediate-release (IR) and extended-release (ER) products on a mg-per-mg basis; if converting from IR guanfacine, discontinue IR treatment and titrate with the ER product as described above. MISSED DOSES: If the patient misses 2 or more consecutive doses, reinitiate therapy at the previous maintenance dose and consider titration for tolerability. DISCONTINUATION: Do not abruptly discontinue. Taper the daily dose by no more than 1 mg every 3 to 7 days to avoid rebound hypertension; monitor blood pressure and pulse with dose reduction or discontinuation.

    Oral dosage (immediate-release tablets)†
    Adults

    Optimal dose is not established. Limited data suggest 0.25 to 2 mg/day PO, given in divided doses, may have a beneficial effect. In a small crossover study, 17 adult patients were treated for 2 weeks with each guanfacine, dextroamphetamine, and placebo with a 4-day washout period between treatments. Guanfacine was initiated at 0.25 mg/day PO once daily in the morning and was increased by 0.25 mg/day or every other day as tolerated. Max: 2 mg/day PO; the mean (SD) daily dose was 1.1 mg (0.6 mg). The effect of guanfacine lasted approximately 6.9 hours. Both drugs showed similar improvement in the severity of ADHD symptoms using the DSM-IV ADHD Behavior Checklist (Adults); the Stroop test also showed positive drug effects. The Copeland Symptom Checklist for Adult Attention Deficit and the COWAT test did not find a statistically significant improvement with either drug.

    Children and Adolescents 4 to 17 years

    0.5 mg PO at bedtime initially, then titrated to 0.5 mg PO 4 times daily for patients weighing less than 45 kg OR 1 mg PO at bedtime initially, then titrated to 1 mg PO 4 times daily for those weighing 45 kg or more is recommended by the American Academy of Child and Adolescent Psychiatry (AACAP). Weight-based daily maximum: 2 mg/day PO for patients 27 to 40.5 kg, 3 mg/day PO for 40.5 to 45 kg, and 4 mg/day PO for more than 45 kg. One randomized, blinded, placebo-controlled study evaluated 0.5 to 4 mg/day PO given in 3 divided doses. Doses were initiated at 0.5 mg/day and titrated by 0.5 mg every 4 days to a maximum of 4 mg/day. Patients receiving guanfacine showed a 37% decrease in the total ADHD rating score (teacher completed) compared to an 8% reduction in patients receiving placebo (p < 0.001). Open-label studies using guanfacine at doses of 0.5 to 4 mg/day, given in divided doses 1 to 4 times daily also showed statistically significant improvements in ADHD rating scales compared to baseline. Two studies included patients with tic disorders and showed statistically significant decreases in tic severity in patients receiving guanfacine. The AACAP also recommends guanfacine as adjunctive therapy in patients who develop tic disorders secondary to stimulant therapy. If therapy is to be discontinued, taper the dose gradually over 1 to 2 weeks to avoid rebound hypertension.

    MAXIMUM DOSAGE

    Adults

    3 to 4 mg/day PO.

    Geriatric

    3 to 4 mg/day PO.

    Adolescents

    3 to 4 mg/day PO (immediate-release); 7 mg/day PO for ADHD (extended-release).

    Children

    6 to 12 years: 4 mg/day PO for ADHD (extended-release).
    4 to 5 years: Safety and efficacy have not been established; however, doses up to 4 mg/day PO (immediate-release) have been used off-label for the treatment of ADHD.
    1 to 4 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Data are lacking in patients with hepatic impairment. Caution is advised in patients with hepatic failure as 50% of dose is metabolized; in the treatment of ADHD, product labeling suggests that it may be necessary to adjust the dose in patients with significantly impaired hepatic function. In patients with mild to moderate hepatic impairment, initiate guanfacine cautiously. Adjust dosage to attain clinical goals.

    Renal Impairment

    CrCl 30 mL/minute or higher: No adjustment needed.
    CrCl less than 30 mL/minute: In the treatment of hypertension, product labeling recommends the lower end of the dosing range for guanfacine since 50% of the drug is excreted renally. In the treatment of attention deficit hyperactivity disorder (ADHD), product labeling suggests that it may be necessary to adjust the guanfacine dose in patients with significantly impaired renal function.
     
    Intermittent hemodialysis
    Follow dosage recommendations for patients with CrCl less than 30 mL/minute. Guanfacine is not significantly removed by hemodialysis.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Immediate-release tablets:
    Administer prior to bedtime to avoid drowsiness.
    Discontinuing treatment: If therapy is to be discontinued, decrease the dose over several days to avoid withdrawal symptoms.
     
    Extended-release tablets:
    Administer tablet whole with water, milk, or other liquid. Do not administer with a high-fat meal.
    Do not crush, chew, or break tablets prior to administration.
    Doses may be administered either in the morning or evening, but should be administered at approximately the same time each day.
    Missed doses: If the patient misses 2 or more consecutive doses, restart therapy at the previous maintenance dose and titrate based on patient tolerability.
    Discontinuing treatment: If therapy is to be discontinued, taper the daily dose in decrements of no more than 1 mg every 3 to 7 days to avoid rebound hypertension; monitor blood pressure and pulse when reducing dose or discontinuing therapy.

    STORAGE

    Intuniv:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Tenex:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Guanfacine is contraindicated in patients with a hypersensitivity to guanfacine or any product-specific inactive ingredient. Rash a pruritus have been reported.

    Acute myocardial infarction, AV block, bradycardia, cardiac disease, cerebrovascular disease, coronary artery disease, dehydration, hypotension, orthostatic hypotension, syncope

    Use caution and titrate guanfacine slowly in patients with a history of hypotension, in those with underlying conditions that may be worsened by hypotension and bradycardia (e.g., AV block, cardiac disease, vascular disease, cerebrovascular disease, coronary artery disease, acute myocardial infarction, chronic renal or hepatic failure), and in those with cardiac conduction abnormalities. Treatment with guanfacine can result in dose-dependent decreases in blood pressure and heart rate, which are usually less pronounced as the time of therapy progresses. In addition, the sympatholytic action of guanfacine may worsen sinus node dysfunction and AV block, especially in those taking other sympatholytic drugs. Measure heart rate and blood pressure at baseline, after dose adjustments, periodically throughout therapy, and upon discontinuation in all patients; monitor vital signs frequently in those with cardiac conduction abnormalities or receiving concomitant therapy with another sympatholytic agent. In patients with a history of or those who have a condition that predisposes them to syncope (e.g., hypotension, orthostatic hypotension, bradycardia, dehydration), advise patients to avoid becoming dehydrated or overheated.

    Hepatic disease, renal disease, renal failure, renal impairment

    Use guanfacine with caution in patients with hepatic disease or renal disease. Guanfacine is cleared by both the liver and kidney, and it may be necessary to reduce the dosage in patients with significant hepatic or renal impairment. In patients with renal failure, the drug is poorly dialyzed.

    Abrupt discontinuation

    To minimize the risk of an increase in blood pressure (e.g., rebound hypertension) upon discontinuation or dose reduction of guanfacine, the dose should be gradually reduced and abrupt discontinuation should be avoided. Hypertensive encephalopathy has also been reported in association with rebound hypertension. Withdrawal symptoms such as confusion, anxiety, irritability, and nervousness may also be associated with abrupt cessation. When discontinuing extended-release guanfacine, the total daily dose should be tapered in decrements of no more than 1 mg every 3 to 7 days. No specific tapering recommendations are available for immediate-release guanfacine. When reducing the dose and/or discontinuing guanfacine products, monitor blood pressure and heart rate. According to the manufacturer of immediate-release guanfacine, the frequency of rebound hypertension is low, and when it occurs, it becomes apparent 2 to 4 days following abrupt withdrawal. Pediatric patients commonly have gastrointestinal illnesses that lead to vomiting and the inability to take medication, which may increase the risk for rebound hypertension. Patients should be advised to contact their provider immediately if they develop vomiting or other condition which suddenly prevents them from continuing treatment with guanfacine. Patients should also be advised to contact their provider if they experience side effects from abrupt withdrawal such as headache, confusion, nervousness, agitation, or tremor and to seek immediate medical attention for symptoms including somnolence, vomiting, severe headache, visual disturbances, or seizures.

    Geriatric

    Geriatric patients may be more sensitive to the CNS depressant and hypotensive effects of guanfacine. The elimination half-life of guanfacine is increased in older patients relative to younger adults. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Safety and efficacy have not been established for the use of guanfacine in older adults with attention-deficit disorder (ADHD); no geriatric subjects were included in clinical trials. According to the Beers Criteria, guanfacine is considered a potentially inappropriate medication (PIM) for use in geriatric patients and should be avoided as routine treatment of hypertension in this population due to the high risk of adverse CNS effects and the possibility of bradycardia or orthostatic hypotension. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. There are many drug interactions that can potentiate the effects of antihypertensives. Some agents require a gradual taper to avoid adverse consequences caused by abrupt discontinuation.

    Driving or operating machinery, ethanol ingestion

    Sedation and somnolence were commonly reported adverse effects during clinical trial evaluation of guanfacine; these effects are similar to other central alpha-2 adrenergic agonists, and are particularly likely to occur at the start of therapy. Caution patients against driving or operating machinery until they know how guanfacine affects them. Advise patients to avoid ethanol ingestion while receiving guanfacine. When guanfacine is used with other centrally active depressants (e.g., phenothiazines, barbiturates, or benzodiazepines), the potential for additive sedative effects should be considered.

    Pregnancy

    There are no adequate and well-controlled studies of the use of guanfacine during pregnancy. Guanfacine should only be used during pregnancy when it is considered essential to achieve therapeutic goals in the mother. Further, guanfacine is not recommended in the treatment of acute hypertension associated with toxemia of pregnancy. If an antihypertensive drug is needed during pregnancy, other agents are preferred, such as methyldopa, for which there are data regarding safety and efficacy in pregnancy. For ADHD treatment, the risks and benefits of continuing or discontinuing guanfacine during pregnancy requires careful consideration. Animal studies have not indicated a risk for developmental toxicity; 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 (MRHD). Higher doses (13.5 times the MRHD in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity. Animal studies are not always predictive of human response. There is no information available on the effects of guanfacine on the course of labor and obstetric delivery.

    Breast-feeding

    It is not known whether guanfacine is excreted in human milk; however, it is excreted into rat milk. Because many drugs are excreted in human milk, caution should be exercised when guanfacine is administered when a woman is breast-feeding an infant. The antihypertensives methyldopa, nifedipine, and the beta-blockers labetalol and propranolol are considered usually compatible with breast-feeding and may represent alternatives to consider for the treatment of hypertension during lactation. While excretion of captopril or enalapril into breast milk is also low, other agents are preferred for hypertensive lactating women taking higher doses of these drugs. Diuretics are generally not recommended since they can reduce the quality of milk production. For ADHD treatment, the risks and benefits of continuing guanfacine or discontinuing guanfacine to allow breast-feeding requires careful consideration. If used, observe breast-fed infants for sedation and somnolence.

    Children, infants

    Safe and effective use of guanfacine in infants and children aged less than 12 years for the treatment of hypertension or in infants and children less than 6 years for the treatment of ADHD has not been established. In the use of guanfacine for attention deficit hyperactivity disorder (ADHD) and other behavior disorders in children, clinicians should be alert for sedation, hypotension and other potential side effects. Mania and aggressive behavioral changes have been reported in some children who received guanfacine for ADHD; these reports were received from one center, and all patients had medical or family risk factors for bipolar disorder. Hallucinations have also been reported in pediatric patients receiving guanfacine for ADHD. Children and adolescents receiving guanfacine should be monitored for changes in blood pressure at treatment initiation, periodically during treatment, and when tapering the drug.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 1.0-10.0
    arrhythmia exacerbation / Early / 2.0
    AV block / Early / 2.0
    bronchospasm / Rapid / 2.0
    renal failure (unspecified) / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    stroke / Early / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 1.0-15.0
    hypotension / Rapid / 1.0-9.0
    orthostatic hypotension / Delayed / 1.0-9.0
    impotence (erectile dysfunction) / Delayed / 3.0-7.0
    palpitations / Early / 0-3.0
    sinus tachycardia / Rapid / 0-3.0
    iritis / Delayed / 0-3.0
    blurred vision / Early / 0-3.0
    conjunctivitis / Delayed / 0-3.0
    dysphagia / Delayed / 0-3.0
    urinary incontinence / Early / 2.0-3.0
    dyspnea / Early / 0-3.0
    paresis / Delayed / 0-3.0
    wheezing / Rapid / 2.0
    chest pain (unspecified) / Early / Incidence not known
    edema / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    hypertension / Early / Incidence not known

    Mild

    xerostomia / Early / 2.0-60.0
    anorexia / Delayed / 4.0-15.0
    abdominal pain / Early / 2.0-11.0
    rhinitis / Early / 0-3.0
    dysgeusia / Early / 0-3.0
    tinnitus / Delayed / 0-3.0
    nausea / Early / 2.0-3.0
    dyspepsia / Early / 2.0-3.0
    hyperhidrosis / Delayed / 0-3.0
    purpura / Delayed / 0-3.0
    pruritus / Rapid / 2.0-3.0
    muscle cramps / Delayed / 0-3.0
    malaise / Early / 0-3.0
    vomiting / Early / 2.0
    diarrhea / Early / 2.0
    weight gain / Delayed / 2.0
    rash / Early / 2.0
    nocturia / Early / 2.0
    syncope / Early / Incidence not known
    pallor / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    increased urinary frequency / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    myalgia / Early / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Acetaminophen; Butalbital: (Major) Monitor patients for guanfacine efficacy and for excess sedation during butalbital coadministration. Guanfacine plasma concentrations can be reduced by butalbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
    Acetaminophen; Butalbital; Caffeine: (Major) Monitor patients for guanfacine efficacy and for excess sedation during butalbital coadministration. Guanfacine plasma concentrations can be reduced by butalbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Monitor patients for guanfacine efficacy and for excess sedation during butalbital coadministration. Guanfacine plasma concentrations can be reduced by butalbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
    Acetazolamide: (Moderate) The concomitant administration of diuretics with other antihypertensive agents can result in additive hypotensive effects. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Aldesleukin, IL-2: (Moderate) Antihypertensive agents may potentiate the hypotension seen with aldesleukin, IL-2.
    Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
    Alprazolam: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Alprostadil: (Minor) The concomitant use of systemic alprostadil injection and central-acting antihypertensive agents may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to alprostadil. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
    Amifostine: (Major) Patients receiving central-acting adrenergic agents should be closely monitored during amifostine infusions due to additive effects. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. If the antihypertensive cannot be stopped, patients should not receive amifostine.
    Amiodarone: (Major) Amiodarone may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon amiodarone discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and amiodarone is a moderate CYP3A4 inhibitor.
    Amitriptyline: (Major) Tricyclic antidepressants (TCAs) can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Consider alternatives to TCAs in patients established on guanfacine therapy for hypertension when possible; it is not clear the effect the combination may have when used in patients treated with guanfacine for attention-deficit, but other options to TCAs should be considered. Increased dosages of guanfacine may be required to control blood pressure in patients who are receiving TCAs concurrently. In addition, concurrent TCAs may enhance the potential for serious rebound hypertension following guanfacine discontinuation, regardless of the indication for treatment. If guanfacine therapy is withdrawn, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension.
    Amitriptyline; Chlordiazepoxide: (Major) Tricyclic antidepressants (TCAs) can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Consider alternatives to TCAs in patients established on guanfacine therapy for hypertension when possible; it is not clear the effect the combination may have when used in patients treated with guanfacine for attention-deficit, but other options to TCAs should be considered. Increased dosages of guanfacine may be required to control blood pressure in patients who are receiving TCAs concurrently. In addition, concurrent TCAs may enhance the potential for serious rebound hypertension following guanfacine discontinuation, regardless of the indication for treatment. If guanfacine therapy is withdrawn, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension. (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Amobarbital: (Major) Monitor patients for guanfacine efficacy and for excess sedation during amobarbital coadministration. Guanfacine plasma concentrations can be reduced by amobarbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
    Amoxapine: (Major) Cyclic antidepressants like amoxapine can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Increased dosages of guanfacine may be required in patients who are receiving amoxapine concurrently. In addition, concurrent amoxapine use may enhance the potential for rebound hypertension following guanfacine discontinuation. If guanfacine is withdrawn in the presence of amoxapine or other cyclic antidepressants, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Clarithromycin may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If clarithromycin is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and clarithromycin is a strong CYP3A4 inhibitor.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Clarithromycin may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If clarithromycin is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and clarithromycin is a strong CYP3A4 inhibitor.
    Amphetamines: (Moderate) Sympathomimetic agents, such as amphetamines, may increase blood pressure and reduce the antihypertensive effects of antihypertensive agents, such as guanfacine. Monitor blood pressure and heart rate periodically when prescribed together. Guanfacine may be used adjunctively to psycostimulants such as amphetamines in the treatment of attention deficit hyperactivity disorder (ADHD). Pharmacokinetic studies reveal that guanfacine does not influence lisdexamfetamine pharmacokinetics and lisdexamfetamine does not affect guanfacine pharmacokinetics. No dosage adjustments are required when guanfacine and amphetamines are used together. Monitor heart rate, blood pressure and for sedation during ADHD treatment.
    Amyl Nitrite: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Apalutamide: (Major) A dose increase of extended-release (ER) guanfacine should be considered if coadministration with apalutamide is necessary. Consider doubling the recommended dose of guanfacine if therapy is added to a patient already taking apalutamide; increase the dose of guanfacine over 1 to 2 weeks if apalutamide therapy is added to a patient already taking guanfacine. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased guanfacine exposure by 70%.
    Apomorphine: (Moderate) Patients receiving apomorphine may experience orthostatic hypotension, hypotension, and/or syncope. Extreme caution should be exercised if apomorphine is used concurrently with antihypertensive agents, or vasodilators such as nitrates.
    Apraclonidine: (Minor) Alpha blockers as a class may reduce heart rate and blood pressure. While no specific drug interactions have been identified with systemic agents and apraclonidine during clinical trials, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Patients using cardiovascular drugs concomitantly with apraclonidine should have their pulse and blood pressure monitored periodically.
    Aprepitant, Fosaprepitant: (Major) Aprepitant may significantly increase guanfacine plasma concentrations when used as a 3-day oral regimen (125mg/80mg/80mg) for chemotherapy-induced nausea and vomiting (CINV). FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together with this regimen, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon aprepitant, fosaprepitant discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and weak inducer. Plasma concentrations of another CYP3A4 substrate, midazolam, increased from 1.25-fold to 3.3-fold after administration of a 3 to 5-day oral aprepitant regimen; midazolam concentrations were subsequently decreased by 19% and 4% on days 8 and 15, respectively. However, as a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, IV fosaprepitant (single dose) is rapidly converted to aprepitant and shares some of the same drug interactions but it only weakly inhibits CYP3A4 for a duration of 2 days, increasing the midazolam AUC by approximately 1.8-fold on day 1 with no effect by day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. There is no evidence of CYP3A4 induction with fosaprepitant.
    Aripiprazole: (Minor) Due to aripiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.
    Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Monitor patients for guanfacine efficacy and for excess sedation during butalbital coadministration. Guanfacine plasma concentrations can be reduced by butalbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Monitor patients for guanfacine efficacy and for excess sedation during butalbital coadministration. Guanfacine plasma concentrations can be reduced by butalbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
    Atazanavir: (Major) Atazanavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If atazanavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and atazanavir is a strong CYP3A4 inhibitor.
    Atazanavir; Cobicistat: (Major) Atazanavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If atazanavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and atazanavir is a strong CYP3A4 inhibitor. (Major) If coadministration of cobicistat with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If cobicstat is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Cobicstast may significantly increase guanfacine plasma concentrations.
    Atenolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Atenolol; Chlorthalidone: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with guanfacine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with guanfacine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Monitor patients for guanfacine efficacy and for excess sedation during phenobarbital coadministration. Guanfacine plasma concentrations can be reduced by phenobarbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
    Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Monitor patients for guanfacine efficacy and for excess sedation during phenobarbital coadministration. Guanfacine plasma concentrations can be reduced by phenobarbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
    Bendroflumethiazide; Nadolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Benzodiazepines: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Beta-blockers: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Betaxolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Bexarotene: (Major) Bexarotene may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if bexarotene is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If bexarotene is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and bexarotene is a moderate CYP3A4 inducer in vitro.
    Bisoprolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Boceprevir: (Major) Boceprevir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If boceprevir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and boceprevir is a strong CYP3A4 inhibitor.
    Bortezomib: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients.
    Bosentan: (Major) Bosentan may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if bosentan is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If bosentan is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Although no specific interactions have been documented, bosentan has vasodilatory effects and may contribute additive hypotensive effects when given with a centrally-acting adrenergic agonist such as guanfacine. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and bosentan is a moderate CYP3A4 inducer.
    Brexpiprazole: (Moderate) Due to brexpiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.
    Brimonidine; Timolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Bupropion: (Moderate) There is one case report that describes a grand mal seizure that occurred in a child of 10 years of age receiving guanfacine and bupropion concurrently. It is not possible, based on this limited report, to determine if guanfacine was a contributor to the event. Causality has not been established.
    Bupropion; Naltrexone: (Moderate) There is one case report that describes a grand mal seizure that occurred in a child of 10 years of age receiving guanfacine and bupropion concurrently. It is not possible, based on this limited report, to determine if guanfacine was a contributor to the event. Causality has not been established.
    Butabarbital: (Major) Monitor patients for guanfacine efficacy and for excess sedation during butabarbital coadministration. Guanfacine plasma concentrations can be reduced by butabarbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and central-acting adrenergic agents. CNS depressants can potentiate the effects of cannabidiol.
    Carbamazepine: (Major) Carbamazepine can significantly decrease guanfacine plasma concentrations; guanfacine dosage adjustment is recommended. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered. If carbamazepine is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If carbamazepine is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and carbamazepine is a strong CYP3A4 inducer.
    Carbidopa; Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Carbonic anhydrase inhibitors: (Moderate) The concomitant administration of diuretics with other antihypertensive agents can result in additive hypotensive effects. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
    Carteolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Carvedilol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Celecoxib: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Chloramphenicol: (Major) Chloramphenicol may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If chloramphenicol is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and chloramphenicol is a strong CYP3A4 inhibitor.
    Chlordiazepoxide: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Chlordiazepoxide; Clidinium: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Chlorpromazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Ciprofloxacin: (Major) Ciprofloxacin may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends decreasing the guanfacine dosage to half the recommended dose if these agents are taken together. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon ciprofloxacin discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and ciprofloxacin is a moderate CYP3A4 inhibitor.
    Clarithromycin: (Major) Clarithromycin may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If clarithromycin is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and clarithromycin is a strong CYP3A4 inhibitor.
    Clomipramine: (Major) Tricyclic antidepressants (TCAs) can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Consider alternatives to TCAs in patients established on guanfacine therapy for hypertension when possible; it is not clear the effect the combination may have when used in patients treated with guanfacine for attention-deficit, but other options to TCAs should be considered. Increased dosages of guanfacine may be required to control blood pressure in patients who are receiving TCAs concurrently. In addition, concurrent TCAs may enhance the potential for serious rebound hypertension following guanfacine discontinuation, regardless of the indication for treatment. If guanfacine therapy is withdrawn, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension.
    Clonazepam: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Clorazepate: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Clozapine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
    Cobicistat: (Major) If coadministration of cobicistat with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If cobicstat is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Cobicstast may significantly increase guanfacine plasma concentrations.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) If coadministration of cobicistat with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If cobicstat is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Cobicstast may significantly increase guanfacine plasma concentrations.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) If coadministration of cobicistat with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If cobicstat is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Cobicstast may significantly increase guanfacine plasma concentrations.
    Cocaine: (Major) Use of cocaine with antihypertensive agents may increase the antihypertensive effects of the antihypertensive medications or may potentiate cocaine-induced sympathetic stimulation.
    Cod Liver Oil: (Moderate) Fish oil supplements may cause mild, dose-dependent reductions in blood pressure in untreated hypertensive patients. Additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents. (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
    Conivaptan: (Severe) Conivaptan may significantly increase guanfacine plasma concentrations; avoid concomitant use. Subsequent therapy with guanfacine may be initiated no sooner than 1 week after the infusion of conivaptan is complete. Guanfacine is primarily metabolized by CYP3A4 and conivaptan is a strong CYP3A4 inhibitor. Additive hypotension may also occur between conivaptan and other agents that can lower blood pressure.
    Crizotinib: (Major) Reduce the extended-release (ER) guanfacine dosage to half of the recommended dose if coadministration with crizotinib is necessary. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If crizotinib is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Crizotinib may significantly increase guanfacine plasma concentrations.
    Cyclosporine: (Major) Cyclosporine may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon cyclosporine discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and cyclosporine is a moderate CYP3A4 inhibitor.
    Darunavir: (Major) Darunavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If darunavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4. Darunavir is a strong CYP3A4 inhibitor, and when administered with ritonavir, potent inhibition is expected.
    Darunavir; Cobicistat: (Major) Darunavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If darunavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4. Darunavir is a strong CYP3A4 inhibitor, and when administered with ritonavir, potent inhibition is expected. (Major) If coadministration of cobicistat with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If cobicstat is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Cobicstast may significantly increase guanfacine plasma concentrations.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Darunavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If darunavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4. Darunavir is a strong CYP3A4 inhibitor, and when administered with ritonavir, potent inhibition is expected. (Major) If coadministration of cobicistat with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If cobicstat is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Cobicstast may significantly increase guanfacine plasma concentrations.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Ritonavir may significantly alter guanfacine plasma concentrations. Guanfacine is primarily metabolized by CYP3A4. Ritonavir is a potent CYP3A4 inhibitor; moderate CYP3A4 induction has been reported with concomitant use of voriconazole. The net effect of this potential interaction is unclear, but guanfacine dosage adjustments, most likely a dose decrease, may be required. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if used with a moderate to strong CYP3A4 inhibitor, the guanfacine dosage should be decreased to half of the recommended dose and the patient should be closely monitored for alpha-adrenergic effects (e.g., hypotension, drowsiness, bradycardia). However, if used with a moderate to strong CYP3A4 inducer, labeling recommends to consider doubling the recommended dose of guanfacine ER; if the inducer is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If the inducer or inhibitor is discontinued, guanfacine ER should return to its recommended dose (with downward titration occurring over 1 to 2 weeks). Specific recommendations for immediate-release (IR) guanfacine are not available.
    Deferasirox: (Major) Deferasirox may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if deferasirox is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If deferasirox is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and deferasirox is a moderate CYP3A4 inducer.
    Delavirdine: (Major) Delavirdine may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If delavirdine is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and delavirdine is a strong CYP3A4 inhibitor.
    Desipramine: (Major) Tricyclic antidepressants (TCAs) can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Consider alternatives to TCAs in patients established on guanfacine therapy for hypertension when possible; it is not clear the effect the combination may have when used in patients treated with guanfacine for attention-deficit, but other options to TCAs should be considered. Increased dosages of guanfacine may be required to control blood pressure in patients who are receiving TCAs concurrently. In addition, concurrent TCAs may enhance the potential for serious rebound hypertension following guanfacine discontinuation, regardless of the indication for treatment. If guanfacine therapy is withdrawn, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension.
    Dexamethasone: (Major) Dexamethasone may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if dexamethasone is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If dexamethasone is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and dexamethasone is a moderate CYP3A4 inducer.
    Dexmethylphenidate: (Moderate) Psychostimulants, such as dexmethylphenidate, may increase blood pressure and reduce the antihypertensive effects of antihypertensive agents, such as guanfacine. Monitor blood pressure and heart rate periodically when prescribed together. Guanfacine may be used adjunctively to dexmethylphenidate in the treatment of attention deficit hyperactivity disorder (ADHD). Patients should be monitored for heart rate, blood pressure, and for sedation during ADHD treatment.
    Dextromethorphan; Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Diazepam: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Diazoxide: (Moderate) Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agents. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving other antihypertensive agents. Diazoxide can enhance the hyperglycemic, hyperuricemic and antihypertensive effects of thiazide diuretics.
    Diclofenac: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Diclofenac; Misoprostol: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Diflunisal: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Diltiazem: (Major) Diltiazem may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon diltiazem discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and diltiazem is a moderate CYP3A4 inhibitor.
    Diphenhydramine; Ibuprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Diphenhydramine; Naproxen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Dorzolamide; Timolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Doxepin: (Major) Tricyclic antidepressants (TCAs) can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Consider alternatives to TCAs in patients established on guanfacine therapy for hypertension when possible; it is not clear the effect the combination may have when used in patients treated with guanfacine for attention-deficit, but other options to TCAs should be considered. Increased dosages of guanfacine may be required to control blood pressure in patients who are receiving TCAs concurrently. In addition, concurrent TCAs may enhance the potential for serious rebound hypertension following guanfacine discontinuation, regardless of the indication for treatment. If guanfacine therapy is withdrawn, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension.
    Dronedarone: (Major) Dronedarone may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon dronedarone discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and dronedarone is a moderate CYP3A4 inhibitor.
    Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
    Duvelisib: (Major) Decrease the dose of extended-release guanfacine by 50% if coadministration with duvelisib is necessary; if duvelisib is discontinued, the dose of extended-release guanfacine may be increased to the recommended level. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Recommendations for immediate-release guanfacine are not available. Guanfacine is a CYP3A substrate and duvelisib is a moderate CYP3A inhibitor.
    Efavirenz: (Major) Efavirenz may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if efavirenz is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If efavirenz is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and efavirenz is a moderate CYP3A4 inducer.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Efavirenz may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if efavirenz is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If efavirenz is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and efavirenz is a moderate CYP3A4 inducer.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Efavirenz may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if efavirenz is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If efavirenz is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and efavirenz is a moderate CYP3A4 inducer.
    Elagolix: (Major) Elagolix may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if elagolix is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If elagolix is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and elagolix is a weak to moderate CYP3A4 inducer.
    Enflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Enzalutamide: (Major) A dose increase of extended-release (ER) guanfacine should be considered if coadministration with enzalutamide is necessary. Consider doubling the recommended dose of guanfacine if therapy is added to a patient already taking enzalutamide; increase the dose of guanfacine over 1 to 2 weeks if enzalutamide therapy is added to a patient already taking guanfacine. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased guanfacine exposure by 70%.
    Epoprostenol: (Moderate) The concomitant administration of epoprostenol with other antihypertensive agents can result in additive hypotensive effects. This can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Erythromycin: (Major) Erythromycin may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon erythromycin discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and erythromycin is a moderate CYP3A4 inhibitor.
    Erythromycin; Sulfisoxazole: (Major) Erythromycin may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon erythromycin discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and erythromycin is a moderate CYP3A4 inhibitor.
    Eslicarbazepine: (Major) Eslicarbazepine may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if eslicarbazepine is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If eslicarbazepine is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and eslicarbazepine is a moderate CYP3A4 inducer.
    Esmolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Esomeprazole; Naproxen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Estazolam: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Estradiol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormone therapy should be monitored for antihypertensive effectiveness.
    Ethanol: (Major) Advise patients to avoid use of alcohol while on guanfacine treatment. Guanfacine has been associated with sedative effects and can potentiate the actions of other central nervous system (CNS) depressants including alcohol. Before using guanfacine 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.
    Etodolac: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Etomidate: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Etravirine: (Major) Etravirine may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if etravirine is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If etravirine is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and etravirine is a moderate CYP3A4 inducer.
    Famotidine; Ibuprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Fenoprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10. (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Fluconazole: (Major) Fluconazole may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon fluconazole discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and fluconazole is a moderate CYP3A4 inhibitor.
    Fluoxetine; Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Fluphenazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Flurazepam: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Flurbiprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Fluvoxamine: (Major) Fluvoxamine may significantly increase plasma concentrations of guanfacine, a primary CYP3A4 substrate. FDA-approved labeling for extended-release (ER) guanfacine recommends that if taken with a moderate CYP3A4 inhibitor, such as fluvoxamine, the guanfacine dosage be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If fluvoxamine is discontinued, the guanfacine ER dosage should be increased back to the recommended dose.
    Fosamprenavir: (Major) Fosamprenavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If fosamprenavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and fosamprenavir is a strong CYP3A4 inhibitor.
    Fosphenytoin: (Major) Monitor patients for guanfacine efficacy during fosphenytoin coadministration. Guanfacine plasma concentrations can be reduced by fosphenytoin, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Fosphenytoin is a strong CYP3A4 inducer. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment.
    Fospropofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    General anesthetics: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Grapefruit juice: (Major) Avoid consumption of grapefruit or grapefruit juice with guanfacine. Grapefruit is a strong CYP3A4 inhibitor, and guanfacine is a CYP3A4 substrate. Consumption may significantly increase exposure to guanfacine and increase the risk of alpha-adrenergic effects (e.g., hypotension, drowsiness, lethargy, bradycardia).
    Haloperidol: (Moderate) Disturbances of orthostatic regulation (e.g., orthostatic hypotension, dizziness, fatigue) and additive sedation may occur in patients receiving concomitant clonidine and antipsychotics. Also, based on observations in patients in a state of alcoholic delirium, high intravenous doses of clonidine may increase the arrhythmogenic potential (QT prolongation, ventricular fibrillation) of high intravenous doses of haloperidol. A causal relationship and relevance for clonidine oral tablets have not been established.
    Halothane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Hydrocodone; Ibuprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Ibuprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Ibuprofen; Oxycodone: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Ibuprofen; Pseudoephedrine: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Idelalisib: (Major) Idelalisib may significantly increase guanfacine plasma concentrations. Guanfacine is primarily metabolized by CYP3A4, and idelalisib is a strong CYP3A4 inhibitor. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if given with a strong CYP3A4 inhibitor, the guanfacine dosage should be decreased to half of the recommended dose. The labeling for idelalisib warns against coadministration with CYP3A4 substrates. If these agents are given together, reduce the guanfacine dosage as recommended and monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If idelalisib is discontinued, the guanfacine ER dosage should be increased back to the recommended dose.
    Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Iloprost: (Moderate) Further reductions in blood pressure may occur when inhaled iloprost is administered to patients receiving other antihypertensive agents.
    Imatinib: (Major) Imatinib may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon imatinib discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and imatinib is a moderate CYP3A4 inhibitor.
    Imipramine: (Major) Tricyclic antidepressants (TCAs) can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Consider alternatives to TCAs in patients established on guanfacine therapy for hypertension when possible; it is not clear the effect the combination may have when used in patients treated with guanfacine for attention-deficit, but other options to TCAs should be considered. Increased dosages of guanfacine may be required to control blood pressure in patients who are receiving TCAs concurrently. In addition, concurrent TCAs may enhance the potential for serious rebound hypertension following guanfacine discontinuation, regardless of the indication for treatment. If guanfacine therapy is withdrawn, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension.
    Indinavir: (Major) Indinavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If indinavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and indinavir is a strong CYP3A4 inhibitor.
    Indomethacin: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Intravenous Lipid Emulsions: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Isavuconazonium: (Major) Isavuconazonium may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon isavuconazonium discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and isavuconazonium is a moderate CYP3A4 inhibitor.
    Isoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifampin may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if rifampin is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. Upon rifampin discontinuation, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and rifampin is a strong CYP3A4 inducer.
    Isoniazid, INH; Rifampin: (Major) Rifampin may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if rifampin is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. Upon rifampin discontinuation, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and rifampin is a strong CYP3A4 inducer.
    Isosorbide Dinitrate, ISDN: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Isosorbide Mononitrate: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Itraconazole: (Major) Itraconazole may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon itraconazole discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and itraconazole is a strong CYP3A4 inhibitor.
    Ketamine: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Ketoconazole: (Major) Ketoconazole may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon ketoconazole discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and ketoconazole is a strong CYP3A4 inhibitor.
    Ketoprofen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Ketorolac: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Labetalol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Lansoprazole; Naproxen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Letermovir: (Major) FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon letermovir discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Levobetaxolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Levobunolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Levomilnacipran: (Major) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of clonidine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. In addition, because levomilnacipran inhibits the reuptake of norepinephrine, it may antagonize the antihypertensive and other pharmacologic effects of guanfacine, a centrally-acting antihypertensive that decreases noradrenergic activity. Use of another antidepressant would be preferable in patients taking guanfacine.
    Lofexidine: (Major) Lofexidine is a central alpha-2 adrenergic agonist, and its effects can be additive to other medications in the same class. Monitor for excessive hypotension, bradycardia, and sedation during coadministration. Patients being given lofexidine in an outpatient setting should be capable of and instructed on self-monitoring for hypotension, orthostasis, bradycardia, and associated symptoms. If clinically significant or symptomatic hypotension and/or bradycardia occur, the next dose of lofexidine should be reduced in amount, delayed, or skipped.
    Lopinavir; Ritonavir: (Major) Ritonavir may significantly alter guanfacine plasma concentrations. Guanfacine is primarily metabolized by CYP3A4. Ritonavir is a potent CYP3A4 inhibitor; moderate CYP3A4 induction has been reported with concomitant use of voriconazole. The net effect of this potential interaction is unclear, but guanfacine dosage adjustments, most likely a dose decrease, may be required. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if used with a moderate to strong CYP3A4 inhibitor, the guanfacine dosage should be decreased to half of the recommended dose and the patient should be closely monitored for alpha-adrenergic effects (e.g., hypotension, drowsiness, bradycardia). However, if used with a moderate to strong CYP3A4 inducer, labeling recommends to consider doubling the recommended dose of guanfacine ER; if the inducer is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If the inducer or inhibitor is discontinued, guanfacine ER should return to its recommended dose (with downward titration occurring over 1 to 2 weeks). Specific recommendations for immediate-release (IR) guanfacine are not available.
    Lorazepam: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Lorlatinib: (Major) A dose increase of extended-release (ER) guanfacine should be considered if coadministration with lorlatinib is necessary. Consider doubling the recommended dose of guanfacine if therapy is added to a patient already taking lorlatinib; increase the dose of guanfacine over 1 to 2 weeks if lorlatinib therapy is added to a patient already taking guanfacine. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Lovastatin; Niacin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. Clonidine has been shown to inhibit niacin-induced flushing. The interaction is harmless unless niacin augments the hypotensive actions of clonidine.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if lumacaftor; ivacaftor is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If lumacaftor; ivacaftor is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and lumacaftor is a strong CYP3A4 inducer.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if lumacaftor; ivacaftor is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If lumacaftor; ivacaftor is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and lumacaftor is a strong CYP3A4 inducer.
    Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
    Maprotiline: (Major) Cyclic antidepressants like maprotiline can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Increased dosages of guanfacine may be required in patients who are receiving maprotiline concurrently. In addition, concurrent maprotiline use may enhance the potential for rebound hypertension following guanfacine discontinuation. If guanfacine is withdrawn in the presence of maprotiline or other cyclic antidepressants, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension.
    Meclofenamate Sodium: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Mefenamic Acid: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Meloxicam: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Mephobarbital: (Major) Monitor patients for guanfacine efficacy and for excess sedation during mephobarbital coadministration. Guanfacine plasma concentrations can be reduced by mephobarbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
    Mesoridazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Mestranol; Norethindrone: (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; monitor patients receiving concurrent therapy to confirm that the desired antihypertensive effect is being obtained.
    Methazolamide: (Moderate) The concomitant administration of diuretics with other antihypertensive agents can result in additive hypotensive effects. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
    Methylphenidate: (Moderate) Psychostimulants, such as methylphenidate, may increase blood pressure and reduce the antihypertensive effects of antihypertensive agents, such as guanfacine. Monitor blood pressure and heart rate periodically when prescribed together. Guanfacine may be used adjunctively to methylphenidate in the treatment of attention deficit hyperactivity disorder (ADHD). Pharmacokinetic studies reveal that guanfacine does not influence methylphenidate pharmacokinetics and methylphenidate does not affect guanfacine pharmacokinetics. No dosage adjustments are required when used together. Patients should be monitored for heart rate, blood pressure, and for sedation during ADHD treatment.
    Metoprolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Midazolam: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Milnacipran: (Major) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. In addition, because levomilnacipran inhibits the reuptake of norepinephrine, it may antagonize the antihypertensive and other pharmacologic effects of clonidine or guanfacine, centrally-acting antihypertensives that decrease noradrenergic activity. Use of another antidepressant would be preferable in patients taking clonidine or guanfacine.
    Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
    Mitotane: (Major) Mitotane may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if mitotane is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If mitotane is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and mitotane is a strong CYP3A4 inducer.
    Monoamine oxidase inhibitors: (Severe) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Certain antihypertensive-MAOI combinations warrant particular caution. If a patient receiving an MAOI is started on clonidine, severe hypertension may occur, and this reaction may be followed by hypotension, which may be severe. Additionally, if a patient is withdrawn from clonidine, an excess of circulating catecholamines may occur. A similar reaction with MAOIs may be anticipated with concurrent administration of guanfacine since both guanfacine and clonidine are centrally-acting alpha-2 adrenergic agonists. Concurrent administration of guanfacine and MAOIs should be avoided if possible.
    Nabumetone: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Nadolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Naproxen: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Naproxen; Pseudoephedrine: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Naproxen; Sumatriptan: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Nebivolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Nebivolol; Valsartan: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Nefazodone: (Major) Nefazodone may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If nefazodone is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and nefazodone is a strong CYP3A4 inhibitor.
    Nelfinavir: (Major) Nelfinavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If nelfinavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and nelfinavir is a strong CYP3A4 inhibitor.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Netupitant may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon netupitant; palonosetron discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and netupitant is a moderate CYP3A4 inhibitor. The inhibitory effect of netupitant can last for multiple days; monitor patients closely.
    Nevirapine: (Major) Nevirapine may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if nevirapine is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If nevirapine is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and nevirapine is a moderate CYP3A4 inducer.
    Niacin, Niacinamide: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. Clonidine has been shown to inhibit niacin-induced flushing. The interaction is harmless unless niacin augments the hypotensive actions of clonidine.
    Niacin; Simvastatin: (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise. Clonidine has been shown to inhibit niacin-induced flushing. The interaction is harmless unless niacin augments the hypotensive actions of clonidine.
    Nilotinib: (Major) Nilotinib may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon nilotinib discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and nilotinib is a moderate CYP3A4 inhibitor.
    Nitrates: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Nitroglycerin: (Moderate) Concomitant use of nitrates with other antihypertensive agents can cause additive hypotensive effects. Dosage adjustments may be necessary.
    Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.
    Nonsteroidal antiinflammatory drugs: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Nortriptyline: (Major) Tricyclic antidepressants (TCAs) can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Consider alternatives to TCAs in patients established on guanfacine therapy for hypertension when possible; it is not clear the effect the combination may have when used in patients treated with guanfacine for attention-deficit, but other options to TCAs should be considered. Increased dosages of guanfacine may be required to control blood pressure in patients who are receiving TCAs concurrently. In addition, concurrent TCAs may enhance the potential for serious rebound hypertension following guanfacine discontinuation, regardless of the indication for treatment. If guanfacine therapy is withdrawn, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension.
    Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Ritonavir may significantly alter guanfacine plasma concentrations. Guanfacine is primarily metabolized by CYP3A4. Ritonavir is a potent CYP3A4 inhibitor; moderate CYP3A4 induction has been reported with concomitant use of voriconazole. The net effect of this potential interaction is unclear, but guanfacine dosage adjustments, most likely a dose decrease, may be required. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if used with a moderate to strong CYP3A4 inhibitor, the guanfacine dosage should be decreased to half of the recommended dose and the patient should be closely monitored for alpha-adrenergic effects (e.g., hypotension, drowsiness, bradycardia). However, if used with a moderate to strong CYP3A4 inducer, labeling recommends to consider doubling the recommended dose of guanfacine ER; if the inducer is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If the inducer or inhibitor is discontinued, guanfacine ER should return to its recommended dose (with downward titration occurring over 1 to 2 weeks). Specific recommendations for immediate-release (IR) guanfacine are not available.
    Opiate Agonists: (Moderate) Central-acting adrenergic agonists like guanfacine have CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    Oxaprozin: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Oxazepam: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by guanfacine. If these drugs are used together, closely monitor for changes in blood pressure.
    Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and central-acting adrenergic agents who are susceptible to hypotension.
    Penbutolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Pentobarbital: (Major) Monitor patients for guanfacine efficacy and for excess sedation during pentobarbital coadministration. Guanfacine plasma concentrations can be reduced by pentobarbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
    Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
    Perphenazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Perphenazine; Amitriptyline: (Major) Tricyclic antidepressants (TCAs) can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Consider alternatives to TCAs in patients established on guanfacine therapy for hypertension when possible; it is not clear the effect the combination may have when used in patients treated with guanfacine for attention-deficit, but other options to TCAs should be considered. Increased dosages of guanfacine may be required to control blood pressure in patients who are receiving TCAs concurrently. In addition, concurrent TCAs may enhance the potential for serious rebound hypertension following guanfacine discontinuation, regardless of the indication for treatment. If guanfacine therapy is withdrawn, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension. (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Phenobarbital: (Major) Monitor patients for guanfacine efficacy and for excess sedation during phenobarbital coadministration. Guanfacine plasma concentrations can be reduced by phenobarbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
    Phenothiazines: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Phenytoin: (Major) Monitor patients for guanfacine efficacy during phenytoin coadministration. Guanfacine plasma concentrations can be reduced by phenytoin, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Phenytoin is a strong CYP3A4 inducer. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment.
    Pindolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Piroxicam: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Posaconazole: (Major) Posaconazole may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon posaconazole discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and posaconazole is a strong CYP3A4 inhibitor.
    Prazosin: (Moderate) Prazosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used.
    Primidone: (Major) Monitor patients for guanfacine efficacy and for excess sedation during primidone coadministration. Guanfacine plasma concentrations can be reduced by primidone, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
    Procainamide: (Moderate) Procainamide can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents. Intravenous administration of procainamide is more likely to cause hypotensive effects.
    Procaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
    Prochlorperazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Propofol: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Propranolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Protriptyline: (Major) Tricyclic antidepressants (TCAs) can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Consider alternatives to TCAs in patients established on guanfacine therapy for hypertension when possible; it is not clear the effect the combination may have when used in patients treated with guanfacine for attention-deficit, but other options to TCAs should be considered. Increased dosages of guanfacine may be required to control blood pressure in patients who are receiving TCAs concurrently. In addition, concurrent TCAs may enhance the potential for serious rebound hypertension following guanfacine discontinuation, regardless of the indication for treatment. If guanfacine therapy is withdrawn, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension.
    Quazepam: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Quinidine: (Moderate) Quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
    Quinine: (Major) Quinine may significantly alter guanfacine plasma concentrations. Guanfacine is primarily metabolized by CYP3A4. Quinine is a moderate inhibitor of CYP3A4; in vitro data suggests it may also moderately induce CYP3A4. The net effect of this potential interaction is unclear, but guanfacine dosage adjustments, most likely a dose decrease, may be required. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if used with a moderate to strong CYP3A4 inhibitor, the guanfacine dosage should be decreased to half of the recommended dose and the patient should be closely monitored for alpha-adrenergic effects (e.g., hypotension, drowsiness, bradycardia). However, if used with a moderate to strong CYP3A4 inducer, labeling recommends to consider doubling the recommended dose of guanfacine ER; if the inducer is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If the inducer or inhibitor is discontinued, guanfacine ER should return to its recommended dose (with downward titration occurring over 1 to 2 weeks). Specific recommendations for immediate-release (IR) guanfacine are not available.
    Rasagiline: (Moderate) Orthostatic hypotension has been reported during administration of rasagiline; caution is advised during concurrent use with antihypertensive agents. Patients receiving rasagiline in combination with an antihypertensive should be instructed to rise slowly from a sitting position, and to report syncope, and changes in heart rate or blood pressure to their health care provider. Rasagiline is a selective MAO-B inhibitor at manufacturer recommended doses; therefore, serious hypertensive reactions with agents affecting catecholamine release (e.g., guanabenz, reserpine, guanethidine) are unlikely.
    Ribociclib: (Major) If coadministration of ribociclib with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If ribociclib is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Ribociclib may significantly increase guanfacine plasma concentrations.
    Ribociclib; Letrozole: (Major) If coadministration of ribociclib with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If ribociclib is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Ribociclib may significantly increase guanfacine plasma concentrations.
    Rifabutin: (Major) Rifabutin may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if rifabutin is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If rifabutin is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and rifabutin is a moderate CYP3A4 inducer.
    Rifampin: (Major) Rifampin may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if rifampin is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. Upon rifampin discontinuation, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and rifampin is a strong CYP3A4 inducer.
    Rifapentine: (Major) Rifapentine may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if rifapentine is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If rifapentine is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and rifapentine is a moderate CYP3A4 inducer.
    Risperidone: (Moderate) Risperidone may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving antihypertensive agents concomitantly.
    Ritonavir: (Major) Ritonavir may significantly alter guanfacine plasma concentrations. Guanfacine is primarily metabolized by CYP3A4. Ritonavir is a potent CYP3A4 inhibitor; moderate CYP3A4 induction has been reported with concomitant use of voriconazole. The net effect of this potential interaction is unclear, but guanfacine dosage adjustments, most likely a dose decrease, may be required. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if used with a moderate to strong CYP3A4 inhibitor, the guanfacine dosage should be decreased to half of the recommended dose and the patient should be closely monitored for alpha-adrenergic effects (e.g., hypotension, drowsiness, bradycardia). However, if used with a moderate to strong CYP3A4 inducer, labeling recommends to consider doubling the recommended dose of guanfacine ER; if the inducer is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If the inducer or inhibitor is discontinued, guanfacine ER should return to its recommended dose (with downward titration occurring over 1 to 2 weeks). Specific recommendations for immediate-release (IR) guanfacine are not available.
    Rofecoxib: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Saquinavir: (Major) Saquinavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If saquinavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and saquinavir is a strong CYP3A4 inhibitor.
    Secobarbital: (Major) Monitor patients for guanfacine efficacy and for excess sedation during secobarbital coadministration. Guanfacine plasma concentrations can be reduced by secobarbital, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Barbiturates (e.g., phenobarbital, primidone) are strong CYP3A4 inducers. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment. Additionally, guanfacine has been associated with sedative effects and can potentiate the actions of CNS depressants, including barbiturates.
    Sevoflurane: (Moderate) General anesthetics can potentiate the hypotensive effects of antihypertensive agents. Reduced dosages of antihypertensives may be required during heavy sedation.
    Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents.
    Sotalol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    St. John's Wort, Hypericum perforatum: (Major) St. John's Wort, Hypericum perforatum may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if St John's Wort is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If St. John's Wort is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and St. John's Wort is a strong CYP3A4 inducer.
    Sulindac: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Telaprevir: (Major) Telaprevir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If telaprevir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and telaprevir is a strong CYP3A4 inhibitor.
    Telithromycin: (Major) Telithromycin may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If telithromycin is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and telithromycin is a strong CYP3A4 inhibitor.
    Temazepam: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Tetrabenazine: (Moderate) Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of tetrabenazine may be necessary in patients receiving antihypertensive agents concomitantly.
    Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents.
    Thiethylperazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Thioridazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible. In addition, thiothixene can antagonize the pharmacologic actions of guanethidine. Both guanethidine and guanadrel should be avoided in patients receiving thiothixene.
    Timolol: (Moderate) Guanfacine can have additive effects when administered with other antihypertensive agents, including beta-blockers. These effects can be used to therapeutic advantage, but dosage adjustments may be necessary.
    Tipranavir: (Major) Tipranavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If tipranavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and tipranavir is a strong CYP3A4 inhibitor.
    Tizanidine: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.
    Tolmetin: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Trandolapril; Verapamil: (Major) Verapamil may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon verapamil discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and verapamil is a moderate CYP3A4 inhibitor.
    Trazodone: (Major) Cyclic antidepressants can interfere with the therapeutic antihypertensive effect of clonidine. Since guanabenz acts similarly to clonidine, it, too, may be affected by cyclic antidepressants. Limited data suggest that a clinically significant interaction occurs between trazodone and clonidine. Until more data are available, a similar interaction should be expected between trazodone and guanabenz or guanfacine. In general, due to additive hypotensive effects, patients receiving other antihypertensive agents concurrently with trazodone may experience hypotension, which could cause dizziness or faintness. Decreased dosage of the antihypertensive agent may be required in some patients.
    Triazolam: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
    Tricyclic antidepressants: (Major) Tricyclic antidepressants (TCAs) can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Consider alternatives to TCAs in patients established on guanfacine therapy for hypertension when possible; it is not clear the effect the combination may have when used in patients treated with guanfacine for attention-deficit, but other options to TCAs should be considered. Increased dosages of guanfacine may be required to control blood pressure in patients who are receiving TCAs concurrently. In addition, concurrent TCAs may enhance the potential for serious rebound hypertension following guanfacine discontinuation, regardless of the indication for treatment. If guanfacine therapy is withdrawn, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension.
    Trifluoperazine: (Moderate) Phenothiazines may produce alpha-adrenergic blockade and appear to have additive hypotensive or CNS effects when administered concurrently with central-acting adrenergic agents.
    Trimipramine: (Major) Tricyclic antidepressants (TCAs) can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Consider alternatives to TCAs in patients established on guanfacine therapy for hypertension when possible; it is not clear the effect the combination may have when used in patients treated with guanfacine for attention-deficit, but other options to TCAs should be considered. Increased dosages of guanfacine may be required to control blood pressure in patients who are receiving TCAs concurrently. In addition, concurrent TCAs may enhance the potential for serious rebound hypertension following guanfacine discontinuation, regardless of the indication for treatment. If guanfacine therapy is withdrawn, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension.
    Valdecoxib: (Moderate) NSAIDs may decrease the effect of antihypertensive agents through various mechanisms, including renal and peripheral vasoactive pathways.
    Verapamil: (Major) Verapamil may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon verapamil discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and verapamil is a moderate CYP3A4 inhibitor.
    Voriconazole: (Major) If coadministration of voriconazole with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If voriconazole is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Voriconazole may significantly increase guanfacine plasma concentrations.
    Yohimbine: (Major) Yohimbine is a selective central alpha 2-adrenoceptor antagonist. This pharmacologic action is the direct opposite of guanfacine. Therefore, yohimbine should not be administered to patients stabilized on these agents. Yohimbine can increase blood pressure and therefore can antagonize the therapeutic action of antihypertensive agents in general. Use with particular caution in hypertensive patients with high or uncontrolled BP.
    Ziprasidone: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies of the use of guanfacine during pregnancy. Guanfacine should only be used during pregnancy when it is considered essential to achieve therapeutic goals in the mother. Further, guanfacine is not recommended in the treatment of acute hypertension associated with toxemia of pregnancy. If an antihypertensive drug is needed during pregnancy, other agents are preferred, such as methyldopa, for which there are data regarding safety and efficacy in pregnancy. For ADHD treatment, the risks and benefits of continuing or discontinuing guanfacine during pregnancy requires careful consideration. Animal studies have not indicated a risk for developmental toxicity; 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 (MRHD). Higher doses (13.5 times the MRHD in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity. Animal studies are not always predictive of human response. There is no information available on the effects of guanfacine on the course of labor and obstetric delivery.

    It is not known whether guanfacine is excreted in human milk; however, it is excreted into rat milk. Because many drugs are excreted in human milk, caution should be exercised when guanfacine is administered when a woman is breast-feeding an infant. The antihypertensives methyldopa, nifedipine, and the beta-blockers labetalol and propranolol are considered usually compatible with breast-feeding and may represent alternatives to consider for the treatment of hypertension during lactation. While excretion of captopril or enalapril into breast milk is also low, other agents are preferred for hypertensive lactating women taking higher doses of these drugs. Diuretics are generally not recommended since they can reduce the quality of milk production. For ADHD treatment, the risks and benefits of continuing guanfacine or discontinuing guanfacine to allow breast-feeding requires careful consideration. If used, observe breast-fed infants for sedation and somnolence.

    MECHANISM OF ACTION

    Guanfacine stimulates central alpha-2-adrenergic receptors, thereby inhibiting sympathetic nervous system outflow, reducing peripheral vascular resistance, and lowering blood pressure. Guanfacine is a selective agonist, exhibiting a greater affinity for alpha-2-adrenergic receptors than for alpha-1-adrenergic receptors. During long-term therapy with guanfacine, total peripheral resistance is decreased, heart rate is slightly reduced (about 5 beats/minute), but cardiac output is generally unchanged. Guanfacine initially stimulates growth hormone secretion; however, long-term use has no effect on growth hormone plasma concentrations. Circulating levels of plasma catecholamines are reduced during guanfacine therapy, and the rebound hypertension that can occur following withdrawal is presumably due to sympathetic overactivity (increased catecholamine levels). Guanfacine reduces left ventricular hypertrophy and has neutral effects on glucose tolerance; but sexual dysfunction can be a significant problem.
     
    It has been theorized that attention-deficit hyperactivity disorder (ADHD) is the result of dysfunction in fronto-striatal pathways, possibly related to dysregulation of neurotransmitters such as catecholamines. Frontal networks control attention and motor intentional behavior. Animal studies have demonstrated that guanfacine improves prefrontal cortical function through post-synaptic alpha-2-receptor agonist effects in the prefrontal cortex. Animal studies indicate that working memory is improved without significant hypotensive and sedative effects. Guanfacine is thought to produce less potent hypotensive effects than other alpha-2-receptors agonists such as clonidine due to its weaker affinity for imidazoline I-1-receptors in the brainstem. In addition, clonidine exhibits more potent inhibition of noradrenergic neurons in the locus ceruleus, which may explain the significant sedation observed with clonidine compared to guanfacine. Clinically, the use of guanfacine in ADHD has resulted in improvements in attention and hyperactive behavior, as well as a reduction in tic severity in those with a comorbid tic disorder.

    PHARMACOKINETICS

    Guanfacine is administered orally. Guanfacine is 70% bound to plasma proteins and is widely distributed to tissues (volume of distribution 6.3 L/kg). Guanfacine is eliminated by renal and metabolic routes. In vitro studies have shown that guanfacine is primarily metabolized by the CYP3A4 isoenzyme. Approximately 50% is excreted unchanged in the urine; the remainder is metabolized primarily as conjugates of metabolites produced by oxidative metabolism of the aromatic ring.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4
    Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected by moderate to strong CYP3A4 inhibitors and inducers. The manufacturer of the extended-release tablets (i.e., Intuniv) recommends a 50% reduction of the target dose during concurrent use of a moderate or strong CYP3A4 inhibitor and consideration of a titration up to double the target dose over 1 to 2 weeks, based on patient response, during concurrent use of a moderate or strong CYP3A4 inducer.

    Oral Route

    Immediate- and extended-release guanfacine formulations have different pharmacokinetic characteristics. The guanfacine immediate-release formulation is 80% bioavailable; the relative bioavailability of the extended-release formulation to the immediate-release tablets is 58%. Compared to the immediate-release tablets, the AUC and Cmax of the extended-release tablets are 43% and 60% lower, respectively. Peak plasma concentrations occur 1 to 4 (average 2.6) hours after a single oral dose of immediate-release tablets in adults and adolescents with hypertension and 5 hours after oral administration of extended-release tablets to children and adolescents with ADHD. Guanfacine exposure following use of extended-release tablets is higher in children 6 to 12 years of age than in adolescents and adults. The elimination half-life of the immediate-release tablet is age dependent and ranges from 10 to 30 hours (average 17 hours). In adults, the half-life of the extended-release tablet is approximately 18 +/- 4 hours. The pharmacokinetics of the extended-release tablet are affected by food; when administered with a high-fat breakfast, mean exposure increased (Cmax approximately 75% and AUC approximately 40%) compared to dosing in a fasted state.