Chemical formula: C₉H₉Cl₂N₃O Molecular mass: 246.093 g/mol PubChem compound: 3519
Guanfacine interacts in the following cases:
Guanfacine causes a decrease in heart rate. Given the effect of guanfacine on heart rate, the concomitant use of guanfacine with QT prolonging medicinal products is generally not recommended.
Caution should be used when guanfacine is administered concomitantly with CNS depressant medicinal products (e.g., alcohol, sedatives, hypnotics, benzodiazepines, barbiturates, and antipsychotics) due to the potential for additive pharmacodynamic effects such as sedation and somnolence.
Based on in vitro studies, guanfacine may be an inhibitor of OCT1 at maximal portal vein concentrations. Concomitant administration of guanfacine with OCT1 substrates with a similar Tmax (e.g., metformin) may result in increases in Cmax of these medicinal products.
Guanfacine is an in vitro inhibitor of MATE1 and the clinical relevance of MATE1 inhibition cannot be excluded. Concomitant administration of guanfacine with MATE1 substrates may result in increases in the plasma concentrations of these medicinal products.
When guanfacine is used concomitantly with CYP3A4/5 inhibitors or inducers, plasma concentrations of guanfacine may be elevated or lowered, potentially affecting the efficacy and safety of guanfacine. Guanfacine can increase plasma concentrations of concomitantly administered medicinal products that are metabolised via CYP3A4/5.
When patients are taking guanfacine concomitantly with a CYP3A4 inducer, an increase in the dose of guanfacine within the recommended dose range is proposed. There was a significant decrease in the rate and extent of guanfacine exposure when co-administered with rifampicin, a CYP3A4 inducer. The peak plasma concentrations (Cmax) and exposure (AUC) of guanfacine decreased by 54% and 70% respectively.
When guanfacine is used concomitantly with CYP3A4/5 inhibitors or inducers, plasma concentrations of guanfacine may be elevated or lowered, potentially affecting the efficacy and safety of guanfacine. Guanfacine can increase plasma concentrations of concomitantly administered medicinal products that are metabolised via CYP3A4/5.
Caution should be used when guanfacine is administered to patients taking ketoconazole and other moderate and strong CYP3A4/5 inhibitors, a decrease in the dose of guanfacine within the recommended dose range is proposed. Co-administration of guanfacine with moderate and strong CYP3A4/5 inhibitors elevates plasma guanfacine concentrations and increases the risk of adverse reactions such as hypotension, bradycardia, and sedation. There was a substantial increase in the rate and extent of guanfacine exposure when administered with ketoconazole; the guanfacine peak plasma concentrations (Cmax) and exposure (AUC) increased 2- and 3-fold, respectively.
Caution should be used when guanfacine is administered concomitantly with antihypertensive medicinal products, due to the potential for additive pharmacodynamic effects such as hypotension and syncope.
There are no or limited amount of data regarding effect on fertility from the use of guanfacine in humans. Animal studies indicate an effect on male fertility.
Co-administration of guanfacine and valproic acid can result in increased concentrations of valproic acid. The mechanism of this interaction is unknown, although both guanfacine and valproic acid are metabolised by glucuronidation, possibly resulting in competitive inhibition. When guanfacine is co-administered with valproic acid, patients should be monitored for potential additive central nervous system (CNS) effects and consideration should be given to the monitoring of serum valproic acid concentrations. Adjustments in the dose of valproic acid and guanfacine may be indicated when coadministered.
Guanfacine should not be administered with high fat meals due to increased exposure, as it has been shown that high fat meals have a significant effect on the absorption of guanfacine.
Prior to initiation of treatment, patient’s cardiovascular status including heart rate and blood pressure parameters, family history of sudden cardiac death/unexplained death, should be assessed to identify patients at increased risk of hypotension, bradycardia, and QT-prolongation/risk of arrhythmia. Monitoring of heart rate and blood pressure parameters should continue on a weekly basis during dose titration and stabilisation and at least every 3 months for the first year, taking into consideration clinical judgement. 6 monthly monitoring should follow thereafter, with more frequent monitoring following any dose adjustment.
Caution is advised when treating patients with guanfacine who have a history of hypotension, heart block, bradycardia, or cardiovascular disease, or who have a history of syncope or a condition that may predispose them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Caution is also advised when treating patients who are being treated concomitantly with antihypertensives or other medicinal products that can reduce blood pressure or heart rate or increase the risk of syncope. Patients should be advised to drink plenty of fluid.
In phase II-III randomised double-blind monotherapy studies respective increases in QTc interval prolongation that exceeded change from baseline greater than >60 ms Fridericia-correction and Bazett-correction were 0 (0.0%) and 2 (0.3%) among placebo and 1 (0.1%) and 1 (0.1%) among Intuniv patients. The clinical relevance of this finding is uncertain.
Guanfacine should be prescribed with caution in patients with a known history of QT prolongation, risk factors for torsade de pointes (e.g. heart block, bradycardia, hypokalaemia) or patients who are taking medicinal products known to prolong the QT interval. These patients should receive further cardiac evaluation based on clinical judgement.
Patients with emergent suicidal ideation or behaviour during treatment for ADHD should be evaluated immediately by their physician. Treatment of an underlying psychiatric condition may be necessary and consideration should be given to a possible change in the ADHD treatment programme.
In a drug interaction study, administration of guanfacine in combination with lisdexamfetamine dimesylate induced a 19% increase in guanfacine maximum plasma concentrations, whereas exposure (AUC) was increased by 7%. These small changes are not expected to be clinically meaningful. In this study, no effect on d-amphetamine exposure was observed following combination of guanfacine and lisdexamfetamine dimesylate.
There are no or limited amount of data from the use of guanfacine in pregnant women. Studies in animals have shown reproductive toxicity. Guanfacine is not recommended during pregnancy and in women of childbearing potential not using contraception.
It is unknown whether guanfacine and its metabolites are excreted in human milk.
Available pharmacodynamic and toxicological data in animals have shown excretion of guanfacine and its metabolites in milk. Therefore, a risk on the breast-fed infant cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue and/or abstain from guanfacine therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
There are no or limited amount of data regarding effect on fertility from the use of guanfacine in humans. Animal studies indicate an effect on male fertility.
Guanfacine can cause dizziness and somnolence. These effects occur predominantly at the start of treatment and may occur less frequently as treatment continues. Syncope has also been observed. It may have a moderate to severe influence on the ability to drive, use machines or cycling. Patients should be warned of these possible effects and be advised that if affected, they should avoid these activities.
The most frequently reported adverse reactions include somnolence (40.6%), headache (27.4%), fatigue (18.1%), abdominal pain upper (12.0%), and sedation (10.2%). The most serious adverse reactions commonly reported include hypotension (3.2%), weight increase (2.9%), bradycardia (1.5%) and syncope (0.7%). The adverse reactions somnolence and sedation occurred predominantly at the start of treatment and may typically last for 2-3 weeks and longer in some cases.
The following list presents all adverse reactions based on clinical trials and spontaneous reporting. All adverse reactions from post-marketing experience are italicised.
The following definitions apply to the frequency terminology used hereafter: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
Adverse reactions:
Uncommon: Hypersensitivity
Common: Decreased appetite
Common: Depression, Anxiety, Affect lability, Insomnia, Middle insomnia, Nightmare
Uncommon: Agitation, Hallucination
Very common: Somnolence, Headache
Common: Sedation, Dizziness, Lethargy
Uncommon: Convulsion, Syncope/loss of consciousness, Postural dizziness
Rare: Hypersomnia
Common: Bradycardia
Uncommon: Atrioventricular block first degree, Tachycardia, Sinus arrhythmia
Common: Hypotension, Orthostatic hypotension
Uncommon: Pallor
Rare: Hypertension
Very rare: Hypertensive encephalopathy
Uncommon: Asthma
Very common: Abdominal pain
Common: Vomiting, Diarrhoea, Nausea, Constipation, Abdominal/stomach discomfort, Dry mouth
Uncommon: Dyspepsia
Common: Rash
Uncommon: Pruritus
Common: Enuresis
Uncommon: Pollakiuria
Not known: Erectile dysfunction
Very common: Fatigue
Common: Irritability
Uncommon: Asthenia, Chest pain
Rare: Malaise
Common: Blood pressure decreased, Weight increased
Uncommon: Blood pressure increased, Heart rate decreased, Alanine aminotransferase increased
In the overall pool of guanfacine-treated patients, somnolence occurred in 40.6% and sedation in 10.2% of guanfacine-treated patients. Bradycardia occurred in 1.5%, hypotension in 3.2% and syncope occurred in 0.7% of all guanfacine-treated patients. The occurrence of somnolence/sedation and hypotension was most prominent in the first few weeks of treatment and diminished gradually thereafter.
Careful follow-up for weight suggests that children and adolescents who took guanfacine in the study (i.e., treatment for 7 days per week throughout the year) have demonstrated by an age- and sex-normalised mean change from baseline in BMI percentile, 4.3 over 1 year (average percentiles at baseline and 12 months were 68.3 and 73.1, respectively). Consequently, as part of routine monitoring height, weight and BMI should be monitored at the start of treatment and every 3 months during the first year, then 6 monthly taking into consideration clinical judgement with maintenance of a growth chart.
The effect of 2 dose levels of immediate-release guanfacine (4 mg and 8 mg) on QT interval was evaluated in a double-blind, randomised, placebo- and active-controlled, cross-over study in healthy adults. An apparent increase in mean QTc was observed for both doses. This finding has no known clinical relevance.
In phase II-III randomised double-blind monotherapy studies respective increases in QTc interval prolongation that exceeded change from baseline greater than 60 ms Fridericia-correction and Bazett-correction were 0 (0.0%) and 2 (0.3%) among placebo and 1 (0.1%) and 1 (0.1%) among guanfacine patients. The clinical relevance of this finding is uncertain.
Blood pressure and pulse may increase following discontinuation of guanfacine. In post-marketing experience, hypertensive encephalopathy has been very rarely reported upon abrupt discontinuation of guanfacine.
In a maintenance of efficacy study in children and adolescents, increases in mean systolic and diastolic blood pressure of approximately 3 mmHg and 1 mmHg, respectively, above original baseline were observed upon discontinuation of guanfacine. However, individuals may have larger increases than reflected by the mean changes. The increases in blood pressure were observed in some individuals at the end of the follow up period which ranged between 3 and 26 weeks post final dose.
Guanfacine has not been studied in adults with ADHD.
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