Intuniv 1 mg, 2 mg, 3 mg, 4 mg Prolonged-Release Tablets: Indications, Dosage, Precautions, Adverse Effects
Россия
  • Россия
  • Украина

Intuniv 1 mg, 2 mg, 3 mg, 4 mg Prolonged-­Release Tablets - Product Information

Manufacture: Shire, Inc.
Country: Great Britain
Condition: ADHD (Attention Deficit Hyperactivity Disorder)
Class: Antiadrenergic agents, centrally acting
Form: Tablets
Ingredients: substance guanfacine, hypromellose, methacrylic acid-ethyl acrylate copolymer, lactose monohydrate, povidone, crospovidone (Type A), microcrystalline cellulose, silica colloidal anhydrous, sodium laurilsulfate, polysorbate 80, fumaric acid, glyceryl dibehenate

Name of the Medicinal Product

Intuniv 1 mg prolonged-release tablets

Intuniv 2 mg prolonged-release tablets

Intuniv 3 mg prolonged-release tablets

Intuniv 4 mg prolonged-release tablets

Qualitative and Quantitative Composition

Intuniv 1 mg Tablet

Each tablet contains guanfacine hydrochloride equivalent to 1 mg of guanfacine.

Intuniv 2 mg Tablet

Each tablet contains guanfacine hydrochloride equivalent to 2 mg of guanfacine.

Intuniv 3 mg Tablet

Each tablet contains guanfacine hydrochloride equivalent to 3 mg of guanfacine.

Intuniv 4 mg Tablet

Each tablet contains guanfacine hydrochloride equivalent to 4 mg of guanfacine.

Excipient(s) With Known Effect

Each 1 mg tablet contains 22.41 mg of lactose (as monohydrate).

Each 2 mg tablet contains 44.82 mg of lactose (as monohydrate).

Each 3 mg tablet contains 37.81 mg of lactose (as monohydrate).

Each 4 mg tablet contains 50.42 mg of lactose (as monohydrate).

For the full list of excipients, see section List of Excipients.

Pharmaceutical Form

Prolonged-release tablet

Intuniv 1 mg Tablet

7.14mm round, white to off-white tablets debossed with '1MG' on one side and '503' on the other side.

Intuniv 2 mg Tablet

12.34mm x 6.10mm oblong shaped, white to off-white tablets debossed with '2MG' on one side and “503” on the other side.

Intuniv 3 mg Tablet

7.94mm round, green tablets debossed with '3MG' on one side and '503' on the other side.

Intuniv 4 mg Tablet

12.34mm x 6.10mm oblong shaped, green tablets debossed with '4MG' on one side and '503' on the other side.

Clinical Particulars

Therapeutic Indications

Intuniv is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents 6-17 years old for whom stimulants are not suitable, not tolerated or have been shown to be ineffective.

Intuniv must be used as a part of a comprehensive ADHD treatment programme, typically including psychological, educational and social measures.

Posology and Method of Administration

Treatment must be initiated under the supervision of an appropriate specialist in childhood and/or adolescent behavioural disorders.

Pre-treatment screening

Prior to prescribing, it is necessary to conduct a baseline evaluation to identify patients at increased risk of somnolence and sedation, hypotension and bradycardia, QT-prolongation arrhythmia and weight increase /risk of obesity. This evaluation should address a patient's cardiovascular status including blood pressure and heart rate, documenting comprehensive history of concomitant medications, past and present co-morbid medical and psychiatric disorders or symptoms, family history of sudden cardiac/unexplained death and accurate recording of pre-treatment height and weight on a growth chart (see section Special Warnings and Precautions for Use).

Posology

Careful dose titration and monitoring is necessary at the start of treatment with Intuniv since clinical improvement and risks for several clinically significant adverse reactions (syncope, hypotension, bradycardia, somnolence and sedation) are dose- and exposure-related. Patients should be advised that somnolence and sedation can occur, particularly early in treatment or with dose increases. If somnolence and sedation are judged to be clinically concerning or persistent, a dose decrease or discontinuation should be considered.

For all patients, the recommended starting dose is 1 mg of guanfacine, taken orally once a day.

The dose may be adjusted in increments of not more than 1mg per week. Dose should be individualised according to the patient's response and tolerability.

Depending on the patient's response and tolerability for Intuniv the recommended maintenance dose range is 0.05-0.12 mg/kg/day. The recommended dose titration for children and adolescents is provided below (see tables 1 and 2). Dose adjustments (increase or decrease) to a maximum tolerated dose within the recommended optimal weight-adjusted dose range based upon clinical judgement of response and tolerability may occur at any weekly interval after the initial dose.

Monitoring during titration

During dose titration, weekly monitoring for signs and symptoms of somnolence and sedation, hypotension and bradycardia should be performed.

Ongoing monitoring

During the first year of treatment, the patient should be assessed at least every 3 months for:

  • Signs and symptoms of:
    • somnolence and sedation
    • hypotension
    • bradycardia
  • weight increase /risk of obesity

It is recommended clinical judgement be exercised during this period. 6 monthly monitoring should follow thereafter, with more frequent monitoring following any dose adjustments (see section Special Warnings and Precautions for Use).

Table 1
Dose Titration Schedule for Children Aged 6-12 years
Weight Group Week 1 Week 2 Week 3 Week 4
25 kg and up
Max Dose= 4 mg
1 mg 2 mg 3 mg 4 mg
Table 2
Dose Titration Schedule for Adolescents (Aged 13-17 Years)
Weight Groupa Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7
3441.4 kg
Max Dose= 4 mg
1 mg 2 mg 3 mg 4 mg
41.549.4 kg
Max Dose= 5 mg
1 mg 2 mg 3 mg 4 mg 5 mg
49.558.4 kg
Max Dose= 6 mg
1 mg 2 mg 3 mg 4 mg 5 mg 6 mg
58.5 kg and above
Max Dose= 7 mg
1 mg 2 mg 3 mg 4 mg 5 mg 6 mg 7 mgb

a Adolescent subjects must weigh at least 34kg.
b Adolescents weighing 58.5 and above may be titrated to a 7mg/day dose after the subject has completed a minimum of 1 week of therapy on a 6mg/day dose and the physician has performed a thorough review of the subject's tolerability and efficacy.

The physician who elects to use guanfacine for extended periods (over 12 months) should re-evaluate the usefulness of guanfacine every 3 months for the first year and then at least yearly based on clinical judgement (see section Special Warnings and Precautions for Use), and consider trial periods off medication to assess the patient's functioning without pharmacotherapy, preferably during times of school holidays.

Downward titration and discontinuation

Patients/caregivers should be instructed not to discontinue guanfacine without consulting their physician.

Blood pressure and pulse may increase following discontinuation of guanfacine. Increases in mean systolic and diastolic blood pressure, of approximately 3 mmHg and 1 mmHg respectively, above original baseline were observed upon discontinuation of Intuniv.

Individuals may have larger increases than reflected by the mean changes. It is therefore recommended that blood pressure and pulse should be monitored in all patients during dose downward titration (decrements of no more than 1mg every 3 to 7 days) and following discontinuation of guanfacine.

Tapering Intuniv dosing during withdrawal is recommended to minimise these potential withdrawal effects.

Missed dose

In the event of a missed dose, Intuniv dosing can resume the next day. If two or more consecutive doses are missed, re-titration is recommended based on the patient's tolerability to guanfacine.

Switching from other formulations of guanfacine

Immediate-release guanfacine tablets should not be substituted on a mg/mg basis, because of differing pharmacokinetic profiles.

Special populations

Adults and elderly

The safety and efficacy of guanfacine in adult and the elderly with ADHD has not been established and therefore should not be used in this group.

Hepatic impairment

Guanfacine is cleared both by the liver and the kidneys, and at least 50% of the clearance of guanfacine is hepatic. Dose reduction may be required in patients with different degrees of hepatic impairment.

The impact of hepatic impairment on the pharmacokinetics of guanfacine in paediatric patients (children and adolescents 6-17 years old) was not assessed.

Renal impairment

Guanfacine is cleared both by the liver and the kidneys, with approximately 30% of an intact medicinal product excreted with urine. Dose reduction may be required in patients with severe renal impairment (GFR 29-15 ml/min) and an end stage renal disease (GFR<15 ml/min) or requiring dialysis.The impact of renal impairment on the pharmacokinetics of guanfacine in paediatric patients (children and adolescents 6-17 years old) was not assessed.

Children under 6 years

Intuniv should not be used in children under the age of 6 years because efficacy and safety in this patient population has not been studied.

Patients treated with CYP3A4 and CYP3A5 inhibitors /inducers

CYP3A4/5 inhibitors have been shown to have a significant effect on the pharmacokinetics of guanfacine when co- administered. Dose adjustment is recommended with concomitant use of moderate/strong CYP3A4/5 inhibitors (e.g. ketoconazole, grapefruit juice), or strong CYP3A4 inducers (e.g. carbamazepine) (see section Interaction With Other Medicinal Products and Other Forms of Interaction). In case of concomitant use of strong and moderate CYP3A inhibitors, a 50% reduction of the guanfacine dose is recommended. Due to variability in interaction effect, further dose titration may be needed (see above). If guanfacine is combined with strong enzyme inducers, a retitration to increase the dose up to a maximum daily dose 7mg (see section Posology and Method of Administration), may be considered if needed. If the inducing treatment is ended, retitration to reduce the guanfacine dose is recommended during the following weeks (see section Interaction With Other Medicinal Products and Other Forms of Interaction).

Method of administration

Oral use.

Intuniv is taken once daily either morning or evening. Intuniv should not be crushed, chewed or broken before swallowing because this increases the rate of guanfacine release.

Treatment is recommended only for children who are able to swallow the tablet whole without problems.

Intuniv can be administered with or without food but should not be administered with high fat meals, due to increased exposure (see section Pharmacokinetic Properties).

Intuniv should not be administered together with grapefruit juice (see section Interaction With Other Medicinal Products and Other Forms of Interaction).

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section List of Excipients.

Special Warnings and Precautions for Use

Hypotension, bradycardia and syncope

Intuniv can cause syncope, hypotension and bradycardia. Syncope may involve risks of falls or accidents, which could result in serious harm (see sections Undesirable Effects and Effects on Ability to Drive and Use Machines)

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 Intuniv 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 with Intuniv 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.

QTc interval

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, hypokalemia) or patients who are taking medicinal products known to prolong the QT interval. These patients should receive further cardiac evaluation based on clinical judgement (see section Undesirable effects).

Sedation and somnolence

Intuniv may cause somnolence and sedation predominantly at the start of treatment and could typically last for 2-3 weeks and longer in some cases. It is therefore recommended that patients will be closely monitored weekly during dose titration and stabilisation (see section Posology and Method of Administration), and every 3 months during the first year, taking into consideration clinical judgement. Before Intuniv is used with any other centrally active depressants (such as alcohol, sedatives, phenothiazines, barbiturates, or benzodiazepines) the potential for additive sedative effects should be considered. Patients should not drink alcohol whilst taking Intuniv. Patients are advised against operating heavy equipment, driving or cycling until they know how they respond to treatment with Intuniv (see section Effects on Ability to Drive and Use Machines).

Suicidal ideation

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.

Effects on height, weight and Body Mass index (BMI)

Children and adolescents treated with Intuniv may show an increase in their BMI. Therefore, monitoring of height, weight and BMI should be done prior to initiation of therapy and then 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.

Excipients

Intuniv contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Interaction With Other Medicinal Products and Other Forms of Interaction

When Intuniv is used concomitantly with CYP3A4/5 inhibitors and inducers, plasma concentrations of guanfacine may be elevated or lowered, potentially affecting the efficacy and safety of Intuniv. Intuniv can increase plasma concentrations of concomitantly administered medicinal products that are metabolised via CYP3A4/5 (see sections Posology and Method of Administration, Special Warnings and Precautions for Use and Pharmacokinetic Properties).

The pharmacodynamic effect of Intuniv can have an additive effect when taken with other products known to cause sedation, hypotension or QT prolongation (see section Special Warnings and Precautions for Use).

All drug-drug interaction studies have been performed in adults, however, the outcome is expected to be similar in the indicated paediatric age range.

QT Prolonging medicinal products

Intuniv causes a decrease in heart rate. Given the effect of Intuniv on heart rate, the concomitant use of Intuniv with QT prolonging medicinal products is generally not recommended (see section Special Warnings and Precautions for Use).

CYP3A4 and CYP3A5 inhibitors

Caution should be used when Intuniv is administered to patients taking ketoconazole and other moderate and strong CYP3A4/5 inhibitors, a decrease in the dose of Intuniv within the recommended dose range is proposed (see section Posology and Method of Administration). Co-administration of Intuniv 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. Other CYP3A4/5 inhibitors may have a comparable effect, see table 3 for a list of examples of moderate and strong CYP3A4/5 inhibitors, this list is not definitive.

CYP3A4 inducers

When patients are taking Intuniv concomitantly with a CYP3A4 inducer, an increase in the dose of Intuniv within the recommended dose range is proposed (see section Posology and Method of Administration). There was a significant decrease in the rate and extent of guanfacine exposure when co-administered with rifampin, a CYP3A4 inducer. The peak plasma concentrations (Cmax) and exposure (AUC) of guanfacine decreased by 54% and 70% respectively. Other CYP3A4 inducers may have a comparable effect, see table 3 for a list of examples of CYP3A4/5 inducers, this list is not definitive.

Table 3
Moderate CYP3A4/5 inhibitors Strong CYP3A4/5 inhibitors CYP3A4 inducers
Aprepitant Boceprevir Bosentan
Atazanavir Chloramphenicol Carbamazepine
Ciprofloxacin Clarithromycin Efavirenz
Crizotinib Indinavir Etravirine
Diltiazem Itraconazole Modafinil
Erythromycin Ketoconazole Nevirapine
Fluconazole Posaconazole Oxcarbazepine
Fosamprenavir Ritonavir Phenobarbital
Imatinib Saquinavir Phenytoin
Verapamil Suboxone Primidone
Grapefruit juice Telaprevir Rifabutin
Telithromycin Rifampicin
St. John's Wort
See section Posology and Method of Administration for further dosing recommendations

Valproic acid

Co-administration of Intuniv 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 Intuniv 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 Intuniv may be indicated when co- administered.

Antihypertensive medicinal products

Caution should be used when Intuniv is administered concomitantly with antihypertensive medicinal products, due to the potential for additive pharmacodynamic effects such as hypotension and syncope.

CNS depressant medicinal products

Caution should be used when Intuniv 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.

Oral Methylphenidate

In a drug interaction study, neither Intuniv nor Osmotic Release Oral System (OROS)-methylphenidate HCl extended- release were found to affect the pharmacokinetics of the other medicinal products when taken in combination.

Lisdexamfetamine dimesylate

In a drug interaction study, administration of Intuniv 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 Intuniv and lisdexamfetamine dimesylate.

Food interactions

Intuniv 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.

Fertility, Pregnancy and Lactation

Pregnancy

There are no or limited amount of data from the use of guanfacine in pregnant women.

Studies in animals have shown reproductive toxicity (see section Preclinical Safety Data).

Intuniv is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

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 (see section Preclinical Safety Data). 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 Intuniv therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

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 (see section Preclinical Safety Data).

Effects on Ability to Drive and Use Machines

Intuniv 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. (see section Special Warnings and Precautions for Use).

Undesirable Effects

Summary of the safety profile

In the data set from controlled, doubled blinded and open-label clinical studies with Intuniv the most frequently reported adverse reactions (very common) include somnolence (40.6%), headache (27.4%), fatigue (18.1%), abdominal pain upper (12.0%), and sedation (10.2%). Serious adverse reactions commonly reported include hypotension (3.2%), weight increase (2.9%), bradycardia (1.5%) and syncope (uncommon) (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.

Tabulated list of adverse reactions

The following table presents all adverse reactions based on clinical trials and spontaneous reporting. All adverse reactions from post-marketing experience are italicized.

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)

Not known (cannot be estimated from the available data).

Table 4. Adverse Drug Reactions Reported with Intuniv
System/Organ Class Incidence Category
Adverse Drug Reaction
Immune system disorders
Hypersensitivity Uncommon
Metabolism and nutrition disorders
Decreased appetite Common
Psychiatric disorders
Depression Common
Anxiety Common
Affect lability Common
Insomnia Common
Middle insomnia Common
Nightmare Common
Agitation Uncommon
Hallucination Uncommon
Nervous system disorders
Somnolence Very common
Headache Very common
Sedation Common
Dizziness Common
Lethargy Common
Convulsion Uncommon
Syncope/loss of consciousness Uncommon
Dizziness postural Uncommon
Hypersomnia Rare
Cardiac disorders
Bradycardia Common
Atrioventricular block first degree Uncommon
Tachycardia Uncommon
Sinus arrhythmia Uncommon
Vascular disorders
Hypotension Common
Orthostatic hypotension Common
Pallor Uncommon
Hypertension Rare
Respiratory, thoracic, and mediastinal disorders
Asthma Uncommon
Gastrointestinal disorders
Abdominal pain Very common
Vomiting Common
Diarrhoea Common
Nausea Common
Constipation Common
Abdominal/stomach discomfort Common
Dry mouth Common
Dyspepsia Uncommon
Skin and subcutaneous tissue disorders
Rash Common
Pruritus Uncommon
Renal and urinary disorders
Enuresis Common
Pollakiuria Uncommon
General disorders
Fatigue Very common
Irritability Common
Asthenia Uncommon
Chest pain Uncommon
Malaise Rare
Investigations
Blood pressure decreased Common
Weight increased Common
Blood pressure increased Uncommon
Heart rate decreased Uncommon
Alanine aminotransferase increased Uncommon

Description of selected adverse reactions

Somnolence /sedation, hypotension, bradycardia and syncope

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.

Effects on height, weight and body Mass index (BMI)

Careful follow-up for weight suggests that children and adolescents who took Intuniv 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 in to consideration clinical judgement with maintenance of a growth chart.

Thorough QT /QTc Study

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 Intuniv patients. The clinical relevance of this finding is uncertain.

Adult patients

Intuniv has not been studied in adults with ADHD.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system:

United Kingdom:

Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard 

Ireland:

HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie 
e-mail: medsafety@hpra.ie 

Overdose

Signs and symptoms of overdose may include hypotension, initial hypertension, bradycardia, lethargy, and respiratory depression. Haemodynamic instability has also been associated with a guanfacine overdose 3 times the recommended daily dose. Management of Intuniv overdose should include monitoring for and treatment of these signs and symptoms.

Paediatric patients (children and adolescents 6-17 years old inclusive) who develop lethargy should be observed for the development of more serious toxicity including coma, bradycardia, and hypotension for up to 24 hours, due to the possibility of delayed onset of these symptoms.

Treatment of overdose may include gastric lavage if it is performed soon after ingestion. Activated charcoal may be useful in limiting the absorption. Guanfacine is not dialyzable in clinically significant amounts (2.4%).

Pharmacological Properties

Pharmacodynamic Properties

Pharmacotherapeutic group: Antihypertensives, antiadrenergic agents, centrally acting ATC code: C02AC02.

Mechanism of action

Guanfacine is a selective alpha2A-adrenergic receptor agonist in that it has 15-20 times higher affinity for this receptor subtype than for the alpha2B or alpha2C subtypes. Guanfacine is a non-stimulant. The mode of action of guanfacine in ADHD is not fully established. Preclinical research suggests guanfacine modulates signalling in the prefrontal cortex and basal ganglia through direct modification of synaptic noradrenalin transmission at the alpha 2- adrenergic receptors.

Pharmacodynamic effects

Guanfacine is a known antihypertensive agent. By stimulating alpha 2A-adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor centre to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and blood pressure, and a reduction in heart rate.

Clinical efficacy and safety

The effects of guanfacine in the treatment of ADHD has been examined in 5 controlled studies in children and adolescents (6 to 17 years), 3 short term controlled trials in children and adolescents aged 6 to 17 years, 1 short-term controlled study in adolescents aged 13 to 17 years, and 1 randomised withdrawal trial in children and adolescents aged 6-17, all of whom met the DSM-IV-TR criteria for ADHD. The majority of patients achieved an optimised dose between 0.05-0.12mg/kg/day.

Three hundred and thirty-seven patients aged 6-17 years were evaluated in the pivotal Phase 3 Study SPD503-316, to assess safety and efficacy of once-daily dosing (children:1-4mg/day, adolescents:1-7 mg/day). In this 12-week (6-12 years) or 15-week (13-17 years), randomised, double-blind, parallel-group, placebo- and active-reference (atomoxetine), dose-titration study, guanfacine showed significantly greater efficacy than placebo on symptoms of ADHD based upon investigator ratings on the ADHD Rating Scale (ADHD-RS). The ADHD Rating Scale is a measure of the core symptoms of ADHD. The result with respect to the primary endpoint study are presented in Table 5.

Table 5. Summary of primary efficacy for study SPD503-316: ADHD-RS-IV
Treatment
groups
N Baseline ADHD-
RSIV (SD)
Change from
baseline (SD)
Difference from
placebo (95%CI)
Effect size
Responders Difference from
placebo (95%CI)
Guanfacine 114 43.1 (5.5) -23.9(12.4) -8.9(-11.9,-5.8)
0.8
64.3% 21.9% (9.2 ; 34.7)
Atomoxetine 112 43.7 (5.9) -18.6(11.9) -3.8(-6.8,-0.7)
0.3
55.4% 13.0% (0.0 ; 26.0)
Placebo 111 43.2 (5.6) -15.0(13.1) NA 42.3% NA

Results of the secondary endpoints were consistent with that of the primary endpoint. The percentages of subjects who met response criteria (≥30% reduction from baseline in ADHD-RS-IV Total Score and a CGI-I value of 1 or 2) was 64.3% for guanfacine, 55.4% for atomoxetine and 42.3% for placebo. Guanfacine also showed significant improvement in learning, school and family functioning as measured with the (WFIRS-P score).

In addition a 15-week, double-blind, randomised, placebo-controlled, dose-optimisation study (SPD503-312) conducted in adolescents aged 13-17 years (n=314) to confirm the efficacy, safety, and tolerability of guanfacine (1-7 mg/day) in the treatment of ADHD. Guanfacine showed a significantly greater improvement in the ADHD-RS-IV total score compared with subjects receiving placebo. Guanfacine-treated patients were in statistically significantly better conditions on the functional outcome as measured by the clinical global impression of severity (CGI-S) at endpoint compared to placebo-treated patients. Superiority (statistical significance) over placebo on the family and school, and learning domains of the WFIRS-P score was not established in this study.

Study (SPD503-315) was a 41 week long term maintenance of efficacy study which included an open-label phase (up to 13 weeks) followed by double-blind, placebo-controlled, randomised-withdrawal phase (up to 26 weeks), conducted in paediatric patients (children and adolescents aged 6-17 years old inclusive) (n=526 in the open-label phase and n=315 in the double-blind randomised-withdrawal phase) to assess the efficacy, safety, and tolerability of once-daily dosing with guanfacine (children: 1-4mg/day, adolescents:1-7 mg/day) in the treatment of ADHD. Guanfacine was superior to placebo in the long-term maintenance of treatment in children and adolescents with ADHD as measured by cumulative treatment failures (49.3% for Intuniv, and 64.9% for placebo, p=0.006). Treatment failure was defined as a ≥50% increase in ADHD-RS-IV total score and a ≥2 point increase in CGI-S score compared to the respective scores at the double-blind baseline visit. At the end of their double-blind treatment, a significantly larger proportion of subjects in the guanfacine compared with placebo group were normal or borderline mentally ill as measured by the clinical global impression of severity (CGI-S) that includes assessment of functioning. Superiority (statistical significance) over placebo on the family and school, and learning domains of the WFIRS-P score was not consistently established in this study.

Similar results for the efficacy of guanfacine in the treatment of ADHD were established in 2 randomised, double-blind, placebo-controlled, fixed-dose (range of 1-4 mg /day) monotherapy trials in paediatric patients (children and adolescents 6-17 years old inclusive). Studies SPD503-301 and SPD503-304 were 8 and 9 weeks in duration, respectively, both conducted in the United States. Guanfacine showed significantly greater improvement compared to placebo on the change from baseline to final on treatment assessment in the ADHD Rating Scale (ADHD-RS-IV) score in both studies (placebo-adjusted reduction in LS mean range from 5.4 to 10.0, p<0.02).

Study SPD503-314 was conducted in children aged 6-12 years to assess the efficacy of once daily dosing with guanfacine (1-4 mg) administered either in the morning or the evening. This was a double-blind, randomised, placebo- controlled, dose-optimisation study, 9-weeks in duration conducted in the United States and Canada. Symptoms of ADHD were evaluated as the change from baseline to week 8 (final on treatment assessment) in the ADHD Rating Scale (ADHD-RS-IV) total scores. Guanfacine showed significantly greater improvement compared to placebo regardless of time (AM or PM) of administration (placebo-adjusted LS mean difference of -9.4 and -9.8 for AM and PM dosing, respectively, p<0.001).

Co-administration with Psychostimulants

The effect of co-administration with psychostimulants was examined in an add-on study in partial responders to psycho- stimulants. The study was double-blind, randomised, placebo-controlled, multi-center, dose-optimisation 9 weeks study. It was designed to evaluate the efficacy and safety of guanfacine (1, 2, 3, and 4mg/day) when co-administered with long-acting psycho-stimulants (amphetamine, lisdexamphetamine, methylphenidate, dexmethylphenidate) in children and adolescents aged 6-17 years with a diagnosis of ADHD and a suboptimal, partial response to psycho-stimulants. Suboptimal response was defined as an ADHD-RS-IV total score of ≥24 and a CGI-S score ≥3 at screening and baseline. The primary efficacy assessment was the ADHD-RS-IV total score.

The results showed that patients treated with add-on guanfacine improved more on the ADHD-RS-IV compared to those treated with add-on placebo (20.7 (12.6) points vs. 15.9 (11.8); difference: 4.9 95% CI 2.6 , 7.2). No age differences were observed with respect to response to the ADHD-RS-IV.

ADHD with Oppositional Symptoms Study

Study SPD503-307 was a 9-week, double-blind, randomised, placebo-controlled, dose-optimisation study with guanfacine (1-4 mg/day) conducted in children aged 6-12 years with ADHD and oppositional symptoms (n=217). Oppositional symptoms were evaluated as the change from baseline to endpoint in the Oppositional Subscale of the Conners' Parent Rating Scale – revised Long Form (CPRS-R:L) score. Results show statistically significantly (p≤0.05) greater mean reductions at endpoint from Baseline (indicating improvement) in oppositional subscale of CPRS-R:L scores in the guanfacine group compared to placebo (10.9 points vs. 6.8 for guanfacine vs. placebo, respectively) and the effect size was 0.6 (p<0.001). These reductions represent a percentage reduction of 56% vs. 33% for guanfacine vs. placebo, respectively.

Pharmacokinetic Properties

Absorption

Guanfacine is readily absorbed, with peak plasma concentrations reached approximately 5 hours after oral administration in paediatric patients (children and adolescents 6-17 years old inclusive). In adults, the mean exposure of guanfacine increased (Cmax ~ 75% and AUC ~ 40%) when Intuniv was taken together with a high fat meal, compared to intake in the fasted state (see section Posology and Method of Administration).

Distribution

Guanfacine is moderately bound to plasma proteins (approximately 70%), independent of drug concentration.

Biotransformation

Guanfacine is metabolised via CYP3A4/5- mediated oxidation, with subsequent phase II reactions of sulfation and glucuronidation. The major circulating metabolite is 3-OH-guanfacine sulphate. Guanfacine is a substrate of CYP3A4 and CYP3A5, and exposure is affected by CYP3A4 and CYP3A5 inducers and inhibitors. In human hepatic microsomes, guanfacine did not inhibit the activities of the other major cytochrome P450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 or CYP3A5).

Elimination

Guanfacine is cleared by the kidneys via filtration and active secretion and the liver. Active renal secretion is mediated via OCT2 transporter. Renal excretion is the major elimination pathway (80%) with parent drug accounting for 30% of the urinary radioactivity. The major urinary metabolites were 3-hydroxy guanfacine glucuronide, guanfacine dihydrodiol, 3-hydroxy guanfacine sulfate. The elimination half-life of guanfacine is approximately 18 hours.

The pharmacokinetics of guanfacine is similar in children (aged 6 to 12) and adolescent (aged 13 to 17) ADHD patients, and healthy adult volunteers.

Special populations

There have been no studies performed in children with ADHD under the age of 6 years with Intuniv. Systemic exposure to guanfacine is similar for men and women given the same mg/kg dose.

Formal pharmacokinetic studies for race have not been conducted. There is no evidence of any impact of ethnicity on the pharmacokinetics of Intuniv.

Preclinical Safety Data

No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice at doses up to 10 mg/kg/day. A significant increase in incidence of adenomas of the pancreatic islet was observed in male rats treated with 5 mg/kg/day guanfacine for 102 weeks but not in female rats. The clinical relevance is unknown.

Guanfacine was not genotoxic in a variety of test models, including the Ames test and an in vitro chromosomal aberration test.

General toxicity observed in animals (rat, dog) upon treatment with guanfacine included prolongation of uncorrected QT interval (heart), atrophic spleen and decreased white blood cells, affected liver – increased bilirubin and ALT levels included, irritated & inflamed intestines, increased creatinine and blood urea nitrogen levels (kidney), corneal clouding (eye) in rat and mouse only, alveolar macrophage infiltration & pneumonitis and reduced spermatogenesis.

No adverse effects were observed in a fertility study in female rats at doses up to 22 times the maximum recommended human dose on a mg/m2 basis.

Male fertility was affected at 8 mg/kg/day, the lowest dose tested, equivalent of 10.8 times the maximum recommended human dose of 0.12 mg/kg on a mg/m2 basis. Due to lack of proper toxicokinetic data, comparison to human clinical exposure was not possible.

Guanfacine showed embryo fetal developmental toxicity in mice and rats (NOAEL 0.5 mg/kg/day) and in rabbits (NOAEL 3.0 mg/kg/day) in the presence of maternal toxicity. Due to a lack of proper toxicokinetic data, comparison to human clinical exposure was not possible.

Pharmaceutical Particulars

List of Excipients

Hypromellose 2208
Methacrylic acid-Ethyl acrylate copolymer
Lactose monohydrate
Povidone
Crospovidone Type A
Microcrystalline cellulose
Silica, colloidal anhydrous
Sodium laurilsulfate
Polysorbate 80
Fumaric acid
Glycerol dibehenate

In addition 3mg and 4mg tablets include

Indigo carmine aluminum lake E 132

Iron oxide yellow E 172

Incompatibilities

Not applicable.

Shelf Life

4 years.

Special Precautions for Storage

This medicinal product does not require any special storage conditions.

Nature and Contents of Container

The blister strips comprise of 2 layers, a clear thermoformable rigid film which is laminated with PCTFE to a PVC backing to which a push-through aluminium foil is adhered. The blisters are contained in cardboard cartons.

Intuniv 1 mg pack sizes: 7 or 28 tablets.

Intuniv 2 mg pack sizes: 7, 28 or 84 tablets.

Intuniv 3 mg pack sizes: 28 or 84 tablets.

Intuniv 4 mg pack sizes: 28 or 84 tablets.

Not all pack sizes may be marketed.

Special Precautions for Disposal and Other Handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Marketing Authorisation Holder

Shire Pharmaceuticals Ireland Limited
5 Riverwalk,
Citywest Business Campus,
Dublin 24,
IRELAND

Marketing Authorisation Number(s)

Intuniv 1 mg tablet

EU/1/15/1040/001-002

Intuniv 2 mg tablet

EU/1/15/1040/003-005

Intuniv 3 mg tablet

EU/1/15/1040/006-007

Intuniv 4 mg tablet

EU/1/15/1040/008-009

Company Contact Details

Shire Pharmaceuticals Limited
http://www.shire.com 

Address
Hampshire International Business Park, Chineham,
Basingstoke, Hampshire , RG24 8EP

Medical Information Direct Line
0800 055 6614

Customer Care direct line
+44 (0)1256 894 107

Telephone
+44 (0)1256 894 000

Medical Information email
medinfoeuceemea@shire.com