Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Shire Pharmaceuticals Ireland Limited, Block 2 & 3 Miesian Plaza, 50–58 Baggot Street Lower, Dublin 2, IRELAND
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.
Treatment must be initiated under the supervision of an appropriate specialist in childhood and/or adolescent behavioural disorders.
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 4.4).
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 1 mg 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.
During dose titration, weekly monitoring for signs and symptoms of somnolence and sedation, hypotension and bradycardia should be performed.
During the first year of treatment, the patient should be assessed at least every 3 months for:
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 4.4).
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 |
|---|---|---|---|---|---|---|---|
| 34-41.4 kg Max Dose=4 mg | 1 mg | 2 mg | 3 mg | 4 mg | |||
| 41.5-49.4 kg Max Dose=5 mg | 1 mg | 2 mg | 3 mg | 4 mg | 5 mg | ||
| 49.5-58.4 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 34 kg.
b Adolescents weighing 58.5 kg and above may be titrated to a 7 mg/day dose after the subject has completed a minimum of 1 week of therapy on a 6 mg/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 4.4), and consider trial periods off medication to assess the patient’s functioning without pharmacotherapy, preferably during times of school holidays.
Patients/caregivers should be instructed not to discontinue guanfacine without consulting their physician.
When stopping Intuniv, the dose must be tapered with decrements of no more than 1 mg every 3 to 7 days, and blood pressure and pulse should be monitored in order to minimise potential withdrawal effects, in particular increases in blood pressure and heart rate (see section 4.4).
In a maintenance of efficacy study, upon switching from guanfacine to placebo, 7/158 (4.4%) subjects experienced increases in blood pressure to values above 5 mmHg and also above the 95 th percentile for age, sex and stature (see sections 4.8 and 5.1).
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.
Immediate-release guanfacine tablets should not be substituted on a mg/mg basis, because of differing pharmacokinetic profiles.
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.
Dose reduction may be required in patients with different degrees of hepatic impairment (see section 5.2). The impact of hepatic impairment on the pharmacokinetics of guanfacine in paediatric patients (children and adolescents 6-17 years old) was not assessed.
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 (see section 5.2).
The safety and efficacy of guanfacine in children aged less than 6 years have not yet been established. No data are available.
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 4.5).
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 7 mg (see section 4.2), 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 4.5).
Oral use.
Guanfacine is taken once daily either morning or evening. Tablets 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.
Guanfacine can be administered with or without food but should not be administered with high fat meals, due to increased exposure (see section 5.2).
Guanfacine should not be administered together with grapefruit juice (see section 4.5).
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 guanfacine 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 dialysable in clinically significant amounts (2.4%).
Shelf life: 4 years.
This medicinal product does not require any special storage conditions.
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 prolonged-release tablet: pack sizes: 7 or 28 tablets.
Intuniv 2 mg prolonged-release tablet: pack sizes: 7, 28 or 84 tablets.
Intuniv 3 mg prolonged-release tablet: pack sizes: 28 or 84 tablets.
Intuniv 4 mg prolonged-release tablet: pack sizes: 28 or 84 tablets.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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