Consumer medicine information

Intuniv

Guanfacine

BRAND INFORMATION

Brand name

Intuniv

Active ingredient

Guanfacine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Intuniv.

What is in this leaflet

Please read this leaflet before you/your child start taking INTUNIV.

This leaflet answers some common questions about INTUNIV. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you/your child taking INTUNIV against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What INTUNIV is used for

INTUNIV is a medicine used to treat the symptoms of Attention Deficit Hyperactivity Disorder (ADHD). INTUNIV is a medicine that can help improve your attention, concentration and make you less impulsive and hyperactive.

INTUNIV should be used as part of a comprehensive treatment program which usually includes psychological, educational and social therapy.

The main ingredient in INTUNIV is guanfacine hydrochloride.

Ask your doctor if you have any questions about why this medicine has been prescribed for you/your child. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

This medicine is available only with a doctor's prescription

Before you take INTUNIV

When you must not take it

Do not take INTUNIV if you/your child have an allergy to:

  • any medicine containing guanfacine hydrochloride
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not give this medicine to a child under the age of 6 years. Safety and effectiveness in children younger than 6 years have not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you/your child should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you/your child have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you/your child have or have had any of the following medical conditions:

  • have heart problems or a low heart rate
  • have fainted
  • have low blood pressure
  • have thoughts or feelings of suicide
  • have liver or kidney problems
  • any other medical conditions

Tell your doctor if you/your child are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/her before you/your child start taking INTUNIV.

Taking other medicines

Tell your doctor or pharmacist if you/your child are taking any other medicines, including any that are available without a prescription from a pharmacy, supermarket or health food shop.

Some medicines and INTUNIV may interfere with each other. These include:

  • medicines that lower blood pressure (antihypertensives)
  • medicines used to treat epilepsy such as valproic acid
  • medicines that make you sleepy
  • medicines for mental health problems such as sedatives, benzodiazepines, barbiturates and antipsychotics
  • medicines that can affect liver metabolism such as ketoconazole, rifampin
  • medicines that can affect enzyme metabolism
  • medicines that contain metformin (used for treatment of type 2 diabetes)

These medicines may be affected by INTUNIV or may affect how well INTUNIV works. You/your child may need different amounts of your medicines, or you/your child may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take INTUNIV

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

Your doctor will normally start you/your child on a low dose. Your doctor will increase the dose based on your/your child's body weight and how INTUNIV is working for you/your child. Your doctor will tell you what dose to take each day and will calculate the dose based on your/your child's body weight.

The daily dose will be between 1-7 mg, but not more than 7 mg. When used together with a stimulant, the usual daily recommended dose is not more than 4 mg.

How to take it

  • Take INTUNIV exactly as prescribed. INTUNIV comes in 4 different strength tablets
  • Take INTUNIV once a day either in the morning or evening
  • INTUNIV can be taken with or without food
  • Do not take INTUNIV with fatty foods

Swallow the tablets whole with a full glass of water. Do not break, crush or chew the tablet. This will affect how INTUNIV works.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

If you forget to take it

If you/your child forget a dose, wait until the next day and take the usual dose.

Do not take a double dose to make up for the missed dose.

If you/your child have missed two or more doses talk to your doctor or pharmacist.

If you/your child have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you/your child take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much INTUNIV. Do this even if there are no signs of discomfort or poisoning. You/your child may need urgent medical attention.

If you/your child take too much INTUNIV you/your child may experience symptoms such as slow heart rate, slow breathing rate, low or high blood pressure, feeling tired or exhausted.

While you/your child are using INTUNIV

Things you must do

If you/your child are about to be started on any new medicine, remind your doctor and pharmacist that you/your child are taking INTUNIV.

Tell any other doctors, dentists, and pharmacists who treat you/your child that you/your child are taking this medicine.

If you/your child become pregnant while taking this medicine, tell your doctor immediately.

If you/your child have a gastrointestinal illness that leads to vomiting tell your doctor.This can be like missing doses which could lead to an increase in blood pressure or heart rate.

Keep all of your/your child's doctor's appointments so that your/your/child's progress can be checked. Your doctor will want to check your/your child's height and weight, and blood pressure and heart rate at least once a year or when your/your child's dose is changed or stopped to make sure the medicine is working and to prevent unwanted side effects.

Things you/your child must not do

Do not take INTUNIV to treat any other complaints unless your doctor tells you to.

Do not give INTUNIV to anyone else, even if they have the same condition as you/your child.

Do not stop taking INTUNIV or lower the dosage without checking with your doctor. If INTUNIV is stopped suddenly, your/your child's condition may worsen or your/your child's blood pressure and heart rate may increase.

Things to be careful of

Do not eat or drink products and juices containing grapefruit while you/your child are being treated with INTUNIV. It may interact with INTUNIV and affect how INTUNIV works in the body.

Be careful driving or operating machinery until you know how INTUNIV affects you. This medicine may cause dizziness, light-headedness, tiredness, drowsiness in some people. If you/your child have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous. Children should be careful when riding bicycles or climbing trees.

Be careful when drinking alcohol while taking INTUNIV because it could make you/your child sleepy and drowsy.

Side effects

Tell your doctor or pharmacist as soon as possible if you/your child do not feel well while you/your child are taking INTUNIV.

Like all medicines, INTUNIV can cause some side effects. Sometimes they are serious, most of the time they are not. You/your child may need medical attention if you/your child get some of the side effects.

If you are over 65 years of age you may have an increased chance of getting side effects (if there is an increased risk of side effects in the elderly).

Do not be alarmed by the following lists of side effects. You/your child may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you/your child notice any of the following and they worry you:

  • feeling sleepy or very drowsy
  • feeling tired or weary
  • headache
  • stomach pain
  • feeling restless or irritable
  • trouble sleeping or broken sleep or nightmares
  • feeling depressed, worried or having mood swings
  • weight gain
  • loss of appetite
  • have a dry mouth
  • wetting yourself
  • feeling or being sick
  • diarrhoea, indigestion (upset stomach) or constipation
  • slow heart beat
  • feeling dizzy or faint
  • fainting
  • trouble breathing or asthma
  • increased blood pressure
  • low blood pressure or feeling dizzy when standing up
  • rash

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • allergic reaction which may result in a rash or more rarely to a sharp drop in blood pressure, difficulty breathing, and hives/itching (anaphylactic reaction)
  • chest pain
  • seizures (fits) or convulsions
  • loss of strength
  • pale skin colour
  • need to urinate frequently
  • feeling agitated
  • sleeping more than normal
  • changes in liver blood test results
  • high blood pressure or an unusual heart rhythm
  • fast heart beat
  • itchy skin

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

Tell your doctor or pharmacist if you notice anything that is making you/your child feel unwell.

Other side effects not listed above may also occur in some people.

After using INTUNIV

Storage

Keep INTUNIV tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Keep INTUNIV tablets in a cool dry place where the temperature stays below 25°C.

Do not store INTUNIV or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep INTUNIV and all medicines out of the reach of children. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What INTUNIV looks like

INTUNIV 1 mg tablets are round and white to off-white, hard tablets, debossed with 1MG on one side and 503 on the other side.

INTUNIV 2 mg tablets are oblong shaped and white to off-white, hard tablets, debossed with 2MG on one side and 503 on the other side.

INTUNIV 3 mg tablets are round and green, hard tablets, debossed with 3MG on one side and 503 on the other side.

INTUNIV 4 mg tablets are oblong shaped and green, hard tablets, debossed with 4MG on one side and 503 on the other side.

Ingredients

Active ingredient

INTUNIV contains guanfacine hydrochloride as the active ingredient.

Other ingredients

  • methacrylic acid - ethyl acrylate copolymer (1:1)
  • sodium lauryl sulfate
  • polysorbate 80
  • hypromellose
  • lactose
  • povidone
  • crospovidone
  • silicified microcrystalline cellulose
  • fumaric acid
  • glycerol dibehenate
  • indigo carmine aluminium lake (3 and 4 mg)
  • iron oxide yellow (3 and 4 mg)

This medicine contains lactose.

Sponsor

Shire Australia Pty Ltd
Shire is now part of Takeda
Level 39
225 George Street
Sydney, NSW 2000
Australia
Phone: 1800 012 612

This leaflet was prepared in February 2020.

Australian Registration Number:

INTUNIV 1 mg AUST R 275278

INTUNIV 2 mg AUST R 275313

INTUNIV 3 mg AUST R 275314

INTUNIV 4 mg AUST R 275315

INTUNIV® is a registered trademark of Shire Pharmaceuticals Ireland Limited.

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Intuniv

Active ingredient

Guanfacine

Schedule

S4

 

1 Name of Medicine

Guanfacine hydrochloride.

6.7 Physicochemical Properties

Formula: C9H9Cl2N3O.HCl.

Chemical structure.


CAS number.

29110-48-3.
Molecular weight: 282.56.

2 Qualitative and Quantitative Composition

Intuniv modified release tablet contains guanfacine hydrochloride equivalent to 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine base.
Intuniv (guanfacine hydrochloride) was developed as a tablet for once-a-day oral administration. The chemical designation for guanfacine hydrochloride is N-(diaminomethylidene)-2-(2,6-dichlorophenyl) acetamide hydrochloride. Guanfacine hydrochloride is a white to off-white crystalline powder that is sparingly soluble in water. Guanfacine hydrochloride has a 2-octanol/water partition coefficient (logP) of 0.10; a dissociation constant of 7.69; and pH of ~4 when dissolved in water.
The modified release tablets of guanfacine hydrochloride are designed such that the drug is released slowly, absorbed over an extended period of time, thereby reducing peak plasma levels; therefore, the tablets should not be crushed or altered.

Excipients with known effect.

Lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Modified release tablets.

Appearance.

Intuniv 1 mg modified release tablet: round, white to off-white tablets debossed with '1MG' on one side and '503' on the other side.
Intuniv 2 mg modified release tablet: oblong-shaped, white to off-white tablets debossed with '2MG' on one side and '503' on the other side.
Intuniv 3 mg modified release tablet: round, green tablets debossed with '3MG' on one side and '503' on the other side.
Intuniv 4 mg modified release tablet: oblong-shaped, green tablets debossed with '4MG' on one side and '503' on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Guanfacine is a selective alpha2A-adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) stimulant, a monoamine transporter inhibitor or releaser of pre-synaptic dopamine or norepinephrine. 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 norepinephrine transmission at the alpha 2-adrenergic receptors.

Pharmacodynamic effects.

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 known antihypertensive agent. By stimulating alpha2A-adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate.
In a thorough QT study, the administration of two dose levels of immediate-release guanfacine (4 mg and 8 mg) produced concentrations approximately 2 to 4 times the concentrations observed with the maximum recommended dose of Intuniv of 0.12 mg/kg. Guanfacine was not shown to prolong the QTc interval to any clinically relevant extent.

Clinical trials.

The effects of Intuniv in the treatment of ADHD has been demonstrated 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 0.05-0.12 mg/kg/day.

Monotherapy studies in ADHD patients.

Fixed-dose studies.

The efficacy of Intuniv in the treatment of ADHD was 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 (n = 345) and SPD503-304 (n = 324) were 8 and 9 weeks in duration, respectively. Signs and symptoms of ADHD were evaluated as the change from baseline to endpoint in ADHD Rating Scale (ADHD-RSIV) scores. In both studies, patients were randomized to 2 mg, 3 mg or 4 mg dose groups, titrated to their target fixed dose, and continued on the same dose until a dose tapering phase started. The lowest dose of 1 mg used in Study SPD503-304 was assigned only to patients less than 50 kg. Patients who weighed less than 25 kg were not included in either study.
Dose-responsive efficacy was evident, particularly when data were examined on a weight adjusted (mg/kg) basis. When evaluated over the dose range of 0.01-0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range of 0.05-0.08 mg/kg/day. If well-tolerated, doses up to 0.12 mg/kg once daily may provide additional benefit. Intuniv 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).

Dose-optimisation studies.

AM/PM dosing study.

SPD503-314 was a 9-week, double-blind, randomised, placebo-controlled, dose-optimisation study conducted in children aged 6-12 years (n = 340) to assess the efficacy of once daily dosing with Intuniv (1-4 mg) administered either in the morning or the evening. 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. Intuniv 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).

ADHD with oppositional symptoms study.

SPD503-307 was a 9-week, double-blind, randomised, placebo-controlled, dose-optimisation study with Intuniv (1-4 mg/day) conducted in children aged 6-12 years with ADHD and oppositional symptoms (n = 217), as measured by the change from baseline score on the oppositional subscale of the Conner's Parent Rating Scale - Revised Long Form (CPRS-RL). Results show statistically significantly (p ≤ 0.001) 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. In addition, symptoms of ADHD were evaluated as the change from baseline to final on treatment assessment in the ADHD Rating Scale (ADHD-RS-IV) total scores. Intuniv showed significantly greater (p < 0.001) improvement compared to placebo.

Adolescents.

SPD503-312 was a 15-week, double-blind, randomised, placebo-controlled, dose-optimisation study conducted in adolescents aged 13-17 years (n=314) to confirm the efficacy, safety, and tolerability of Intuniv (1-7 mg/day; optimised dose range of 0.05-0.12 mg/kg/day) in the treatment of ADHD as measured by the ADHD Rating Scale-IV (ADHD-RS-IV). Subjects receiving Intuniv showed significantly greater improvement on the ADHD-RS-IV total score compared with subjects receiving placebo (p < 0.001). 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.

Children and adolescents.

SPD503-316 was a 12-week (6-12 years) or 15-week (13-17 years), randomised, double-blind, parallel-group, placebo and active-reference (Strattera), dose optimisation study conducted in paediatric patients (children and adolescents aged 6-17 years old inclusive) (n=337) to assess the efficacy and safety of once-daily dosing (children: 1-4 mg/day, adolescents: 1-7 mg/day; optimised dose range of 0.05 to 0.12 mg/kg/day) in the treatment of ADHD. Intuniv was superior to placebo on symptoms of ADHD in subjects 6-17 years as measured by change from baseline in ADHD-RS-IV total scores (p < 0.001).
The ADHD Rating Scale is a measure of the core symptoms of ADHD. The results with respect to the primary endpoint study are presented in Table 3.
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 Intuniv, 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).
SPD503-316 was not intended either as a superiority or non-inferiority study and no conclusions with regard to superiority or equivalence can be made from the study.

Long-term maintenance of efficacy study.

SPD503-315 was a 41-week long-term maintenance of efficacy study, with an open-label phase (up to 13 weeks) followed by a 2-week blinded taper and a 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 Intuniv (children: 1-4 mg/day, adolescents: 1-7 mg/day; optimised dose range of 0.05 to 0.12 mg/kg/day) in the treatment of ADHD. Intuniv 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 (worsening) 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. A subject who met the treatment failure criteria on two consecutive visits or discontinued for any reason was identified (or included) as a treatment failure.

Cognitive function study.

SPD503-206 was a 15-week, double-blind, dose-optimisation, safety and tolerability study conducted in paediatric patients (children and adolescents 6-17 years old inclusive) (n = 182) comparing the effects of Intuniv (1-3 mg) to placebo on the Choice Reaction Time Test (Cambridge Neuropsychological Test Automated Battery - CANTAB). There was no evidence of impairment in speed processing compared to placebo.

Co-administration with psychostimulants study.

Dose-optimisation study.

SPD503-313 was a 9-week, double-blind, placebo-controlled, dose-optimisation, co-administration study conducted in paediatric patients (children and adolescents aged 6-17 years old inclusive) with a diagnosis of ADHD and a sub-optimal response to stimulants.
The safety and efficacy of Intuniv (1-4 mg/day) were evaluated when co-administered with psychostimulants (longer-acting formulations of mixed salts of a single-entity amphetamine product, lisdexamfetamine dimesylate, methylphenidate HCl, and dexmethylphenidate HCl). Patients continued to take their psychostimulant in the morning and were dosed either in the morning or the evening with Intuniv (1-4 mg/day) or with placebo in addition to their psychostimulant.
The majority of subjects reached optimal doses in the 0.05-0.12 mg/kg/day range.
Symptoms of ADHD were evaluated as the change from baseline to endpoint (Week 8 LOCF) in ADHD Rating Scale (ADHD-RS-IV) total scores. The mean reductions in ADHD-RS-IV total scores at endpoint were significantly greater for Intuniv co-administered with a psychostimulant compared to placebo taken with a psychostimulant (20.7 (12.6) points vs. 15.9 (11.8); difference: 4.9 95% CI: 2.6, 7.2). This result was consistent for both AM and PM dosing (p = 0.002 for placebo vs AM and p < 0.001 for placebo vs PM, applying Dunnett's adjustment). No age differences were observed with respect to response to the ADHD-RS-IV.

5.2 Pharmacokinetic Properties

Absorption.

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

Distribution.

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

Metabolism.

In vitro studies with human liver microsomes and recombinant CYPs demonstrated that guanfacine is primarily metabolised via CYP3A-mediated oxidation, with subsequent phase II reactions of sulfation and glucuronidation. In pooled human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP3A5); guanfacine is also not expected to be an inducer of CYP3A, CYP1A2 and CYP2B6. Guanfacine is a substrate of CYP3A4/3A5 and exposure is affected by CYP3A4/3A5 inducers such as rifampicin and inhibitors such as ketoconazole (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Transporters.

Based on in vitro studies, guanfacine is a substrate of OCT1 and OCT2, but not BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1 or MATE2. Guanfacine is not an inhibitor of BSEP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2 or MATE2K, but it is an inhibitor of MATE1 and may be an inhibitor of OCT1 at maximal portal vein concentrations.

Excretion.

Guanfacine elimination involves both hepatic metabolism and renal excretion via the OCT2 transporter. Following dosing with radioactively-labelled guanfacine, over 80% of the radioactivity was recovered in the urine. The major urinary radioactive components were parent drug and 3 hydroxy guanfacine glucuronide, which each comprised around 30% of the recovered radioactivity. Other urinary metabolites included guanfacine dihydrodiol and 3 hydroxy guanfacine sulfate. The elimination half-life of guanfacine is approximately 18 hours. The pharmacokinetics of guanfacine are similar in children (aged 6 to 12) and adolescent (aged 13 to 17) ADHD patients, and healthy adult volunteers.

5.3 Preclinical Safety Data

Genotoxicity.

Guanfacine was not genotoxic in a variety of test models, including the Ames test and an in vitro chromosomal aberration test; however, a marginal increase in numerical aberrations (polyploidy) was observed in the latter study.

Carcinogenicity.

No carcinogenic effect was observed when mice and rats received guanfacine in their diets at doses up to 7 times the maximum recommended human dose (MHRD) of 0.12 mg/kg/day on a mg/m2 basis for periods of 78 and 102 weeks, respectively. Exposures achieved in these studies were not measured but likely to be similar to clinical exposure at the MRHD. The negative results from genotoxicity and carcinogenicity studies suggest that guanfacine has low carcinogenic potential in humans.

4 Clinical Particulars

4.1 Therapeutic Indications

Intuniv is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents 6-17 years old, as monotherapy (when stimulants or atomoxetine are not suitable, not tolerated or have been shown to be ineffective) or as adjunctive therapy to psychostimulants (where there has been a sub-optimal response to psychostimulants).
Intuniv must be used as part of a comprehensive ADHD management programme, typically including psychological, educational and social measures.

4.3 Contraindications

Intuniv is contraindicated in patients with a history of hypersensitivity to Intuniv, its excipients, or other products containing guanfacine.

4.4 Special Warnings and Precautions for Use

Intuniv can cause syncope, hypotension, and bradycardia.
In short-term paediatric monotherapy and co-administration trials, dose dependent decreases in mean heart rate (6-9 bpm) and decreases in mean blood pressure (systolic [4-5 mmHg] and diastolic [3 mmHg]) were observed.
In long-term, monotherapy, open-label studies (mean exposure of approximately 10 months), maximum decreases in systolic and diastolic blood pressure occurred in the first month of therapy. The majority of syncope cases occurred in the long-term, open-label studies.
Measure patients' heart rates and blood pressures prior to initiation of treatment, following dose increases, and periodically while on therapy.
Measurements of heart rate and blood pressure should be performed prior to initiating therapy, following dose adjustments, periodically during treatment and following drug discontinuation. Observe caution if using Intuniv in patients who have a history of hypotension, heart block, bradycardia, or other cardiovascular disease (e.g. arrhythmia, sick sinus syndrome, ischemic heart disease, congestive heart failure, or congenital long QT syndrome), as Intuniv can decrease blood pressure and heart rate. Caution is advised when treating patients with Intuniv who have a history of syncope or a condition that may predispose them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Given the effect on blood pressure and heart rate, caution is advised when treating patients with Intuniv who are being treated concomitantly with antihypertensives or other drugs that reduce blood pressure or heart rate, QT prolonging drugs, and drugs that increase the risk of syncope (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Antihypertensive drugs). Patients/caregivers should be advised that patients should avoid becoming dehydrated or overheated.

Sedation and somnolence.

Intuniv may cause somnolence and sedation. Before Intuniv is used with other centrally active depressants (such as alcohol, sedatives, hypnotics, antipsychotics, phenothiazines, barbiturates, or benzodiazepines), the potential for additive sedative effects should be considered. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with Intuniv. Patients should avoid use with alcohol.
Use caution when Intuniv is administered concomitantly with CNS depressant drugs (e.g. alcohol, sedatives, hypnotics, benzodiazepines, barbiturates, and antipsychotics) due to the potential for additive pharmacodynamic effects such as sedation and somnolence.

Suicidal ideation.

There have been post-marketing reports of suicide-related events in patients treated with ADHD drugs, including cases of ideation, attempts, and very rarely, completed suicide. The mechanism of this risk is not known. ADHD and its related co-morbidities may be associated with increased risk of suicidal ideation and/or behaviour. Therefore, it is recommended for patients treated with ADHD drugs that caregivers and physicians monitor for signs of suicide-related behaviour, including at dose initiation/optimisation and drug discontinuation. Patients should be encouraged to report any distressing thoughts or feelings at any time to their healthcare professional. Patients with emergent suicidal ideation and behaviour should be evaluated immediately. The physician should initiate appropriate treatment of the underlying psychiatric condition and consider a possible change in the ADHD treatment regimen.

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.

Rebound effects (blood pressure and heart rate increase) upon discontinuation or treatment interruption.

Blood pressure and pulse may increase following discontinuation of Intuniv.
Abrupt discontinuation of Intuniv can lead to clinically significant and persistent rebound hypertension. In the post-marketing setting, cases of rebound hypertension including hypertensive encephalopathy have been reported rarely following discontinuation or treatment interruption (see Section 4.8 Adverse Effects (Undesirable Effects)). Concomitant stimulant use was also reported, which may potentially increase the hypertensive response upon abrupt discontinuation of guanfacine.
Caution is recommended in children who have gastrointestinal illnesses that lead to vomiting because the resulting inability to take medications may lead to a risk of guanfacine rebound effects.
To minimize the risk of an increase in blood pressure upon discontinuation, the total daily dose of Intuniv should be tapered in decrements of no more than 1 mg every 3 to 7 days (see Section 4.2 Dose and Method of Administration). Blood pressure and pulse should be monitored when reducing the dose or discontinuing Intuniv.

Use in hepatic impairment.

Guanfacine is cleared by the liver, and approximately 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 inclusive) has not been assessed.

Use in renal impairment.

Guanfacine is also cleared by the kidneys, with approximately 30% of the drug excreted unchanged in the 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) has not been assessed.

Use in adults and the elderly.

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

Paediatric use.

Paediatric patients taking Intuniv demonstrated similar growth compared to normative data.
The safety and efficacy of Intuniv in paediatric patients less than 6 years of age have not been established.
Studies using juvenile rats showed that co-administration of guanfacine and methylphenidate increased plasma exposure values (both Cmax and AUC) for the former by a factor of approximately 2-4 (as cf. administration of guanfacine alone) but had no effect on exposure values for the latter compound. The basis for this effect on guanfacine exposure is not known.

Effects on laboratory tests.

No data available.

Abuse and dependence.

Intuniv has no known potential for abuse or dependence.

4.5 Interactions with Other Medicines and Other Forms of Interactions

CYP3A4 and CYP3A5 inhibitors.

Use caution when Intuniv is administered to patients taking ketoconazole and other moderate and strong CYP3A4/5 inhibitors, since elevation of plasma guanfacine concentration increases the risk of adverse events 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 exposure increased 3-fold (area under the curve [AUC]).

CYP3A4 inducers.

When patients are taking Intuniv concomitantly with a CYP3A4 inducer, an increase in the dose of Intuniv within the recommended dose range may be considered. There was a significant decrease in the rate and extent of guanfacine exposure when co-administered with rifampin, a CYP3A4 inducer. The exposure to guanfacine decreased by 70% (AUC).

Transporters.

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. Furthermore, 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.

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 metabolized by glucuronidation, possibly resulting in competitive inhibition. When Intuniv is co-administered with valproic acid, monitor patients for potential additive central nervous system (CNS) effects and give consideration to the monitoring of serum valproic acid concentrations. Adjustments in the dose of valproic acid and Intuniv may be indicated when co-administered.

Antihypertensive drugs.

Use caution when Intuniv is administered concomitantly with antihypertensive drugs, due to the potential for additive pharmacodynamic effects such as hypotension and syncope.

Oral methylphenidate.

In a drug interaction study, neither Intuniv nor methylphenidate HCl modified-release were found to affect the pharmacokinetics of the other drug 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 co-administration of Intuniv and lisdexamfetamine dimesylate.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No adverse effects were observed in fertility studies in male and female mice and rats given oral doses up to 22 times the maximum recommended human dose (MRHD) of 0.12 mg/kg/day on a mg/m2 basis. Exposures achieved in these studies were not measured but likely to be similar to clinical exposure at the MRHD.
(Category B3)
There are no adequate, well-controlled studies of Intuniv in pregnant women. Intuniv should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the foetus.
Rat experiments have shown that guanfacine crosses the placenta. Oral administration of guanfacine to rats and rabbits at about 4 and 3 times, respectively, the maximum recommended human dose (MRHD) of 0.12 mg/kg/day on a mg/m2 basis, resulted in no evidence of harm to the foetus. Higher doses (14 times or greater the MRHD were associated with reduced foetal survival and maternal toxicity in both species. Exposures achieved in these studies were not measured but likely to be similar to clinical exposure at the MRHD.
There are no clinical data on the use of Intuniv in women who are breast feeding. In non-clinical studies, guanfacine was excreted into rat milk. It is not known if guanfacine would also be excreted into human milk. Use caution when Intuniv is administered to a woman who is breast feeding.
Oral administration of guanfacine to rats from late gestation to weaning at about 6 times the maximum recommended human dose (MRHD) of 0.12 mg/kg/day on a mg/m2 basis did not affect pup development. Higher doses were associated with reduced pup weight and pup mortality. Exposures achieved in these studies were not measured but likely to be similar to clinical exposure at the MRHD.

4.8 Adverse Effects (Undesirable Effects)

Adverse drug reactions (ADRs) reported with Intuniv.

Table 2 presents all adverse drug reactions based on all safety information available, sorted by MedDRA SOC and decreasing categories of frequency.

Post-marketing experience.

There have been post-marketing reports of suicide-related events, including completed suicide, suicide attempt, and suicidal ideation in patients treated with ADHD drugs. In some of these reports, comorbid conditions may have contributed to the event (see Section 4.4 Special Warnings and Precautions for Use, Suicidal ideation).

Description of selected adverse drug reactions (ADRs).

Rebound effects (blood pressure and heart rate increase) upon discontinuation or treatment interruption of Intuniv.

Blood pressure and pulse may increase following discontinuation of Intuniv. In postmarketing experience, hypertensive encephalopathy has been very rarely reported upon abrupt discontinuation of Intuniv (see Section 4.4 Special Warnings and Precautions for Use).
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 Intuniv. 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 postfinal dose. More than 90% of patients' blood pressure measurements remained within normal limits (i.e. less than the 95th percentile based on age, sex and stature). Mean increases in pulse of approximately 1.5 bpm were observed at approximately 2 weeks after the last dose of Intuniv and then decreased to baseline 4 weeks later. In this study, the increases in blood pressure and pulse were not considered serious or associated with adverse events. However, individuals may have larger increases than reflected by the mean changes (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Method of administration.

Intuniv is a modified-release tablet and 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. 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. Intuniv should not be administered together with grapefruit juice.

Dosage in paediatric patients (children and adolescents).

The recommended starting dose for Intuniv is 1 mg, taken orally once a day, for both monotherapy and when co-administered with psychostimulants.
The dose is adjusted in increments of no more than 1 mg/week for both monotherapy and when co-administered with psychostimulants.
In monotherapy clinical trials, there was dose and exposure-related clinical improvement as well as risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). To balance the exposure-related potential benefits and risks, the recommended maintenance dose range depending on clinical response and tolerability for Intuniv is 0.05-0.12 mg/kg/day (total daily dose between 1-7 mg. See Table 1).
In the co-administration trial which evaluated Intuniv treatment with psychostimulants, the majority of subjects reached optimal doses in the 0.05-0.12 mg/kg/day range. Doses above 4 mg/day have not been studied in co-administration trials and therefore are not recommended.

Long-term use.

Pharmacological treatment of ADHD may be needed for extended periods. The benefit of maintaining children and adolescent patients (6-17 years) with ADHD on Intuniv was demonstrated in a controlled randomised withdrawal trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The majority of children and adolescents reached optimal doses in the 0.05-0.12 mg/kg/day range. Doses above 4 mg/day have not been evaluated in children (ages 6-12 years) and above 7 mg/day have not been evaluated in adolescents (ages 13-17 years).
The clinician who elects to use Intuniv for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Missed doses.

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 Intuniv.

Downward titration and discontinuation.

Patients/caregivers should be instructed not to discontinue Intuniv without consulting their physician. The total daily dose should be tapered in decrements of no more than 1 mg every 3 to 7 days to minimize the risk of an increase in blood pressure upon discontinuation. Blood pressure and pulse should be monitored when reducing the dose or discontinuing Intuniv (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
Tapering Intuniv dosing during withdrawal is recommended to minimise these potential withdrawal effects.

Sub-optimal responders to psychostimulants.

Intuniv may be co-administered with psychostimulants in patients in whom psychostimulants alone have not provided an adequate response (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Dosing should follow the recommended doses as described above.
The recommended maintenance dose for Intuniv when co-administered with psychostimulants is within the range of 1-4 mg/day, depending on clinical response and tolerability. Doses above 4 mg/day have not been evaluated in co-administration trials (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.
However, patients should be advised that treatment with Intuniv can cause dizziness, sedation, fatigue and somnolence. These effects occur predominantly at the start of treatment and may occur less frequently as treatment continues. Syncope has also been observed in patients receiving treatment with Intuniv.
If patients experience the above mentioned side effects, they should avoid potentially hazardous tasks such as driving or operating machinery.

4.9 Overdose

Signs and symptoms of overdose may include hypotension, initial hypertension, bradycardia, lethargy, and respiratory depression. 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%).
For information on the management of overdose, contact the Poisons Information Centre telephone: 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Intuniv modified release tablets contain the following inactive ingredients: hypromellose, methacrylic acid - ethyl acrylate copolymer (1:1), sodium lauryl sulfate, polysorbate 80, lactose, povidone, crospovidone, colloidal anhydrous silica, microcrystalline cellulose, fumaric acid, glycerol dibehenate.
The 3 mg and 4 mg tablets also contain indigo carmine aluminium lake and iron oxide yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

4 years.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Container type.

Blister pack.

Pack size.

7 or 28 tablets. Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes