Consumer medicine information

Concerta

Methylphenidate hydrochloride

BRAND INFORMATION

Brand name

Concerta Extended-Release Tablets

Active ingredient

Methylphenidate hydrochloride

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Concerta.

What is in this leaflet

This leaflet answers some common questions about CONCERTA extended-release tablets. 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 or your child taking CONCERTA against the benefits this medicine is expected to have for you or your child.

If you have any concerns about taking CONCERTA ask your doctor or pharmacist.

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

What is CONCERTA used for

CONCERTA is used to treat Attention Deficit Hyperactivity Disorder (ADHD). CONCERTA is part of a comprehensive treatment program which usually includes psychological, educational and social therapy.

CONCERTA is a stimulant that increases attention and decreases impulsiveness and hyperactivity in patients with ADHD.

CONCERTA should be used as part of a total treatment program for ADHD that may include counselling or other therapies.

CONCERTA is not recommended for use in children less than 6 years and elderly over 65 years because it has not been studied in these age groups.

CONCERTA tablets are made in an extended release form. This means that they release the active ingredient slowly. The outer layer of the CONCERTA tablet dissolves right after it is swallowed in the morning, giving an initial dose of methylphenidate hydrochloride.

The tablets have a special shell that allows the rest of the methylphenidate hydrochloride to be released from the tablet at a slow rate throughout the day.

The tablet shell does not dissolve completely after all the drug has been released and sometimes the tablet shell may be seen in your stool. This is normal.

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

CONCERTA can be abused or lead to dependence. Keep CONCERTA in a safe place to prevent misuse and abuse.

Before you take CONCERTA

When you must not take it

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

  • methylphenidate hydrochloride (the active ingredient in CONCERTA) or
  • any of the other ingredients in CONCERTA. See Product Description at the end of this leaflet for a list of ingredients.

Symptoms of an allergic reaction may include: rash, itching or hives on the skin; shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body.

Do not take CONCERTA if you/your child have any of the following medical conditions:

  • glaucoma (increased pressure in the eye) which is poorly controlled
  • overactive thyroid gland
  • heart problems, including severe angina (chest pain), irregular heart beat, heart muscle diseasehigh blood pressure (untreated or not under control)
  • severe depression, anorexia nervosa, suicidal tendency or other mental illness
  • phaeochromocytoma (a tumour of the adrenal gland)

Do not take CONCERTA if you/your child:

  • have a history of drug or alcohol abuse
  • currently taking or have taken a monoamine oxidase (MAO) inhibitor, medicines used to treat major depression (eg. phenelzine, tranylcypromine) or medicines used in Parkinson's disease (eg. selegiline) within the last 14 days

Do not use CONCERTA if the packaging is torn or shows signs of tampering.

Do not use CONCERTA beyond the expiry date (month and year) printed on the pack. If you/your child take CONCERTA after the expiry date it may not work.

Before you/your child start to take it

You must tell your doctor if you/your child:

  • are/is pregnant or planning to become pregnant
  • are/is breastfeeding or wish to breastfeed.
    The active ingredient in CONCERTA passes into breast milk and there is a possibility that your baby may be affected. Your doctor can discuss with you the risks and benefits involved
  • are/is or have/has been alcohol or drug dependent
  • have/has seizures or fits
  • have/has heart problems
    Heart-related problems including sudden death in patients who have heart problems or heart defects, stroke and heart attack in adults and increased blood pressure and heart rate have been reported with the use of methylphenidate, the active ingredient in CONCERTA.
  • have / had thoughts about suicide or attempted suicide
  • have/has high blood pressure
  • have/has aggressive behaviour or hostility
  • have/has a narrowing or blockage in your digestive tract (stomach, small or large intestine)
  • have tics (movements or sounds that you cannot control) or Tourette's syndrome, or a family history of these conditions
  • have/has a problem with the blood vessels in your brain (such as an aneurysm)
  • have/has eye problems, such as increased pressure in the eye, a condition called "glaucoma" or long-sightedness (difficulty seeing near objects)
  • have/has liver or kidney problems
  • have/has mental problems including psychosis, mania, bipolar illness, or depression.
    Mental (psychiatric) problems may develop or get worse, including behaviour and thought problems, bipolar illness, aggressive behaviour or hostility.

Your doctor may need to adjust the dose or adapt your treatment if you/your child have any of these conditions.

If you have not told your doctor or pharmacist about any of the above, tell them before you/your child start taking CONCERTA.

Taking other medicines:

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

In particular, tell your doctor or pharmacist if you/your child are taking any of the following:

  • Monoamine oxidase (MAO) inhibitors such as phenelzine, selegiline
  • medicines that increase blood pressure
  • medicines used to treat depression or anxiety such as venlafaxine, sertraline, amitriptyline and imipramine
  • medicines used to prevent seizures such as phenytoin, phenobarbitone, primidone and valproate.
  • antipsychotic medicines such as olanzapine, risperidone and quetiapine used to improve the symptoms of certain types of mental illness, e.g. schizophrenia and bipolar disorder.

These medicines may be affected by CONCERTA or may affect how well CONCERTA works. Your doctor or pharmacist can tell you what to do if you/your child are taking any of these medicines.

Taking CONCERTA

Follow the directions given to you by your doctor and pharmacist. These directions may differ from the information contained in this leaflet.

How much to take:

If you/your child are currently taking other formulations of methylphenidate, your doctor will decide the best starting dose

Children and Adolescents

  • The starting dose is one CONCERTA 18 mg extended-release tablet in the morning
  • The maximum dose is 54 mg a day taken as one dose.

Adults

  • The starting dose is one CONCERTA 18 mg or 36 mg extended-release tablet in the morning
  • The maximum dose is 72 mg a day taken as one dose.

Follow your doctor's instructions carefully and do not change or stop your dosage without consulting your doctor first. Your doctor may adjust the amount of CONCERTA you take until it is right for you.

How to take it:

  • CONCERTA should be swallowed whole with a glass of liquid. It should not be chewed, broken or crushed
  • CONCERTA may be taken with or without food.

If you do not understand the instructions provided with this medicine, ask your doctor or pharmacist for help.

If you/your child forget to take it

  • It may be best to wait until the following morning to take the next dose. Remember the effects of CONCERTA are designed to last approximately 12 hours from the time it is taken.
  • Do not take or give your child a double dose to make up for the dose missed.

If you/your child have missed more than one dose, or are not sure what to do, check with your doctor or pharmacist.

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

If you/your child have taken too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone number 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital.

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 CONCERTA you/your child may experience symptoms such as vomiting, agitation, muscle twitching, hallucination, dry mouth, excessive sweating, fever, headache, irregular or fast heart beat, dilated pupils, convulsions/fits, breathing problems, confusion and seizures.

While you are taking CONCERTA

Things you must do

  • Always follow your doctor's instructions carefully
  • Take CONCERTA exactly as your doctor has prescribed. Like all stimulants, CONCERTA may become habit-forming and can be abused by some people. If you/your child take it correctly as instructed by your doctor, abuse or dependence should not be a problem, either now or later in life
  • Be sure to keep all of your doctor's appointments so that your/your child's progress can be checked
  • Your doctor will want to check your/your child's blood pressure and pulse and do blood test from time to time to prevent unwanted side effects
  • Tell your doctor if you/your child become pregnant while taking CONCERTA
  • Parents and/or caregivers should be alert for the development of thoughts or acts of self-harm, hallucinations, abnormal thinking (psychosis) or new or worsening hostility. These were uncommon symptoms seen in clinical studies with CONCERTA and it is not known if they were caused by CONCERTA. Contact your/your child's doctor or mental health professional straight away or seek urgent medical attention if these occur
  • Tell your doctor if you or your child become aggressive, anxious or agitated, or feel more aggressive, anxious or agitated than usual
  • Parents and/or caregivers should contact their/their child's doctor or seek urgent treatment if they/their child develops chest pain, tightness in the chest, shortness of breath, irregular heart beat, feeling faint or loss of consciousness while taking CONCERTA
  • Tell your doctor if you or your child develop severe headaches, weakness or paralysis of any body part, or develop problems with coordination, vision, speaking, finding words or with your memory
  • Children should have their height and weight checked regularly as CONCERTA may slow children's rate of growth
  • Tell your doctor if you/your child experience numbness, tingling and a changing colour of the fingers and toes when cold (‘Raynaud’s phenomenon’)
  • Tell your doctor if you or your child develop prolonged and painful erections, seek immediate medical attention
  • Tell your doctor if you/your child are about to start taking a new medicine, that you/your child are taking CONCERTA

Things you must not do

  • Do not use CONCERTA to treat any other complaint unless your doctor says so.
  • Do not give this medicine to anyone else, even if their symptoms seem similar.
  • Do not stop treatment without first checking with your doctor.
    If you/your child suddenly stop taking this medicine, you/your child's condition may reappear or you/your child may get unwanted effects such as depression. Your doctor may want to gradually reduce the amount of medicine taken each day before stopping it completely.

Things to be careful of

  • CONCERTA may impair your ability to operate potentially hazardous machinery or vehicles. You should exercise caution until you are reasonably certain how you react to CONCERTA before you drive a car, operate machinery, or do anything else that could be dangerous.

Side Effects

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You/your child may need medical treatment if you get some side effects. Do not be alarmed by this list of possible 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 if you/your child experience any of the following and they worry you:

stomach or bowel problems such as:

  • loss of appetite
  • stomach pain
  • nausea
  • vomiting
  • dry mouth
  • indigestion
  • constipation
  • weight loss
  • diarrhoea

difficulty thinking or working because of:

  • headache
  • trouble sleeping
  • dizziness

throat or lung infections such as:

  • cold
  • cough
  • sore throat and hoarse/ loss of voice
  • feeling of tension or fullness in the nose, cheeks and behind your eyes, sometimes with a throbbing ache, fever, stuffy nose and loss of the sense of smell

joints or movement changes such as:

  • painful and/ or swollen joints
  • aching muscles, muscle tightness, spasm, tenderness or weakness, not caused by exercise
  • difficulty opening the mouth
  • clenching or grinding the teeth

other changes such as:

  • decreased sex drive or difficulty getting and keeping an erection
  • feeling very tired or weak
  • excessive thirst
  • feeling sleepy
  • loss of bladder control

Tell your doctor immediately if you notice any of the following behavioural changes such as:

  • aggression
  • confusion
  • disorientation
  • seeing, feeling or hearing things that are not there
  • mood swings, overexcitement over-activity and uninhibited behaviour
  • feeling depressed
  • feeling tense
  • nervousness or anxiety
  • brief periods of acute anxiety where symptoms suddenly and usually include difficulty breathing, chest pains, fast heart rate, dizziness and lightheadedness, sweating, trembling and faintness
  • restlessness
  • agitation and irritability
  • movements or sounds that you cannot control (tics)

nervous system changes such as:

  • convulsions, fits or seizures
  • muscle twitching or tremor
  • numbness and tingling feeling in fingers and toes

reproductive system changes such as:

  • prolonged and painful erections

changes in your sight, namely:

  • visual disturbance
  • blurred or double vision
  • dilated pupils

changes to the skin or hair such as:

  • unusual hair loss or thinning of the hair
  • redness of the skin
  • excessive sweating
  • signs of allergy such rash, itching or hives on the skin; shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body

body temperature changes such as:

  • fever
  • hot flushes

heart or blood problems such as:

  • fast or abnormal heart beat
  • increased blood pressure
  • chest pain
  • chest discomfort
  • low white blood cell count
  • low platelet count

other side effects such as:

  • shortness of breath
  • slowing of growth (height and weight) in children)
  • blockage of the oesophagus, stomach, small or large intestine in patients who already have a narrowing in any of these organs
  • increased levels of the liver enzyme ALT

Other side effects not listed above may also occur in some people. Tell your doctor if you notice any other effects.

After using CONCERTA

Storage

Keep the tablets in the bottle until it is time to take them.

Store CONCERTA in a cool dry place where the temperature is below 25°C. Keep the container tightly closed.

Keep medicines where children cannot reach them. A locked cupboard at least one-and-a-half metres (1.5 m) above the ground is a good place to store medicines.

Do not store CONCERTA, or any other medicine, in the bathroom or near a sink. Do not leave medicines in the car or on windowsills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you/your child to stop taking CONCERTA extendedrelease tablets or the medicine has passed its expiry date, ask your pharmacist what to do with any medicine that may be left over.

Product Description

What it looks like

CONCERTA 18 mg are yellow capsule-shaped tablets, with "alza 18" printed in black ink on one side [AUST R 93862].

CONCERTA 27 mg are grey capsule-shaped tablets, with "alza 27" printed in black ink on one side [AUST R 124502].

CONCERTA 36 mg are white capsule-shaped tablets, with "alza 36" printed in black ink on one side [AUST R 93863].

CONCERTA 54 mg are brownish-red capsule-shaped tablets, with "alza 54" printed in black ink on one side [AUST R 93864].

CONCERTA products are supplied in bottles of 28, 30, 56, 60 or 100 tablets.

Not all pack sizes are marketed.

Ingredients

Each CONCERTA extended-release tablet contains 18 mg, 27 mg, 36 mg or 54 mg of methylphenidate hydrochloride as the active ingredient.

CONCERTA extended-release tablets contain lactose monohydrate.

Each tablet also contains the following other ingredients:

  • butylated hydroxytoluene
  • carnauba wax
  • cellulose acetate
  • hypromellose
  • phosphoric acid
  • poloxamer
  • polyethylene oxide
  • povidone
  • sodium chloride
  • stearic acid
  • succinic acid
  • iron oxide black
  • iron oxide yellow
  • iron oxide red (27mg & 56 mg tabs only)
  • OPACODE WB monograming ink NS-78-17715 Black (PI 4424)
  • OPADRY complete film coating system YS-1-19025-A Clear (PI 4421)
  • The 18 mg tablet also contains Opadry II yellow YS-30-12788-A
  • The 27 mg tablet also contains Opadry II grey Y-30-17528
  • The 36 mg tablet also contains Opadry II white Y-30-18037
  • The 54 mg tablet also contains Opadry II red Y-30-15567-A.

Sponsor

JANSSEN-CILAG Pty Ltd
1-5 Khartoum Road
Macquarie Park NSW 2113 Australia
Telephone: 1800 226 334

This leaflet was prepared in February 2020.

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Concerta Extended-Release Tablets

Active ingredient

Methylphenidate hydrochloride

Schedule

S8

 

1 Name of Medicine

Methylphenidate hydrochloride.

6.7 Physicochemical Properties

Methylphenidate hydrochloride is the racemic mixture of d,l-threo-methyl α-phenyl-2-piperidineacetate hydrochloride. The d-(R,R)-isomer is pharmacologically more active than the l-(S,S)-isomer. Methylphenidate hydrochloride is a white, odourless crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone.

Chemical structure.


C14H19NO2.HCl. MW: 269.77.

CAS number.

CAS-298-59-9 (methylphenidate hydrochloride).

2 Qualitative and Quantitative Composition

Concerta is available as an extended-release tablet for once-a-day oral administration containing 18, 27, 36 or 54 mg methylphenidate hydrochloride. It is designed to have a 12-hour duration of effect.

Excipient(s) with known effect.

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

3 Pharmaceutical Form

Concerta 18 mg are yellow capsule-shaped tablets, with "alza 18" printed in black ink on one side.
Concerta 27 mg are grey capsule-shaped tablets, with "alza 27" printed in black ink on one side.
Concerta 36 mg are white capsule-shaped tablets, with "alza 36" printed in black ink on one side.
Concerta 54 mg are brownish-red capsule-shaped tablets, with "alza 54" printed in black ink on one side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Methylphenidate is a central nervous system stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of noradrenaline and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

Clinical trials.

Children.

Concerta was demonstrated to be effective in the treatment of ADHD, in children aged 6 to 12 years, in three pivotal studies. Studies 1 and 2 were single centre, double blind, double dummy, randomised, placebo and active controlled, crossover comparisons (n = 64 and 70). Study 3 was a multicentre, 4 week, double blind, double dummy, randomised, placebo and active controlled, parallel study (n = 282). The primary comparison of interest in all three trials was Concerta versus placebo.
The primary efficacy parameter for Concerta was the Inattention/Overactivity with Aggression (IOWA) Conners I/O subscale rated by the community school teacher. Statistically significant (p < 0.001) reduction in the Inattention/Overactivity subscale versus placebo was shown consistently across all three controlled studies for Concerta once daily.
Onset and duration of efficacy were assessed by the laboratory school teacher using the SKAMP (Swanson, Kotkin, Agler, M-Fynn and Pelham) combined attention ratings for studies 1 and 2. The onset of efficacy was estimated to be 1.5 hours and duration continued through to 12 hours. Patients demonstrated higher productivity and greater accuracy during Concerta treatment.

Adults.

Two double blind, placebo controlled studies were conducted in 627 adults aged 18 to 65 years. The controlled studies compared Concerta administered once daily and placebo in a multi-centre, parallel group, 5 week, fixed dose study (study 4) (18, 36 and 72 mg/day) and in a multi-centre, parallel group, 7 week dose titration study (study 5) (36 to 108 mg/day).
Study 4 was a multi-centre, double blind, randomized, placebo controlled, parallel group, dose response study (5 week duration) with 3 fixed dose groups (18, 36 and 72 mg). Patients were randomized to receive Concerta administered at doses of 18 mg (n = 101), 36 mg (n = 102), 72 mg/day (n = 102) or placebo (n = 96). All three doses of Concerta were statistically significantly more effective than placebo in improving CAARS (Conners' Adult ADHD Rating Scale) total scores at double blind endpoint in adult subjects with ADHD.
Study 5 demonstrated the effectiveness of Concerta in the treatment of ADHD in adults aged 18 to 65 years at doses from 36 mg/day to 108 mg/day based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS). Of 226 patients who entered the 7 week trial, 110 were randomized to Concerta and 116 were randomized to placebo. Treatment was initiated at 36 mg/day and patients continued with incremental increases of 18 mg/day (36 to 108 mg/day) based on meeting specific improvement criteria with acceptable tolerability. At the final study visit, mean change scores (LS mean, SEM) for the investigator rating on the AISRS demonstrated that Concerta was statistically significantly superior to placebo.

5.2 Pharmacokinetic Properties

Absorption.

Methylphenidate is readily absorbed. Following oral administration of Concerta to adults, the drug overcoat dissolves and plasma methylphenidate concentrations increase rapidly reaching an initial maximum at about 1 to 2 hours. The methylphenidate contained in two internal drug layers is gradually released over the next few hours. Peak plasma concentrations are achieved at about 6 to 8 hours after which plasma levels of methylphenidate gradually decrease. Concerta once daily minimises the fluctuations between peak and trough concentrations associated with immediate release methylphenidate three times daily. The extent of absorption of Concerta once daily is generally comparable to conventional immediate release preparations given three times daily.
Following the administration of Concerta 18 mg once daily in 36 adults, the mean pharmacokinetic parameters were Cmax 3.7 ± 1.0 nanogram/mL, Tmax 6.8 ± 1.8 hours, AUC 41.8 ± 13.9 nanogram.hour/mL and t1/2 3.5 ± 0.4 hours. No differences in the pharmacokinetics of Concerta were noted following single and repeated once daily dosing indicating no significant drug accumulation. The AUC and t1/2 following repeated once daily dosing are similar to those following the first dose of Concerta 18 mg.
Following administration of Concerta in single doses of 18, 36 and 54 mg/day to adults, Cmax and AUCinf of d-methylphenidate were proportional to dose, whereas l-methylphenidate Cmax and AUCinf increased disproportionately with respect to dose. Following administration of Concerta, plasma concentrations of the l-isomer were approximately 1/40th the plasma concentrations of the d-isomer.
In healthy adults, single and multiple dosing of once daily Concerta doses from 54 to 144 mg/day resulted in linear and dose proportional increases in Cmax and AUCinf for total methylphenidate (MPH) and its major metabolite, (alpha)-phenyl-piperidine acetic acid (PPAA). The single dose and steady-state (day 4) clearance and half-life parameters were similar, indicating that there was no time dependency in the pharmacokinetics of methylphenidate. The ratio of metabolite (PPAA) to parent drug (MPH) was constant across doses from 54 to 144 mg/day, both after single dose and upon multiple dosing.
Pharmacokinetic equivalence has been demonstrated for two 27 mg Concerta tablets with three Concerta 18 mg tablets. The mean values of the treatment ratio (2 x 27 mg fasted/3 x 18 mg fasted) of the log transformed pharmacokinetic values for Cmax, Tmax and AUCinf were 101.1%, 104.3% and 100.3%, respectively. The 90% CIs for the treatment ratios were within the pre-specified 80% - 125% range.
Studies on the effects of dosing after overnight fasting, after consumption of a normal breakfast and a high fat breakfast showed no differences in pharmacokinetics or pharmacodynamics of Concerta. There is no evidence of dose dumping in the presence or absence of food.

Distribution.

Plasma methylphenidate concentrations in adults decline biexponentially following oral administration. The terminal plasma half-life of methylphenidate in adults following oral administration of Concerta was approximately 3.5 hours.

Metabolism.

In humans, methylphenidate is metabolised primarily by de-esterification to α-phenyl-piperidine acetic acid (PPAA) which has little or no pharmacologic activity. In adults the metabolism of Concerta once daily, as evaluated by metabolism to PPAA, is similar to that of methylphenidate three times daily. The metabolism of single and repeated once daily doses of Concerta is similar.

Excretion.

After oral dosing of radiolabelled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is not expected to have a significant effect on the pharmacokinetics of Concerta.

5.3 Preclinical Safety Data

Genotoxicity.

Methylphenidate was not mutagenic in the in vitro assays (Ames reverse mutation assay, mouse lymphoma cell forward mutation assay). Methylphenidate was weakly clastogenic in vitro (Chinese hamster ovary cells) but was negative in vivo (mouse bone marrow micronucleus assay). Sister chromatid exchange assay results were positive only at high (cytotoxic) concentrations.

Carcinogenicity.

In a lifetime dietary carcinogenicity study carried out in mice, methylphenidate caused an increase in hepatocellular adenomas at a dose of 60-80 mg/kg/day and, in males only, an increase in hepatoblastomas (a relatively rare rodent malignant tumour type) at 60 mg/kg/day. These dose levels are approximately 3 to 8-fold the maximal recommended clinical dose on a mg/m2 basis. There was no increase in tumours at 30-40 mg/kg/day (approximately 1 to 4-fold the maximal recommended clinical dose on a mg/m2 basis). The mouse strain used is sensitive to the development of hepatic tumours, and the significance of these results to humans is not known. There was no evidence of carcinogenicity in two strains of transgenic mice administered methylphenidate in the diet for 24 weeks at doses up to 60-74 mg/kg/day (approximately 3 to 8-fold the maximal recommended clinical dose on a mg/m2 basis) or in a lifetime dietary study in rats at doses up to 50 mg/kg/day (approximately 4 to 10-fold the maximal recommended clinical dose on a mg/m2 basis).

4 Clinical Particulars

4.1 Therapeutic Indications

Concerta is indicated for the treatment of attention deficit hyperactivity disorder (ADHD). Treatment should be commenced by a specialist.
A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of hyperactive impulsive or inattentive symptoms that caused impairment and were present before age 7 years.

Need for comprehensive treatment programme.

Concerta is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational and social) for patients with this syndrome. Stimulants are not intended for use in the patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms.

Long term use.

The effectiveness of Concerta for long-term use has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Concerta for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

4.3 Contraindications

Concerta is contraindicated:
in patients with known hypersensitivity to methylphenidate or any inactive ingredient used in this product (see Section 6.1 List of Excipients);
in patients with poorly-controlled open-angle or angle-closure glaucoma;
in combination with nonselective, irreversible monoamine oxidase (MAO) inhibitors/ selective MAO-A inhibitors or within a minimum of 14 days following discontinuation of a nonselective, irreversible MAO inhibitor/ selective MAO-A inhibitor (hypertensive crises may result);
in patients with hyperthyroidism;
in patients with severe angina pectoris;
in patients with cardiac arrhythmia;
in patients with phaeochromocytoma;
in patients with known drug dependence or alcohol abuse;
in patients with uncontrolled hypertension;
in patients with cardiomyopathies;
in patients with ischaemic heart disease;
in patients with myocardial infarctions;
in patients who currently exhibit severe depression, anorexia nervosa, psychotic symptoms or suicidal tendency, since Concerta might worsen these conditions.

4.4 Special Warnings and Precautions for Use

Use with caution in the following circumstances.

Drug dependence.

Concerta should be given cautiously to patients with a history of drug or alcohol dependence. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behaviour. Careful supervision is required during withdrawal from abusive use since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.

Depression and psychosis.

Concerta should not be used to treat severe depression or for the prevention or treatment of normal fatigue states. In psychotic patients administration of methylphenidate may exacerbate symptoms of behaviour disturbance and thought disorder.
Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/ manic episode in such patients.
Treatment emergent psychotic or manic symptoms, e.g. hallucinations, delusional thinking or mania in patients without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant and discontinuation of treatment may be appropriate.

Seizures.

There is some clinical evidence that methylphenidate may lower the convulsive threshold in a small minority of patients. Patients treated with methylphenidate should be monitored for the new appearance of seizures or a reduction in seizure-control. If the seizure frequency increases following the initiation of methylphenidate, consideration should be given to discontinuation of the drug.

Potential for gastrointestinal obstruction.

Concerta tablet is non-deformable and does not appreciably change in shape in the GIT. It should not ordinarily be administered to patients with pre-existing severe GI narrowing (pathologic or iatrogenic) or in patients with dysphagia or significant difficulty in swallowing tablets. Due to the prolonged release design of the tablet, Concerta should only be used in patients who are able to swallow the tablet whole.

Increased intraocular pressure and glaucoma.

There have been reports of a transient elevation of intraocular pressure (IOP) associated with methylphenidate treatment. It is recommended to prescribe Concerta to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Patients with a history of abnormally increased IOP or open-angle glaucoma, and patients at risk for acute angle-closure glaucoma (e.g. patients with significant hyperopia) must be closely monitored.
Concerta is not recommended in patients with angle-closure glaucoma.
Concerta is contraindicated in all patients with poorly-controlled glaucoma (see Section 4.3 Contraindications).

Motor and verbal tics and worsening of Tourette's syndrome.

Methylphenidate has been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette's syndrome has also been reported. It is recommended that the family history be assessed, and that the patient is clinically evaluated for tics or Tourette's syndrome before initiating methylphenidate. Regular monitoring for the emergence or worsening of tics or Tourette's syndrome during treatment with methylphenidate is recommended at every dose adjustment and every visit, and treatment discontinued if clinically appropriate.

Sudden death and pre-existing structural cardiac abnormalities or other serious heart problems.

Children and adolescents.

Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug.

Adults.

Sudden deaths, stroke and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs.
It is essential that children, adolescents or adults with pre-existing structural cardiac abnormalities or other serious heart problems being considered for treatment are assessed by a cardiologist before initiating treatment. Ongoing cardiologist supervision should be maintained throughout treatment in these patients.

Hypertension and other cardiovascular conditions.

Children, adolescents or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease and should receive further cardiac evaluation if findings suggest such disease. Patients who develop symptoms such as exertional chest pain, unexplained syncope or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.
In the laboratory clinical trials in children, both Concerta and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm Hg during the day, relative to placebo. In placebo controlled studies in adults, mean increases in resting pulse rate of approximately 4 to 6 bpm were observed with Concerta at endpoint vs. a mean change of roughly -2 to 3 bpm with placebo. Mean changes in blood pressure at endpoint ranged from about -1 to 1 mm Hg (systolic) and 0 to 1 mm Hg (diastolic) for Concerta and from -1 to 1 mm Hg (systolic) and -2 to 0 mm Hg (diastolic) for placebo. Therefore, caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate. Blood pressure and cardiovascular status should be reviewed regularly during treatment with Concerta.

Aggression, anxiety and agitation.

Aggressive behaviour, marked anxiety or agitation are often observed in patients with ADHD, and have been reported in patients treated with Concerta (see Section 4.8 Adverse Effects (Undesirable Effects)). Anxiety led to discontinuation of Concerta in some patients. It is recommended that patients be monitored for the appearance of, or worsening of, aggressive behaviour, marked anxiety, or agitation, at the beginning of treatment with Concerta, following every dose adjustment, and regularly during continued treatment at a steady dose.

Priapism.

Prolonged and painful erections requiring immediate medical attention (sometimes including surgical intervention) have been reported with methylphenidate products, including Concerta, in both paediatric and adult patients (see Section 4.8 Adverse Effects (Undesirable Effects)). Priapism can develop after some time on methylphenidate, often subsequent to an increase in dose. Priapism has also appeared during a period of methylphenidate withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained erections or frequent and painful erections should seek immediate medical attention.

Peripheral vasculopathy, including Raynaud's phenomenon.

Stimulants, including Concerta, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, have been observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g. rheumatology referral) may be appropriate for certain patients.

Cerebrovascular disorders.

Cerebrovascular disorders (including cerebral vasculitis and cerebral haemorrhage) have been reported with the use of Concerta (see Section 4.8 Adverse Effects (Undesirable Effects)). Consider cerebrovascular disorders as a possible diagnosis in any patient who develops new neurological symptoms that are consistent with cerebral ischemia during Concerta therapy. These symptoms could include severe headache, unilateral weakness or paralysis, and impairment of coordination, vision, speech, language, or memory. If a cerebrovascular disorder is suspected during treatment, discontinue Concerta immediately. Early diagnosis may guide subsequent treatment.
In patients with pre-existing cerebrovascular disorders (e.g. aneurysm, vascular malformations/anomalies), treatment with Concerta is not recommended.

Haematologic monitoring.

Periodic full blood count, differential and platelet counts are advised during prolonged therapy.

Long-term suppression of growth.

Careful follow-up of weight and height in children aged 7 to 10 years who were randomized to either methylphenidate or nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate treated and nonmedication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e. treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development.
Published data are inadequate to determine whether chronic use of amphetamines may cause similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

Instructions to the patient.

Concerta must be swallowed whole with the aid of liquids. Tablets should not be chewed, divided or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.

Use in hepatic impairment.

There is no experience with the use of Concerta in patients with hepatic insufficiency.

Use in renal impairment.

There is no experience with the use of Concerta in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of PPAA. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of Concerta.

Use in the elderly.

No data available.

Paediatric use.

The safety and efficacy of Concerta in children under 6 years old have not been established.
Long-term effects of methylphenidate in children are not yet available. Although a causal relationship has not been established, suppression of growth (i.e. weight gain and/or height) has been reported with the long-term use of stimulants in children. Therefore, patients requiring long-term therapy should be carefully monitored. Patients who are not growing or gaining weight as expected should have their treatment interrupted.

Effects on laboratory tests.

See "Haematologic monitoring" above.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Concerta should not be used in patients being treated (currently or within the preceding 2 weeks) with MAO inhibitors (see Section 4.3 Contraindications).
Because of possible effects on blood pressure, Concerta should be used cautiously with vasopressor agents.
Coadministration of methylphenidate with anticonvulsants (e.g. phenobarbital, phenytoin, primidone), and some antidepressants (tricyclics and selective serotonin reuptake inhibitors) has occasionally been reported to lead to serious adverse effects. Patients should be monitored for adverse events during concomitant use. Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate, and it may be necessary to monitor plasma drug concentrations of anticonvulsants and tricyclic antidepressants.
There have been reports of serotonin syndrome following coadministration of methylphenidate with serotonergic drugs. If concomitant use of Concerta with a serotonergic drug is warranted, prompt recognition of the symptoms of serotonin syndrome is important. Concerta must be discontinued as soon as possible if serotonin syndrome is suspected.
Because a predominant action of methylphenidate is to increase extracellular dopamine levels, Concerta may be associated with pharmacodynamic interactions when co-administered with some antipsychotics. Caution is warranted in patients receiving both Concerta and an antipsychotic, as extrapyramidal symptoms could emerge when these drugs are administered concomitantly or when adjusting the dosage of one or both drugs.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Dietary administration of methylphenidate to male and female mice at doses up to 150-160 mg/kg/day did not impair fertility in an 18 week continuous breeding study in which both parents and offspring were treated. This dose was approximately 7 to 16-fold the maximal recommended human dose on a mg/m2 basis.

Women of child-bearing potential.

Methylphenidate should not be prescribed for women of childbearing age unless, in the opinion of the physician, the potential benefits outweigh the possible risks (see Use in pregnancy).
(Category D)
The safety of methylphenidate for use during human pregnancy has not been established. Cases of fetal cardiac malformations have been identified in large observational studies.
Methylphenidate should not be prescribed for pregnant women unless, in opinion of the physician, the potential benefits outweigh the possible risks.

Reproductive animal toxicity.

Oral administration of methylphenidate to rabbits during the period of organogenesis has produced teratogenic effects at doses of 200 mg/kg/day, associated with systemic exposure (plasma AUC) approximately 5-fold that in humans receiving the maximal recommended dose. The exposure at the no effect dose in rabbits (60 mg/kg/day) was less than human exposure. Teratogenic effects were not seen in rats at oral methylphenidate doses up to 75 mg/kg/day, associated with systemic exposure of approximately 20-fold that in humans receiving the maximal dose. Oral administration of methylphenidate to rats from early pregnancy until weaning was associated with maternal toxicity, reduced offspring weight and marginal alterations in neuromotor performance in offspring at a maternal dose of 30 mg/kg/day, approximately 3 to 6-fold the maximum recommended clinical dose on a mg/m2 basis. Oral administration of methylphenidate to juvenile male and female rats at doses of 12.5 mg/kg/day or greater from weaning through mating, pregnancy and lactation until offspring weaning was associated with reduced bodyweight gain and motor activity in males as well as reduced offspring weight and postnatal survival. The systemic exposure (plasma AUC) was 1 to 3-fold that expected in adults or children given the maximum recommended clinical dose, while the exposure at the no effect dose was less than clinical exposure.
Oral administration of methylphenidate to rats from early pregnancy until weaning was associated with maternal toxicity, reduced offspring weight and marginal alterations in neuromotor performance in offspring at a maternal dose of 30 mg/kg/day, approximately 3 to 6-fold the maximum recommended clinical dose on a mg/m2 basis. Oral administration of methylphenidate to juvenile male and female rats at doses of 12.5 mg/kg/day or greater from weaning through mating, pregnancy and lactation until offspring weaning was associated with reduced body weight gain and motor activity in males as well as reduced offspring weight and postnatal survival. The systemic exposure (plasma AUC) was 1 to 3-fold that expected in adults or children given the maximum recommended clinical dose, while the exposure at the no effect dose was less than clinical exposure.
Methylphenidate and/or its metabolites are excreted in milk in lactating rats at similar levels to plasma level.
Methylphenidate has been detected in human milk. Caution should be exercised if Concerta is administered to a nursing woman; infants should be monitored in terms of irritability, sleeping difficulties and inadequate weight gain. The long-term neurodevelopmental effects of the maternal use of Concerta on the breastfed infant are unknown.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

Double blind data - adverse events reported at ≥ 1% frequency.

Adverse events (AEs) in either the paediatric or adult double blind studies (Table 2 and Table 3) may be relevant for both patient populations.

Paediatric patients.

The safety of Concerta was evaluated in 639 paediatric patients (children and adolescents) with ADHD who participated in 4 placebo controlled, double blind clinical trials. Three of the studies were conducted in children aged 6-12 years of age: two were crossover studies in which patients received Concerta (doses of either 18 mg, 36 mg or 54 mg/day), immediate release methylphenidate and placebo for each of 7 days. The third study was a parallel group comparison in which patients were randomised to Concerta (doses of either 18 mg, 36 mg or 54 mg/day), immediate release methylphenidate or placebo for 28 days. In a fourth study, adolescents aged 13-18 years, receiving Concerta doses of 18 mg, 36 mg, 54 mg or 72 mg/day were randomised into a two week placebo controlled, double blind phase following an open label 4 weeks titration phase. The information presented in this section was derived from pooled data.
Adverse events (AEs) reported by ≥ 1% of Concerta treated children and adolescents patients in these trials are shown in Table 2.
The majority of AEs were mild to moderate in severity.

Adult patients.

The safety of Concerta was evaluated in 905 adult subjects with ADHD who participated in 3 placebo controlled, double blind clinical trials. The information presented in this section was derived from pooled data.
Adverse events (AEs) reported by ≥ 1% of Concerta treated adult subjects in these trials are shown in Table 3.
The majority of AEs were mild to moderate in severity.

Open label data - adverse drug reactions reported at ≥ 1% frequency.

The safety of Concerta was evaluated in 3782 paediatric and adult patients with ADHD who participated in 12 open label clinical trials. The information presented in this section was derived from pooled data.
Adverse drug reactions (ADRs) reported by ≥ 1% of Concerta treated subjects in these trials and not listed in Table 2 and Table 3 are shown in Table 4.
The majority of ADRs were mild to moderate in severity.

Double blind and open label data - adverse drug reactions reported at < 1% frequency.

Additional ADRs that occurred in < 1% of Concerta treated paediatric and adult patients in the double blind and open label clinical datasets are listed in Table 5.
The majority of ADRs were mild to moderate in severity.

Postmarketing data.

Adverse events first identified as ADRs during postmarketing experience with Concerta are included in Table 6. The frequencies are provided according to the following convention. Very common ≥ 1/10. Common ≥ 1/100 and < 1/10. Uncommon ≥ 1/1000 and < 1/100. Rare ≥ 1/10,000 and < 1/1000. Very rare < 1/10,000 including isolated reports.
Adverse events reported since market introduction in patients taking methylphenidate include suicide, suicide attempt and suicide ideation. No causal relationship between methylphenidate and these events have been established.

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 www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Concerta is administered orally once daily and should be taken in the morning.
Concerta must be swallowed whole with the aid of liquids and must not be chewed, divided or crushed.
Concerta may be administered with or without food.
Treatment should be started on the lowest possible dose.

Children (greater than 6 years old) and adolescents.

Dosage may be adjusted in 9 mg increments between 18 mg and 36 mg and consecutively in an 18 mg increment to a maximum of 54 mg/day taken once daily in the morning. In general, dosage adjustment may proceed at approximately weekly intervals.

Adults.

Dosage can be adjusted from an initial dose of 18 or 36 mg/day in 18 mg increments to a maximum of 72 mg/day taken once daily in the morning. In general, dosage adjustment may proceed at approximately weekly intervals.
Patients respond at different dose levels and Concerta must be titrated to effect on an individual patient needs and response basis.
If treatment is restarted following discontinuation then dosing will need to be re-titrated rather than restarted from the previous dose. This approach should be considered for a discontinuation period of greater than 3 months.
Patients should be reviewed at least annually to assess if there is an ongoing requirement for treatment with Concerta. Blood pressure and cardiovascular status should also be regularly reviewed.

Patients new to methylphenidate.

The recommended starting dose of Concerta for patients who are not currently taking methylphenidate, or for patients who are on stimulants other than methylphenidate, is 18 mg once daily.

Patients currently using methylphenidate.

The recommended dose of Concerta for patients who are currently taking methylphenidate three times daily at doses of 15 - 60 mg per day is provided in Table 1.
Clinical judgement should be used when selecting the dose for patients currently taking methylphenidate in other regimens. If improvement is not observed after appropriate dosage adjustments over a one month period, the drug should be discontinued.

Use in infants and children.

Use of Concerta in patients under six years of age has not been studied in controlled trials. Concerta should not be used in patients under six years old.

Use in elderly.

Use of Concerta in patients over 65 years of age has not been studied in controlled trials.

4.7 Effects on Ability to Drive and Use Machines

Stimulants may impair the ability of the patient to operate potentially hazardous machinery or vehicles. Patients should be cautioned accordingly until they are reasonably certain that Concerta does not adversely affect their ability to engage in such activities.

4.9 Overdose

The prolonged release of methylphenidate from Concerta should be considered when treating patients with overdose.

Signs and symptoms.

Signs and symptoms of Concerta overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: vomiting, agitation, muscle twitching, convulsions, grand mal convulsions, confusional state, hallucinations (auditory and/or visual), hyperhidrosis, headache, pyrexia, tachycardia, palpitations, heart rate increased, sinus arrhythmias, hypertension, mydriasis and dry mouth.

Treatment.

Treatment consists of appropriate supportive measures. The patient must be protected against self injury and against external stimuli that would aggravate overstimulation already present. The efficacy of activated charcoal has not been established. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia.
Efficacy of peritoneal dialysis or extracorporeal haemodialysis for Concerta overdosage has not been established.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S8.

6 Pharmaceutical Particulars

6.1 List of Excipients

Concerta tablets contain the following inactive ingredients: butylated hydroxytoluene, carnauba wax, cellulose acetate, hypromellose, lactose monohydrate, phosphoric acid, poloxamer, polyethylene oxide, povidone, sodium chloride, stearic acid, succinic acid, iron oxide black, iron oxide yellow, iron oxide red (27 mg and 56 mg tabs only), Opacode WB monograming ink NS-78-17715 Black (PI 4424), Opadry complete film coating system YS-1-19025-A Clear (PI 4421), Opadry II complete film coating system YS-30-12788-A Yellow (PI 10244) (18 mg tabs only), Opadry II complete film coating system Y-30-17528 Gray (PI 12131) (27 mg tabs only), Opadry II Y-30-18037 White (PI 3667) (36 mg tabs only), Opadry II complete film coating system Y-30-15567-A Red (PI 10245) (54 mg tabs only).

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Keep container tightly closed.

6.5 Nature and Contents of Container

Concerta tablets are supplied in HDPE bottles containing silica gel desiccant of 28, 30, 56, 60 or 100 tablets.

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