Data Sheet
Concerta®
Methylphenidate hydrochloride extended release tablets.
name of MEDICINE
CONCERTA® Extended - Release Tablets
Methylphenidate hydrochloride
DESCRIPTION
Methylphenidate hydrochloride is the racemic mixture of d,l methyl α-phenyl-2-piperidineacetate hydrochloride. The d-isomer is pharmacologically more active than the l-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. It has the following structural formula:
C14H19NO2.HCl MW 269.77
CAS-298-59-9 (methylphenidate hydrochloride)
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.
CONCERTA tablets contain the following inactive ingredients: butylated hydroxytoluene, carnauba wax, cellulose acetate, hypromellose, lactose, Opacode black NS-78-17715, Opadry clear YS-1-19025-A, phosphoric acid, poloxamer, polyethylene oxide, povidone, sodium chloride, stearic acid, succinic acid and synthetic iron oxides. 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.
Pharmacology
Pharmacodynamics
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.
Pharmacokinetics
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 ng/mL, Tmax 6.8 + 1.8 h, AUC∞ 41.8 + 13.9 ngh/mL and t1/2 3.5 + 0.4 h. 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 AUC0-∞ of d-methylphenidate were proportional to dose, whereas l-methylphenidate Cmax and AUC0-∞ 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 18-mg CONCERTA 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.
In a multiple dose study in adolescent ADHD patients aged 13 to 16 administered their prescribed dose (18 to 72 mg/day) of CONCERTA, mean Cmax and AUCTAU of methylphenidate increased proportionally with respect to dose.
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.
Elimination: 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.
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 significantly more effective than placebo in improving CAARS (Conners' Adult ADHD Rating Scale) total scores at double-blind end point 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 significantly superior to placebo.
INDICATIONS
CONCERTA is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).
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.
CONTRAINDICATIONS
CONCERTA is contraindicated:
- in patients with known hypersensitivity to methylphenidate or any inactive ingredient used in this product (see DESCRIPTION);
- in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms;
- in patients with glaucoma;
- in patients with a family history or diagnosis of Tourette's syndrome;
- during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of a monoamine oxidase inhibitor (hypertensive crises may result);
- in patients with hyperthyroidism;
- in patients with severe angina pectoris;
- in patients with cardiac arrhythmia.
PRECAUTIONS
Use with caution in the following circumstances
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.
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.
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.
Seizures: There is some clinical evidence that methylphenidate may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and very rarely in absence of history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued.
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.
Visual Disturbance: Symptoms of visual disturbances have been encountered in rare cases. Difficulties with accommodation and blurring of vision have been reported.
Sudden Death and Pre-existing Structural Cardiac Abnormalities
Although a causal relationship has not been established, sudden death has been reported in patients with structural cardiac abnormalities treated with ADHD drugs with stimulant effects. These treatments should be used with caution in patients with structural cardiac abnormalities.
Hypertension and Cardiovascular Conditions
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.
Aggression
Aggressive behaviour or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behaviour or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behaviour or hostility.
Haematologic Monitoring
Periodic full blood count, differential and platelet counts are advised during prolonged therapy.
Use in patients with 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 patients with hepatic impairment
There is no experience with the use of CONCERTA in patients with hepatic insufficiency.
Use in children
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 (ie 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.
Carcinogenicity, mutagenicity, impairment of fertility
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 3-8 fold the maximal recommended clinical dose on a mg/m2 basis. There was no increase in tumours at 30-40 mg/kg/day (approximately 1-4 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 3-8 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 4-10 fold the maximal recommended clinical dose on a mg/m2 basis).
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.
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 7-16 fold the maximal recommended human dose on a mg/m2 basis.
Use in pregnancy
Category B3
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 5-6 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 21-25 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 3-6 fold the maximum recommended clinical dose on a mg/m2 basis.
The safety of methylphenidate for use during human pregnancy has not been established, and no studies are available on the use of CONCERTA in pregnant women. CONCERTA should be used during pregnancy only if the potential benefit justifies the potential risk.
Use in lactation
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 3-6 fold the maximum recommended clinical dose on a mg/m2 basis.
It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if CONCERTA is administered to a nursing woman.
Interactions with other drugs
Because of possible effects on blood pressure, CONCERTA should be used cautiously with pressor agents.
Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g. phenobarbital, phenytoin, primidone), and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate.
Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systematically evaluated.
Effect on ability to drive or operate machinery
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.
Long-term Suppression of Growth
Sufficient data on the safety of long-term use of methylphenidate in children are not yet available. Although a causal relationship has not been established, suppression of growth (ie 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.
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 the their stool something that looks like a tablet.
aDVERSE EFFECTS
Clinical Trial Data
Double-Blind Data - Adverse Drug Reactions Reported at ≥ 1% Frequency
Adverse Drug Reactions (ADRs) in either the paediatric or adult double-blind studies (Table 1 and 2) 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. The information presented in this section was derived from pooled data.
Adverse Drug Reactions (ADRs) reported by ≥ 1% of CONCERTA-treated children and adolescents and more frequently than placebo in these trials are shown in Table 1.
| Table 1. Adverse Drug Reactions Reported by ≥ 1% of CONCERTA-Treated children and adolescents and More Frequently than Placebo in 4 Placebo-Controlled, Double-Blind Clinical Trials | ||
|---|---|---|
| System/Organ Class Adverse Drug Reaction |
CONCERTA (n=321) % |
Placebo (n=318) % |
| Infections and Infestations | ||
| Nasopharyngitis | 2.8 | 2.2 |
| Psychiatric Disorders | ||
| Insomnia | 2.8 | 0.3 |
| Nervous System Disorders | ||
| Headache | 10.6 | 11.9 |
| Dizziness | 1.9 | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | ||
| Cough | 1.9 | 0.3 |
| Pharyngolaryngeal Pain | 1.2 | 0.9 |
| Gastrointestinal Disorders | ||
| Abdominal Pain upper | 5.9 | 3.8 |
| Vomiting | 2.8 | 1.6 |
| General Disorders and Administration Site Conditions | ||
| Pyrexia | 2.2 | 0.9 |
The majority of ADRs were mild to moderate in severity.
Adult Patients
The safety of CONCERTA was evaluated in 627 adult patients with ADHD who participated in 2 placebo-controlled, double-blind clinical trials. The information presented in this section was derived from pooled data.
Adverse Drug Reactions (ADRs) reported by ≥ 1% of CONCERTA-treated patients in these trails are shown in Table 2.
| Table 2. Adverse Drug Reactions Reported by ≥ 1% of CONCERTA-Treated Adult Patients in 2 Placebo-Controlled, Double-Blind Clinical Trials | ||
|---|---|---|
| System/Organ Class Adverse Drug Reaction |
CONCERTA (n=415) % |
Placebo (n=212) % |
| Infections and Infestations | ||
| Upper respiratory tract infection | 2.2 | 0.9 |
| Metabolism and Nutrition Disorders | ||
| Decreased appetite | 25.3 | 6.6 |
| Anorexia | 1.7 | 0 |
| Psychiatric Disorders | ||
| Insomnia | 12.3 | 6.1 |
| Anxiety | 8.2 | 2.4 |
| Initial insomnia | 4.3 | 2.8 |
| Depressed mood | 3.9 | 1.4 |
| Nervousness | 3.1 | 0.5 |
| Restlessness | 3.1 | 0 |
| Agitation | 2.2 | 0.5 |
| Aggression | 1.7 | 0.5 |
| Bruxism | 1.7 | 0.5 |
| Depression | 1.7 | 0.9 |
| Libido decreased | 1.7 | 0.5 |
| Affect lability | 1.4 | 0.9 |
| Confusional state | 1.2 | 0.5 |
| Tension | 1.2 | 0.5 |
| Nervous System Disorders | ||
| Headache | 22.2 | 15.6 |
| Dizziness | 6.7 | 5.2 |
| Tremor | 2.7 | 0.5 |
| Paresthesia | 1.2 | 0 |
| Sedation | 1.2 | 0 |
| Tension headache | 1.2 | 0.5 |
| Eye Disorders | ||
| Vision blurred | 1.7 | 0.5 |
| Ear and Labyrinth Disorders | ||
| Vertigo | 1.7 | 0 |
| Cardiac Disorders | ||
| Tachycardia | 4.8 | 0 |
| Palpitations | 3.1 | 0.9 |
| Respiratory, Thoracic and Mediastinal Disorders | ||
| Pharyngolaryngeal pain | 1.7 | 1.4 |
| Gastrointestinal Disorders | ||
| Dry mouth | 14.0 | 3.8 |
| Nausea | 12.8 | 3.3 |
| Dyspepsia | 2.2 | 0.9 |
| Vomiting | 1.7 | 0.5 |
| Constipation | 1.4 | 0.9 |
| Skin and Subcutaneous Tissue Disorders | ||
| Hyperhidrosis | 5.1 | 0.9 |
| Musculoskeletal and Connective Tissue Disorders | ||
| Muscle tightness | 1.9 | 0 |
| General Disorders and Administration Site Conditions | ||
| Irritability | 5.8 | 1.4 |
| Investigations | ||
| Weight decreased | 6.5 | 3.3 |
The majority of ADRs were mild to moderate in severity.
Open-Label Data - Adverse Drug Reactions Reported at ≥ 1% Frequency
The safety of CONCERTA was evaluated in 3590 paediatric and adult patients with ADHD who participated in 11 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 patients in these trials and not listed in Table 1 and 2 are shown in Table 3
| Table 3. Adverse Drug Reactions Reported by ≥ 1% of CONCERTA-Treated Patients in 11 Open-Label Clinical Trials | |
|---|---|
|
System/Organ Class |
CONCERTA (n=3590) % |
| Gastrointestinal Disorders | |
| Diarrhea | 1.8 |
| Abdominal pain | 1.1 |
| Stomach discomfort | 1.0 |
| Skin and Subcutaneous Disorders | |
| Rash | 1.3 |
| General Disorders and Administration Site Conditions | |
| Fatigue | 2.0 |
| Feeling jittery | 1.0 |
| Investigations | |
| Blood pressure increased | 1.8 |
| Heart rate increased | 1.4 |
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 4.
| Table 4. Adverse Drug Reactions Reported by <1% of CONCERTA- Treated Pediatric and Adult Patients in Either Double-Blind or Open-Label Clinical Trials |
|---|
| Blood and Lymphatic System Disorders |
| Leukopenia |
| Psychiatric Disorders |
| Anger, Hypervigilance, Mood altered, Mood swings, Sleep disorder, Tearfulness, Tic |
| Nervous System Disorders |
| Lethargy, Somnolence, Psychomotor hyperactivity |
| Eye Disorders |
| Dry eyes |
| Vascular Disorders |
| Hypertension |
| Respiratory, Thoracic and Mediastinal Disorders |
| Dyspnea |
| Skin and Subcutaneous Tissue Disorders |
| Rash-Macular |
| Reproductive System and Breast Disorders |
| Erectile dysfunction |
| Investigations |
| Cardiac murmur |
The majority of ADRs were mild to moderate in severity.
Postmarketing Data
ADRs identified during postmarketing experience with CONCERTA are included in Table 5. The frequencies are provided according to the following convention:
Very common ≥ 1/10
Common ≥1/100 to <1/10
Uncommon ≥1/1,000 to <1/100
Rare ≥1/10,000 to <1/1,000
Very rare <1/10,000, including isolated reports
| Table 5. Adverse Drug Reactions Identified During Postmarketing Experience with CONCERTA by Frequency Category Estimated from Spontaneous Reporting Rates | |
|---|---|
| Blood and Lymphatic System Disorders | |
| Very rare | Pancytopenia,Thrombocytopenia, Thrombocytopenic Purpura |
Immune System Disorders |
|
| Rare | Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions and Exanthemas NEC |
Psychiatric Disorders |
|
| Very rare | Disorientation, Hallucinations, Hallucinations Auditory, Hallucinations Visual, Mania |
Nervous System Disorders |
|
| Convulsions, Grand Mal Convulsions | |
Eye Disorders |
|
| Very rare | Diplopia, Mydriasis, Visual Disturbance |
Cardiac Disorders |
|
| Very rare | Angina Pectoris, Bradycardia, Extrasystoles, Supraventricular Tachycardia, Ventricular Extrasystoles |
Vascular Disorders |
|
| Very rare | Raynaud's Phenomenon |
Skin and Subcutaneous Tissue Disorders |
|
| Very rare | Alopecia, Erythema, Hyperhidrosis, Pruritus, Pruritus Generalized |
Musculoskeletal, Connective Tissue and Bone Disorders |
|
| Very rare | Arthralgia, Myalgia, Muscle Twitching |
General Disorders and Administration Site Conditions |
|
| Rare | Therapeutic Response Decreased |
| Very rare | Chest Pain, Chest Discomfort, Drug Effect Decreased, Hyperpyrexia |
Investigations |
|
| Rare | Weight Decreased |
| Very rare | Blood Alkaline Phosphatase Increased, Blood Bilirubin Increased, Hepatic Enzyme Increased, Platelet Count Decreased, White Blood Cell Count Abnormal |
DOSAGE AND 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 (over 6 years of age) and adolescents:
Dosage may be adjusted in 9 mg increments between 18 mg and 36mg and consecutively in 18 mg increments to a maximum of 54 mg/day for children aged between 6-12 years and to a maximum of 72 mg/day for adolescents aged between 13-18 years. 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 18mg increments to a maximum of 72mg/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. A maximum dose of 108 mg/day have been included in clinical trials (see CLINICAL TRIALS).
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 for children and adolescents and 18 or 36 mg once daily for adults.
Patients Currently Using Methylphenidate: The recommended dose of CONCERTA for patients who are currently taking methylphenidate two or three times daily at doses of 10 - 60 mg per day is provided in Table 6.
Table 6: Recommended dose conversions from methylphenidate regimens to CONCERTA
| Previous methylphenidate daily dose | Recommended CONCERTA starting dose |
|---|---|
| 5 mg methylphenidate three times daily | 18 mg every morning |
| 10 mg methylphenidate three times daily | 36 mg every morning |
| 15 mg methylphenidate three times daily | 54 mg every morning |
| 20 mg methylphenidate three times daily | 72 mg every morning |
Clinical judgement should be used when selecting the dose for patients currently taking methylphenidate in other regimens. Daily dosage above 54 mg is not recommended for children aged between 6-12 years. Daily dosage above 72 mg is not recommended for adolescents aged between 13-18 years.
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.
OVERDOSAGE
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, convulsion, grand mal convulsion, confusional state, hallucination (auditory and/or visual), hyperhidrosis, headache, pyrexia, tachycardia, palpitations, heart rate increased, sinus arrhythmia, 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. Gastric contents may be evacuated by gastric lavage as indicated. Before performing gastric lavage, control agitation and seizures if present and protect the airway. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for pyrexia.
Efficacy of peritoneal dialysis or extracorporeal haemodialysis for CONCERTA overdosage has not been established.
PRESENTATION
CONCERTA 18 mg are yellow capsule-shaped tablets, with "alza 18" 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 27 mg are grey capsule-shaped tablets, with "alza 27" 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.
CONCERTA tablets are supplied in HDPE bottles of 30 containing silica gel desiccant.
MEDICINE CLASSIFICATION
Controlled Drug - B2
STORAGE
Store below 25°C. Keep container tightly closed.
SHELF LIFE
3 years
Name and Address
New Zealand Sponsor
Janssen-Cilag (New Zealand) Ltd
Ground Floor, 105 Carlton Gore Road, Newmarket
Auckland, NEW ZEALAND
Tel: (09) 523 8700
Date of Preparation
2 February 2009