WARNINGS
DEPRESSION
CONCERTA® should not be used to treat severe depression.
FATIGUE
CONCERTA® should not be used for the prevention or treatment of normal fatigue states.
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.
PSYCHOSIS
Clinical experience suggests that in psychotic patients, administration of methylphenidate may exacerbate symptoms of behavior disturbance and thought disorder.
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
Because the CONCERTA® tablet is nondeformable and does not appreciably change in shape in the GI tract, CONCERTA® should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel's diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable controlled-release formulations. Due to the controlled-release design of the tablet, CONCERTA® should only be used in patients who are able to swallow the tablet whole (see PRECAUTIONS: Information for Patients).
HYPERTENSION AND OTHER CARDIOVASCULAR CONDITIONS
Use cautiously in patients with hypertension. Blood pressure should be monitored at appropriate intervals in patients taking CONCERTA®, especially patients with hypertension. In the laboratory classroom clinical trials (Studies 1 and 2), both CONCERTA® and methylphenidate tid increased resting pulse by an average of 2-6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1-4 mm Hg during the day, relative to placebo. Therefore, caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, eg, those with preexisting hypertension, heart failure, recent myocardial infarction, or hyperthyroidism.
VISUAL DISTURBANCE
Symptoms of visual disturbances have been encountered in rare cases. Difficulties with accommodation and blurring of vision have been reported.
USE IN CHILDREN UNDER SIX YEARS OF AGE
CONCERTA® should not be used in children under six years, since safety and efficacy in this age group have not been established.
DRUG DEPENDENCE
CONCERTA® should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. 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.
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PRECAUTIONS
HEMATOLOGIC MONITORING
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
INFORMATION FOR PATIENTS
Patients should be informed that CONCERTA® should 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.
Patient information is printed at the end of this insert. To assure safe and effective use of CONCERTA®, the information and instructions provided in the patient information section should be discussed with patients.
DRUG INTERACTIONS
CONCERTA® should not be used in patients being treated (currently or within the proceeding 2 weeks) with MAO inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors).
Because of possible effects on blood pressure, CONCERTA® should be used cautiously with vasopressor agents.
Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (eg, 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.
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and 4 times the maximum recommended human dose of CONCERTA® on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown.
Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5 times the maximum recommended human dose of CONCERTA® on a mg/kg and mg/m2 basis, respectively.
In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate.
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay.
Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended human dose of CONCERTA® on a mg/kg and mg/m2 basis, respectively.
PREGNANCY: TERATOGENIC EFFECTS
Pregnancy Category C: Methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 100 times and 40 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively.
A reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day, approximately 15-fold and 3-fold the maximum recommended human dose of CONCERTA® on a mg/kg and mg/m2 basis, respectively. The approximate plasma exposure to methylphenidate plus its main metabolite PPA in pregnant rats was 2 times that seen in trials in volunteers and patients with the maximum recommended dose of CONCERTA® based on the AUC.
The safety of methylphenidate for use during human pregnancy has not been established. There are no adequate and well-controlled studies in pregnant women. CONCERTA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NURSING MOTHERS
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.
PEDIATRIC USE
The safety and efficacy of CONCERTA® in children under 6 years old have not been established. Long-term effects of methylphenidate in children have not been well established (see WARNINGS).
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