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RITALIN

Submitted by on Nisan 6, 2007 – 2:42 pm | 3.467 Kez Görüntülendi

Prescribing Information
DESCRIPTION
hydrochloride, USP, is a mild central nervous system (CNS) , available as tablets of 5, 10, and 20 mg for oral administration; Ritalin-SR is available as sustained-release tablets of 20 mg for oral administration. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is Methylphenidate hydrochloride USP is a white, odorless, fine 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. Its molecular weight is 269.77.
Inactive Ingredients. Ritalin tablets: D&C Yellow No. 10 (5-mg and 20-mg tablets), FD&C Green No. 3 (10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg tablets), sucrose, talc, and tragacanth (20-mg tablets).
Ritalin-SR tablets: Cellulose compounds, cetostearyl alcohol, lactose, magnesium stearate, mineral oil, povidone, titanium dioxide, and zein.
CLINICAL PHARMACOLOGY
Ritalin is a mild central nervous system stimulant.
The mode of action in man is not completely understood, but Ritalin presumably activates the brain stem arousal system and cortex to produce its stimulant effect. There is neither specific evidence which clearly establishes the mechanism whereby Ritalin produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system.
Ritalin in the SR tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the SR tablet compared to the Ritalin tablet, measured by the urinary excretion of Ritalin major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49%-168%) in children and 101% (85%-152%) in adults. The time to peak rate in children was 4.7 hours (1.3-8.2 hours) for the SR tablets and 1.9 hours (0.3-4.4 hours) for the tablets. An average of 67% of SR tablet dose was excreted in children as compared to 86% in adults.
In a clinical study involving adult subjects who received SR tablets, plasma concentrations of Ritalin’s major metabolite appeared to be greater in females than in males. No gender differences were observed for Ritalin plasma concentration in the same subjects.
INDICATIONS
,
Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms being used to describe the behavioral syndrome below include: , , , . Ritalin is indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted.
Special Diagnostic Considerations
Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources.
Characteristics commonly reported include: chronic history of short attention span, distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity; minor neurological signs and abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of one or more of these characteristics.
Drug treatment is not indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is generally necessary. 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 child’s symptoms.
CONTRAINDICATIONS
Marked anxiety, tension, and agitation are contraindications to Ritalin, since the drug may aggravate these symptoms. Ritalin is contraindicated also in patients known to be hypersensitive to the drug, in patients with glaucoma, and in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome.
Ritalin is contraindicated 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).
WARNINGS
Serious Cardiovascular Events
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 death, 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.
Hypertension and Other Cardiovascular Conditions
Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.
Assessing Cardiovascular Status in Patients being Treated with Stimulant
Medications
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 (e.g., electrocardiogram and echocardiogram). 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.
Psychiatric Adverse Events
Pre-Existing Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.
Bipolar Illness
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. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
Emergence of New Psychotic or Manic Symptoms
Treatment emergent psychotic or manic symptoms, e. g., hallucinations, delusional thinking, or mania in children and adolescents 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. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients.
Aggression
Aggressive behavior 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 behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility.
Long-Term Suppression of Growth
Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication 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 a 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.
Seizures
There is some clinical evidence that stimulants 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 patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued.
Visual Disturbance
Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
Use in Children Under Six Years of Age
Ritalin should not be used in children under 6 years, since safety and efficacy in this age group have not been established.
Drug Dependence
Ritalin 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.
PRECAUTIONS
Patients with an element of agitation may react adversely; discontinue therapy if necessary.
Periodic CBC, differential, and platelet counts are advised during prolonged therapy. Drug treatment is not indicated in all cases of this behavioral syndrome and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe Ritalin should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics.
When these symptoms are associated with acute stress reactions, treatment with Ritalin is usually not indicated.
Drug Interactions
Ritalin should not be used in patients being treated (currently or within the proceeding two weeks) with MAO Inhibitors (see CONTRAINDICATIONS, Monoamine Oxidase Inhibitors). Because of possible effects on blood pressure, Ritalin should be used cautiously with pressor agents.
Methylphenidate may decrease the effectiveness of drugs used to treat hypertension. Methylphenidate is metabolized primarily to ritalinic acid by de-esterification and not through oxidative pathways.
Human pharmacologic studies have shown that racemic methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine). Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentration (or, in case of coumarin, coagulation times), when initiating or discontinuing 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/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 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 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 60-74 mg/kg/day of methylphenidate. Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in 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 (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay.
Methlyphenidate 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 dose on a mg/kg and mg/m2 basis, respectively.
PREGNANCY
Pregnancy Category C
In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75
and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased
incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40
times the maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for
embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis).
Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin 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 Ritalin is administered to a nursing woman.
Pediatric Use
Ritalin should not be used in children under six years of age (see WARNINGS). In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
ADVERSE REACTIONS
Nervousness and insomnia are the most common adverse reactions but are usually controlled by
reducing dosage and omitting the drug in the afternoon or evening. Other reactions include
hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema
multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura);
anorexia; nausea; dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse
changes, both up and down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss
during prolonged therapy. There have been rare reports of Tourette’s syndrome. Toxic psychosis has
been reported. Although a definite causal relationship has not been established, the following have
been reported in patients taking this drug: instances of abnormal liver function, ranging from
transaminase elevation to hepatic coma; isolated cases of cerebral arteritis and/or occlusion;
leukopenia and/or anemia; transient depressed mood; aggressive behavior; a few instances of scalp
hair loss. Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed above may also occur.
DOSAGE AND ADMINISTRATION
Dosage should be individualized according to the needs and responses of the patient.
Adults
Tablets: Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In others, 10 to 15 mg daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m.
SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or chewed.
Children (6 years and over)
Ritalin should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is not recommended.
If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.
Tablets: Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg weekly.
SR Tablets: Ritalin-SR tablets have a duration of action of approximately 8 hours. Therefore, Ritalin-SR tablets may be used in place of Ritalin tablets when the 8-hour dosage of Ritalin-SR corresponds to the titrated 8-hour dosage of Ritalin. Ritalin-SR tablets must be swallowed whole and never crushed or chewed.
If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug.
Ritalin should be periodically discontinued to assess the child’s condition. Improvement may be sustained when the drug is either temporarily or permanently discontinued. Drug treatment should not and need not be indefinite and usually may be discontinued after puberty.
OVERDOSAGE
Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice.
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. In the presence of severe intoxication, use a carefully titrated dosage of a short-acting barbiturate before performing gastric lavage. 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 hyperpyrexia. Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Ritalin overdosage has not been established.
HOW SUPPLIED
Tablets 5 mg – round, yellow (imprinted CIBA 7)
Bottles of 100…………………………………………………………………NDC
0078-0439-05
Tablets 10 mg – round, pale green, scored (imprinted CIBA 3)
Bottles of 100…………………………………………………………………NDC
0078-0440-05
Tablets 20 mg – round, pale yellow, scored (imprinted CIBA 34) Bottles of 100…………………………………………………………………NDC 0078-0441-05 Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from light.
Dispense in tight, light-resistant container (USP).
SR Tablets 20 mg – round, white, coated (imprinted CIBA 16) Bottles of 100………………………………………………………………NDC 0078-0442-05 Note: SR Tablets are color-additive free.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture.
Dispense in tight, light-resistant container (USP).
T2006-56
REV: JUNE 2006
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T2006-62
Ritalin LA®
(methylphenidate hydrochloride)
extended-release capsules
Rx only
Prescribing Information
DESCRIPTION
Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is an extended-release formulation of methylphenidate with a bi-modal release profile. Ritalin LA® uses the proprietary SODAS® (Spheroidal Oral Drug Absorption System) technology. Each bead-filled Ritalin LA capsule contains half the dose as immediate-release beads and half as enteric-coated, delayed-release beads, thus providing an immediate release of methylphenidate and a second delayed release of methylphenidate. Ritalin LA 10, 20, 30, and 40 mg capsules provide in a single dose the same amount of methylphenidate as dosages of 5, 10, 15, or 20 mg of Ritalin® tablets given b.i.d.
The active substance in Ritalin LA is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is Methylphenidate hydrochloride USP is a white, odorless, fine 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. Its molecular weight is 269.77. Inactive ingredients: ammonio methacrylate copolymer, black iron oxide (10 and 40 mg capsules only), gelatin, methacrylic acid copolymer, polyethylene glycol, red iron oxide (10 and 40 mg capsules only), sugar spheres, talc, titanium dioxide, triethyl citrate, and yellow iron oxide (10, 30, and 40 mg capsules only).
CLINICAL PHARMACOLOGY
Pharmacodynamics
Methylphenidate hydrochloride, the active ingredient in Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer.
Pharmacokinetics
Absorption
Ritalin LA produces a bi-modal plasma concentration-time profile (i.e., two distinct peaks approximately four hours apart) when orally administered to children diagnosed with ADHD and to healthy adults. The initial rate of absorption for Ritalin LA is similar to that of Ritalin tablets as shown by the similar rate parameters between the two formulations, i.e., initial lag time (Tlag), first peak concentration (Cmax1), and time to the first peak (Tmax1), which is reached in 1-3 hours. The mean time to the interpeak minimum (Tminip), and time to the second peak (Tmax2) are also similar for Ritalin LA given once daily and Ritalin tablets given in two doses 4 hours apart (see Figure 1 and Table 1), although the ranges observed are greater for Ritalin LA.
Ritalin LA given once daily exhibits a lower second peak concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and less peak and trough fluctuations than Ritalin tablets given in two doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1 and Table 1). The relative bioavailability of Ritalin LA given once daily is comparable to the same total dose of Ritalin tablets given in two doses 4 hours apart in both children and in adults.
Figure 1. Mean plasma concentration time-profile of methylphenidate after a
single dose of Ritalin LA® 40 mg q.d. and Ritalin® 20 mg given in two doses
four hours apart
Table 1. Mean ± SD and range of pharmacokinetic parameters of
methylphenidate after a single dose of Ritalin LA® and Ritalin® given in two
doses 4 hours apart
Population Children Adult Males
Formulation
Dose
Ritalin®
10 mg & 10 mg
Ritalin LA®
20 mg
Ritalin®
10 mg & 10 mg
Ritalin LA®
20 mg
N 21 18 9 8
Tlag (h) 0.24 ± 0.44 0.28 ± 0.46 1.0 ± 0.5 0.7 ± 0.2
0 – 1 0 – 1 0.7 – 1.3 0.3 – 1.0
Tmax1 (h) 1.8 ± 0.6 2.0 ± 0.8 1.9 ± 0.4 2.0 ± 0.9
1 – 3 1 – 3 1.3 – 2.7 1.3 – 4.0
Cmax1 (ng/mL) 10.2 ± 4.2 10.3 ± 5.1 4.3 ± 2.3 5.3 ± 0.9
4.2 – 20.2 5.5 – 26.6 1.8 – 7.5 3.8 – 6.9
Tminip (h) 4.0 ± 0.2 4.5 ± 1.2 3.8 ± 0.4 3.6 ± 0.6
4 – 5 2 – 6 3.3 – 4.3 2.7 – 4.3
Cminip (ng/mL) 5.8 ± 2.7 6.1 ± 4.1 1.2 ± 1.4 3.0 ± 0.8
3.1 – 14.4 2.9 – 21.0 0.0 – 3.7 1.7 – 4.0
Tmax2 (h) 5.6 ± 0.7 6.6 ± 1.5 5.9 ± 0.5 5.5 ± 0.8
5 – 8 5 – 11 5.0 – 6.5 4.3 – 6.5
Cmax2 (ng/mL) 15.3 ± 7.0 10.2 ± 5.9 5.3 ± 1.4 6.2 ± 1.6
6.2 – 32.8 4.5 – 31.1 3.6 – 7.2 3.9 – 8.3
AUC(0-∞) 102.4 ± 54.6 86.6 ± 64.0a 37.8 ± 21.9 45.8 ± 10.0
(ng/mL x h-1) 40.5 – 261.6 43.3 – 301.44 14.3 – 85.3 34.0 – 61.6
t1/2 (h) 2.5 ± 0.8 2.4 ± 0.7a 3.5 ± 1.9 3.3 ± 0.4
1.8 – 5.3 1.5 – 4.0 1.3 – 7.7 3.0 – 4.2
a N = 15
Dose Proportionality
After oral administration of Ritalin LA 20 mg and 40 mg capsules to adults there is a slight upward trend in the methylphenidate area under the curve (AUC) and peak plasma concentrations (Cmax1 and Cmax2).
Distribution
Binding to plasma proteins is low (10%-33%), and the apparent distribution volume at steady state with intravenous administration has been reported to be approximately 6 L/kg.
Metabolism
The absolute oral bioavailability of methylphenidate in children has been reported to be about 30% (range 10%-52%), suggesting pronounced presystemic metabolism. Biotransformation of methylphenidate is rapid and extensive leading to the main, de-esterified metabolite α-phenyl-2-piperidine acetic acid (ritalinic acid). Only small amounts of hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in plasma. Therapeutic activity is principally due to the parent compound.
Elimination
In studies with Ritalin LA and Ritalin tablets in adults, methylphenidate from Ritalin tablets is eliminated from plasma with an average half-life of about 3.5 hours, (range 1.3 – 7.7 hours). In children the average half-life is about 2.5 hours, with a range of about 1.5 – 5.0 hours. The rapid half-life in both children and adults may result in unmeasurable concentrations between the morning and mid-day doses with Ritalin tablets. No accumulation of methylphenidate is expected following multiple once a day oral dosing with Ritalin LA. The half-life of ritalinic acid is about 3-4 hours.
After oral administration of an immediate release formulation of methylphenidate, 78%-97% of the dose is excreted in the urine and 1%-3% in the feces in the form of metabolites within 48-96 hours. Only small quantities (<1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60%-86%), the remainder being accounted for by minor metabolites.
Food Effects
Administration times relative to meals and meal composition may need to be individually titrated.
When Ritalin LA was administered with a high fat breakfast to adults, Ritalin LA had a longer lag time until absorption began and variable delays in the time until the first peak concentration, the time until the interpeak minimum, and the time until the second peak. The first peak concentration and the extent of absorption were unchanged after food relative to the fasting state, although the second peak was approximately 25% lower. The effect of a high fat lunch was not examined.
There were no differences in the pharmacokinetics of Ritalin LA when administered with applesauce, compared to administration in the fasting condition. There is no evidence of dose dumping in the presence or absence of food.
For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered (see DOSAGE AND ADMINISTRATION).
Special Populations
Age: The pharmacokinetics of Ritalin LA was examined in 18 children with ADHD between 7 and 12 years of age. Fifteen of these children were between 10 and 12 years of age. The time until the between peak minimum, and the time until the second peak were delayed and more variable in children compared to adults. After a 20-mg dose of Ritalin LA, concentrations in children were approximately twice the concentrations observed in 18 to 35 year old adults. This higher exposure is almost completely due to the smaller body size and total volume of distribution in children, as apparent clearance normalized to body weight is independent of age.
Gender: There were no apparent gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults when administered Ritalin LA. Renal Insufficiency: Ritalin LA has not been studied in renally-impaired patients. Renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity. Hepatic Insufficiency: Ritalin LA has not been studied in patients with hepatic insufficiency. Hepatic insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.
CLINICAL STUDIES
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules was evaluated in a randomized, double-blind, placebo-controlled, parallel group clinical study in which 134 children, ages 6 to 12, with DSM-IV diagnoses of Attention Deficit Hyperactivity Disorder (ADHD) received a single morning dose of Ritalin LA in the range of 10-40 mg/day, or placebo, for up to 2 weeks. The doses used were the optimal doses established in a previous individual dose titration phase. In that titration phase, 53 of 164 patients (32%) started on a daily dose of 10 mg and 111 of 164 patients (68%) started on a daily dose of 20 mg or higher. The patient’s regular schoolteacher completed the Conners ADHD/DSM-IV Scale for Teachers (CADS-T) at baseline and the end of each week. The CADS-T assesses symptoms of hyperactivity and inattention. The change from baseline of the (CADS-T) scores during the last week of treatment was analyzed as the primary efficacy parameter. Patients treated with Ritalin LA showed a statistically significant improvement in symptom scores from baseline over patients who received placebo. (See Figure 2.) This demonstrates that a single morning dose of Ritalin LA exerts a treatment effect in ADHD.
Figure 2. CADS-T total subscale – Mean change from baseline*
INDICATIONS AND USAGE
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). The efficacy of Ritalin LA in the treatment of ADHD was established in one controlled trial of children aged 6 to 12 who met DSM-IV criteria for ADHD (see CLINICAL PHARMACOLOGY).
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. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go;” excessive talking; blurting answers; can’t wait turn; intrusive. The Combined Types requires both inattentive and hyperactive-impulsive criteria to be met.
Special Diagnostic Considerations
Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of the required number of DSM-IV characteristics.
Need for Comprehensive Treatment Program
Ritalin LA is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome.
Drug treatment may not be indicated for all children with this syndrome. Stimulants are not
intended for use in the child 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 child’s symptoms.
Long-Term Use
The effectiveness of Ritalin LA for long-term use, i.e., for more than 2 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Ritalin LA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
Agitation
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is contraindicated in marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.
Hypersensitivity to Methylphenidate
Ritalin LA is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product.
Glaucoma
Ritalin LA is contraindicated in patients with glaucoma.
Tics
Ritalin LA is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome. (See ADVERSE REACTIONS.)
Monoamine Oxidase Inhibitors
Ritalin LA is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result).
WARNINGS
Serious Cardiovascular Events
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 death, 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.
Hypertension and Other Cardiovascular Conditions
Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.
Assessing Cardiovascular Status in Patients being Treated with Stimulant
Medications
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 (e.g., electrocardiogram and echocardiogram). 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.
Psychiatric Adverse Events
Pre-Existing Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.
Bipolar Illness
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. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
Emergence of New Psychotic or Manic Symptoms
Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents 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. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients.
Aggression
Aggressive behavior 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 behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility.
Long-Term Suppression of Growth
Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication 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. In the double-blind placebo-controlled study of Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, the mean weight gain was greater for patients receiving placebo (+1.0 kg) than for patients receiving Ritalin LA (+0.1 kg). Published data are inadequate to determine whether chronic use of amphetamines may cause a 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.
Seizures
There is some clinical evidence that stimulants 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 patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued.
Visual Disturbance
Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
Use in Children Under Six Years of Age
Ritalin LA should not be used in children under six years of age, since safety and efficacy in this age group have not been established.
Drug Dependence
Ritalin LA 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.
PRECAUTIONS
Hematologic Monitoring
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
Information for Patients
Patient information is provided at the end of this insert. To assure safe and effective use of Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, the patient information should be discussed with patients.
Drug Interactions
Methylphenidate is metabolized primarily by de-esterification (nonmicrosomal hydrolytic esterases) to ritalinic acid and not through oxidative pathways. The effects of gastrointestinal pH alterations on the absorption of methylphenidate from Ritalin LA have not been studied. Since the modified release characteristics of Ritalin LA are pH dependent, the coadministration of antacids or acid suppressants could alter the release of methylphenidate.
Methylphenidate may decrease the hypotensive effect of guanethidine. Because of possible effects on blood pressure, methylphenidate 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 tricyclic drugs (e.g., imipramine, clomipramine, desipramine). 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 of methylphenidate 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/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 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 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 60-74 mg/kg/day of methylphenidate.
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in 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 (CHO) 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 dose on a mg/kg and mg/m2 basis, respectively.
Pregnancy
Pregnancy Category C
In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m2 basis), which was also maternally toxic.
The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the
MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout
pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was
decreased at the highest dose (4 times the MRHD on a mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis). Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin LA 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 Ritalin LA is administered to a nursing woman.
Pediatric Use
Long-term effects of methylphenidate in children have not been well established. Ritalin LA should not be used in children under six years of age (see WARNINGS). In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
ADVERSE REACTIONS
The clinical program for Ritalin LA® (methylphenidate hydrochloride) extended-release capsules consisted of six studies: two controlled clinical studies conducted in children with ADHD aged 6-12 years and four clinical pharmacology studies conducted in healthy adult volunteers. These studies included a total of 256 subjects; 195 children with ADHD and 61 healthy adult volunteers. The subjects received Ritalin LA in doses of 10-40 mg per day. Safety of Ritalin LA was assessed by evaluating frequency and nature of adverse events, routine laboratory tests, vital signs, and body weight.
Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and listings that follow, MEDRA terminology has been used to classify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
Adverse Events in a Double-Blind, Placebo-Controlled Clinical Trial with
Ritalin LA
Treatment-Emergent Adverse Events
A placebo-controlled, double-blind, parallel-group study was conducted to evaluate the efficacy and safety of Ritalin LA in children with ADHD aged 6-12 years. All subjects received Ritalin LA for up to 4 weeks, and had their dose optimally adjusted, prior to entering the double-blind phase of the trial. In the two-week double-blind treatment phase of this study, patients received either placebo or Ritalin LA at their individually-titrated dose (range 10 mg-40 mg).
The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.
Adverse events with an incidence >5% during the initial four-week single-blind Ritalin LA titration period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia.
Treatment-emergent adverse events with an incidence >2% among Ritalin LA-treated subjects, during the two-week double-blind phase of the clinical study, were as follows:
Preferred term Ritalin LA®
N=65
N (%)
Placebo
N=71
N (%)
Anorexia 2 (3.1) 0 (0.0)
Insomnia 2 (3.1) 0 (0.0)
Adverse Events Associated with Discontinuation of Treatment
In the two-week double-blind treatment phase of a placebo-controlled parallel-group study in children with ADHD, only one Ritalin LA-treated subject (1/65, 1.5%) discontinued due to an adverse event (depression).
In the single-blind titration period of this study, subjects received Ritalin LA for up to 4 weeks. During this period a total of six subjects (6/161, 3.7%) discontinued due to adverse events. The adverse events leading to discontinuation were anger (in 2 patients), hypomania, anxiety, depressed mood, fatigue, migraine and lethargy.
Adverse Events with Other Methylphenidate HCl Dosage Forms
Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed below may also occur.
Other reactions include:
Cardiac: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia Gastrointestinal: abdominal pain, nausea Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura.
Metabolism/Nutrition: anorexia, weight loss during prolonged therapy Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette’s syndrome, toxic psychosis Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate:
Blood/Lymphatic: leukopenia and/or anemia
Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma Psychiatric: transient depressed mood, aggressive behavior Skin/Subcutaneous: scalp hair loss Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause.
DRUG ABUSE AND DEPENDENCE
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, like other products containing methylphenidate, is a Schedule II controlled substance. (See WARNINGS for boxed warning containing drug abuse and dependence information.)
OVERDOSAGE
Signs and Symptoms
Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.
Poison Control Center
Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice.
Recommended Treatment
As with the management of all overdosage, the possibility of multiple drug ingestion should be considered.
When treating overdose, practitioners should bear in mind that there is a prolonged release of methylphenidate from Ritalin LA® (methylphenidate hydrochloride) extendedrelease capsules.
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 hyperpyrexia.
Efficacy of peritoneal dialysis or extracorporeal hemodialysis for methylphenidate overdosage has not been established; also, dialysis is considered unlikely to be of benefit due to the large volume of distribution of methylphenidate.
DOSAGE AND ADMINISTRATION
Administration of Dose
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is for oral administration once daily in the morning. Ritalin LA may be swallowed as whole capsules or alternatively may be administered by sprinkling the capsule contents on a small amount of applesauce (see specific instructions below). Ritalin LA and/or their contents should not be crushed, chewed, or divided.
The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. The applesauce should not be warm because it could affect the modified release properties of this formulation. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use.
Dosing Recommendations
Dosage should be individualized according to the needs and responses of the patients.
Initial Treatment
The recommended starting dose of Ritalin LA is 20 mg once daily. Dosage may be adjusted in
weekly 10 mg increments to a maximum of 60 mg/day taken once daily in the morning,
depending on tolerability and degree of efficacy observed. Daily dosage above 60 mg is not
recommended. When in the judgement of the clinician a lower initial dose is appropriate, patients may begin treatment with Ritalin LA 10 mg.
Patients Currently Receiving Methylphenidate
The recommended dose of Ritalin LA for patients currently taking methylphenidate b.i.d. or sustained release (SR) is provided below.
Previous Methylphenidate Dose Recommended Ritalin LA® Dose
5 mg methylphenidate-b.i.d. 10 mg q.d.
10 mg methylphenidate b.i.d.
or 20 mg methylphenidate-SR 20 mg q.d.
15 mg methylphenidate b.i.d. 30 mg q.d.
20 mg methylphenidate b.i.d.
or 40 mg of methylphenidate-SR 40 mg q.d.
30 mg methylphenidate b.i.d.
or 60 mg methylphenidate-SR 60 mg q.d.
For other methylphenidate regimens, clinical judgment should be used when selecting the starting dose. Ritalin LA dosage may be adjusted at weekly intervals in 10 mg increments. Daily dosage above 60 mg is not recommended.
Maintenance/Extended Treatment
There is no body of evidence available from controlled trials to indicate how long the patient with ADHD should be treated with Ritalin LA. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use Ritalin LA for extended periods in patients with ADHD should periodically re-evaluate the long-term usefulness of the drug for the individual patient with trials off medication to assess the patient’s functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued.
Dose Reduction and Discontinuation
If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be reduced, or, if necessary, the drug should be discontinued. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.
HOW SUPPLIED
Ritalin LA capsules 10 mg: white/light brown (imprinted NVR R10) Bottles of 100………………………………………………………NDC 0078-0424-05 Ritalin LA capsules 20 mg: white (imprinted NVR R20) Bottles of 100………………………………………………………NDC 0078-0370-05 Ritalin LA capsules 30 mg: yellow (imprinted NVR R30)
Bottles of 100………………………………………………………NDC 0078-0371-05 Ritalin LA capsules 40 mg: light brown (imprinted NVR R40) Bottles of 100………………………………………………………NDC 0078-0372-05 Store at 25°C (77°F), excursions permitted 15°C-30°C (59°F-86°F). [See USP controlled room temperature]
Dispense in tight container (USP).
Ritalin LA® is a trademark of Novartis AG.
SODAS® is a trademark of Elan Corporation, plc.
This product is covered by US patents including US 5,837,284 and 6,228,398.
REFERENCE
American Psychiatric Association. Diagnosis and Statistical Manual of Mental Disorders.
4th edition. Washington DC: American Psychiatric Association 1994.
REV: JUNE 2006 T2006-62
INFORMATION FOR PATIENTS TAKING RITALIN LA®, OR FOR
THEIR PARENTS OR CAREGIVERS
Once Daily
Ritalin LA®
(methylphenidate hydrochloride)
extended-release capsules
This information for patients or their parents or caregivers is about Ritalin LA. Please read this before you start taking Ritalin LA. Also, read the information you get each time you renew your prescription, in case anything has changed. Remember, this information does not take the place of your doctor’s instructions. If you have any questions about this information or about Ritalin LA, talk to your doctor or pharmacist.
WHAT IS RITALIN LA?
Ritalin LA is a once-a-day treatment for Attention Deficit Hyperactivity Disorder, or ADHD. Ritalin LA contains the drug methylphenidate (Ritalin®), a central nervous system stimulant that has been used to treat ADHD for more than 30 years. Ritalin is available in several forms including Ritalin LA, an extended-release form of methylphenidate hydrochloride available as 10, 20, 30, and 40 mg extended-release capsules. Ritalin LA is taken by mouth, once each day in the morning, before breakfast.
WHAT IS ATTENTION DEFICIT HYPERACTIVITY DISORDER?
ADHD has three main types of symptoms: inattention, hyperactivity, and impulsiveness. Symptoms of inattention include not paying attention, making careless mistakes, not listening, not finishing tasks, not following directions, and being easily distracted. Symptoms of hyperactivity and impulsiveness include fidgeting, talking excessively, running around at inappropriate times, and interrupting others. Some patients have more symptoms of hyperactivity and impulsiveness while others have more symptoms of inattentiveness. Some patients have all three types of symptoms.
Many people have symptoms like these from time to time, but patients with ADHD have these symptoms more than others their age. Symptoms must be present for at least 6 months to be certain of the diagnosis.
HOW DOES RITALIN LA WORK?
When you take a Ritalin LA capsule, half of the beads provide an immediate dose of
methylphenidate and the other half provide a delayed second release of the drug to continue to
help lessen the symptoms of ADHD during the day. Methylphenidate, the active ingredient in
Ritalin LA, helps increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.
BEFORE RITALIN LA TREATMENT
It is very important that ADHD be accurately diagnosed and that the need for medication be carefully assessed. It is important to remember that Ritalin is only part of the overall management of ADHD. Parents, teachers, physicians and other professionals are part of a team that must work together.
Before Ritalin treatment, your doctor should be made aware of any current or past physical or mental problems. Tell your doctor if there is a history of drug or alcohol abuse, depression, bipolar disorder, psychosis, epilepsy or seizure disorders, high blood pressure, heart defects, irregular heart rhythms, other heart problems, glaucoma, and facial tics (involuntary movements). Also tell your doctor if there is a family history of sudden death, irregular heart rhythm, suicide, bipolar disorder, depression or Tourette’s syndrome. Both your doctor and your pharmacist should also be informed of all medicines that you are taking, even if these drugs are not taken on a regular basis and are available without prescription. Your doctor will decide whether you can take Ritalin with other medicines. Methylphenidate is known to interact with a number of other drugs. These include medicines to treat depression, such as monoamine oxidase inhibitors; to control seizures; and to thin blood. Sometimes these interactions may require a change in dosage, or occasionally stopping one of the drugs involved.
Tell your doctor if you are pregnant or nursing a baby.
WHO SHOULD NOT TAKE RITALIN LA ?
You should NOT take Ritalin LA if:
You have known serious heart defects, serious heart rhythm irregularities, or other serious heart problems.
You have significant anxiety, tension, or agitation since Ritalin LA may make these conditions worse.
You are allergic to methylphenidate or any of the other ingredients in Ritalin LA.
You have glaucoma, an eye disease.
You have tics or Tourette’s syndrome, or a family history of Tourette’s syndrome.
You are taking a monoamine oxidase inhibitor, a type of drug, or have discontinued a monoamine oxidase inhibitor in the last 14 days.
Talk to your doctor if you believe any of these conditions apply to you.
HOW SHOULD I TAKE RITALIN LA ?
Take Ritalin LA once each day in the morning.
Take the dose prescribed by your doctor. Your doctor may adjust the amount of drug you take until it is right for you. From time to time, your doctor may interrupt your treatment to check your symptoms while you are not taking the drug. Ritalin LA capsules may be taken at the same time as food or without food, although food may delay the absorption of Ritalin LA. The Ritalin LA capsule may be swallowed as whole capsules or the capsule may be opened and sprinkled on a small amount of applesauce. The capsule should not be crushed or chewed or its contents divided. To sprinkle the contents of the capsule, open the capsule carefully and sprinkle the beads over a spoonful of applesauce. The applesauce should not be warm because it could affect the modified release properties of this formulation. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use.
If you also take antiacids or drugs that suppress stomach acids, you should discuss with your physician or pharmacist how to take these drugs with Ritalin LA.
WHAT ARE THE POSSIBLE SIDE EFFECTS OF RITALIN LA?
The most common side effects of Ritalin LA are:
Nervousness
Stomach pain
Sleeplessness
Decreased appetite
Other side effects seen with methylphenidate, the active ingredient in Ritalin LA, include nausea, vomiting, dizziness, tics, allergic reactions, increased blood pressure and psychosis (abnormal thinking or hallucinations).
Dependence
Abuse of methylphenidate can lead to dependence. Tell your doctor if you have ever abused or been dependent on alcohol or drugs, or if you are now abusing or dependent on alcohol or drugs. Misuse of stimulants may be associated with sudden death and serious cardiovascular adverse events.
Blurred Vision
Tell your doctor if you have blurred vision when taking Ritalin LA. This could be a sign of a serious problem.
Slower Growth
Slower growth (weight gain and/or height) has been reported with long-term use of methylphenidate in children. Your doctor will be carefully watching your height and weight. If you are not growing or gaining weight as your doctor expects, your doctor may stop your Ritalin LA treatment.
This is not a complete list of possible side effects. Ask your doctor about other side effects. If you develop any side effect, talk to your doctor.
WHAT MUST I DISCUSS WITH MY DOCTOR BEFORE TAKING RITALIN LA?
Talk to your doctor before taking RITALIN LA if you:
Have high blood pressure.
Have an abnormal heart rate or rhythm.
Have had any other current or previous heart problems.
Have a family history of sudden death or heart rhythm problems.
Are being treated for depression or bipolar disorder, or have symptoms of depression such as feelings of sadness, worthlessness, and hopelessness.
Have a family history of suicide, bipolar disorder or depression.
Have motion tics (hard-to-control, repeated twitching of any parts of your body) or verbal tics (hard-to-control repeating of sounds or words).
Have someone in your family with motion tics, verbal tics, or Tourette’s syndrome.
Have abnormal thoughts or visions, hear abnormal sounds, or have been diagnosed with psychosis.
Have had seizures (convulsions, epilepsy) or abnormal EEGs (electroencephalograms).
Tell your doctor immediately if you develop any of the above conditions or symptoms while taking Ritalin LA.
CAN I TAKE RITALIN LA WITH OTHER MEDICINES?
Tell your doctor about all medicines that you are taking or intend to take. Your doctor should decide whether you can take Ritalin LA with other medicines. These include:
Other medicines that a doctor has prescribed.
All medicines that you buy yourself without a prescription.
Any herbal remedies that you may be taking.
Monoamine Oxidase (MAO) Inhibitors
You should not take Ritalin LA with (MAO) inhibitors or within 14 days of stopping a MAO inhibitor.
Starting a New Medicine
While on Ritalin LA, do not start taking a new medicine or herbal remedy before checking with your doctor.
Other Medicines You May Be Taking
Ritalin LA may change the way your body reacts to certain medicines. These include medicines used to treat depression, prevent seizures, or prevent blood clots (commonly called “blood thinners”). Your doctor may need to change your dose of these medicines if you are taking them with Ritalin LA.
Other Important Safety Information
Pregnancy and Nursing
Before taking Ritalin LA, tell your doctor if you are pregnant or plan on becoming pregnant. If you take methylphenidate, it may be in your breast milk. Tell your doctor if you are nursing a baby.
Overdose
Call your doctor immediately if you take more than the amount of Ritalin LA prescribed by your doctor.
WHAT ELSE SHOULD I KNOW ABOUT RITALIN LA ?
Ritalin LA has not been studied in children under 6 years of age. Ritalin LA may be a part of your overall treatment for ADHD. Your doctor may also recommend that you have counseling or other therapy.
As with all medicines, never share Ritalin LA with anyone else and take only the number of Ritalin LA capsules prescribed by your doctor. Ritalin LA should be stored in a safe place at room temperature (between 59°F-86°F). Do not store this medicine in hot, damp, or humid places. Keep the container of Ritalin LA in a safe place, away from high-traffic areas where other people could have accidental or unauthorized access to the medication. Keep track of the number of capsules so that you will know if any are missing. Someone who has easy access to Ritalin may be able to give the capsules to others or misuse the medication.
Keep out of the reach of children.
This leaflet summarizes the most important information about Ritalin LA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Ritalin LA that is written for health professionals. You can also call 1-888 NOWNOVA (1-888-669-6682).
REV: JUNE 2006 T2006-63
REV: JUNE 2006 PRINTED IN U.S.A. T2006-62/ T2006-63
Manufactured for
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
By ELAN HOLDINGS INC.
Pharmaceutical Division
Gainesville, GA 30504
©Novartis

Source: http://www.fda.gov/cder/foi/label/2006/010187s66s67,018029s37s38,021284s6s8lbl.pdf

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