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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
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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).
Ritalin LA® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), in pediatric patients 6 to 12 years of age [see Clinical Studies].
Prior to treating patients with Ritalin LA, assess:
The recommended starting dose for Ritalin LA is 20 mg once daily. Increase dosage gradually, in increments of 10 mg weekly. Daily dosage above 60 mg is not recommended. When a lower initial dose is appropriate, patients may begin treatment with 10 mg.
Administer Ritalin LA orally once daily in the morning. Ritalin LA may be swallowed as whole capsules or 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.
The recommended dose of Ritalin LA for patients currently taking Ritalin twice daily is provided below in Table 1.
Table 1: Recommended Dose Conversion from Ritalin
| Previous Ritalin dose | Recommended Ritalin LA dose |
| 5 mg Ritalin twice daily | 10 mg once daily |
| 10 mg Ritalin twice daily | 20 mg once daily |
| 15 mg Ritalin twice daily | 30 mg once daily |
| 20 mg Ritalin twice daily | 40 mg once daily |
| 30 mg Ritalin twice daily | 60 mg once daily |
If switching from other methylphenidate products, discontinue that treatment, and titrate with Ritalin LA using the titration schedule.
Do not substitute for other methylphenidate products on a milligram-per-milligram basis, because different methylphenidate base compositions and differing pharmacokinetic profiles [see DESCRIPTION, CLINICAL PHARMACOLOGY].
Clinical judgment should be used when selecting the starting dose. Daily dosage above 60 mg is not recommended.
If paradoxical worsening of symptoms or other adverse reactions occur, reduce the dosage, or, if necessary, discontinue Ritalin LA. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.
10 mg extended-release capsules (NDC 0078-0424-05) white/light brown, (imprinted “NVR R10”) supplied in bottles of 100
20 mg extended-release capsules (NDC 0078-0370-05) white, (imprinted “NVR R20”) supplied in bottles of 100
30 mg extended-release capsules (NDC 0078-0371-05) yellow, (imprinted “NVR R30”) supplied in bottles of 100
40 mg extended-release capsules (NDC 0078-0372-05) light brown, (imprinted “NVR R40”) supplied in bottles of 100
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP controlled room temperature].
Dispense in tight container (USP).
Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936. Revised: Oct 2023
The following are discussed in more detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The clinical program for Ritalin LA consisted of 6 studies: 2 controlled clinical studies conducted in children with ADHD aged 6 to 12 years and 4 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 to 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. 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 to 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 2-week double-blind treatment phase of this study, patients received either placebo or Ritalin LA at their individually-titrated dose (range, 10 mg to 40 mg).
Adverse reactions with an incidence greater than 5% during the initial 4-week single-blind Ritalin LA titration period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia.
Adverse reactions with an incidence greater than 2% among Ritalin LA-treated subjects, during the 2-week doubleblind phase of the clinical study, are shown in Table 2.
Table 2: Adverse Reactions in Greater Than 2% Ritalin LA-Treated Subjects in the 2-Week Double-Blind Phase
| 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) |
In the 2-week double-blind treatment phase of a placebo-controlled parallel-group study in children with ADHD, one Ritalin LA-treated subject (1/65, 1.5%) discontinued due to an adverse event (depressed mood).
In the single-blind titration period of this study, subjects received Ritalin LA for up to 4 weeks. During this period a total of 6 subjects (6/161, 3.7%) discontinued due to adverse events. The adverse events leading to discontinuation were anger (2 patients), hypomania, anxiety, depressed mood, fatigue, migraine, and lethargy.
The following adverse reactions have been identified during the post approval use of methylphenidate products. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.
Infections and Infestations: nasopharyngitis
Blood and the Lymphatic System Disorders: leukopenia, thrombocytopenia, anemia
Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis
Metabolism and Nutrition Disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in children
Psychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood, depression
Nervous System Disorders: headache, dizziness, tremor, dyskinesia, including choreoathetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs
Eye Disorders: blurred vision, difficulties in visual accommodation
Cardiac Disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris
Respiratory, Thoracic, and Mediastinal Disorders: cough
Gastrointestinal Disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia
Hepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury
Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura
Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramps, rhabdomyolysis, trismus
Investigations: weight loss (adult ADHD patients)
Vascular Disorders: peripheral coldness, Raynaud's phenomenon
The list below shows adverse reactions not listed with Ritalin, or Ritalin LA formulations that have been reported with other methylphenidate-containing products.
Blood and Lymphatic Disorders: pancytopenia
Immune System Disorders: hypersensitivity reactions, such as auricular swelling, bullous conditions, eruptions, exanthemas
Psychiatric Disorders: affect lability, mania, disorientation, libido changes
Nervous System Disorders: migraine, motor and verbal tics
Eye Disorders: diplopia, increased intraocular pressure, mydriasis
Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole
Respiratory, Thoracic, and Mediastinal Disorders: pharyngolaryngeal pain, dyspnea
Gastrointestinal Disorders: diarrhea, constipation
Skin and Subcutaneous Tissue Disorders: angioneurotic edema, erythema, fixed drug eruption
Musculoskeletal, Connective Tissue, and Bone Disorders: myalgia, muscle twitching
Renal and Urinary Disorders: hematuria
Reproductive System and Breast Disorders: gynecomastia
General Disorders: fatigue, hyperpyrexia
Urogenital Disorders: priapism
Table 3 presents clinically important drug interactions with Ritalin LA.
Table 3: Clinically Important Drug Interactions with Ritalin LA
| Monoamine Oxidase Inhibitors (MAOI) | |
| Clinical impact | Concomitant use of MAOIs and CNS stimulants, including Ritalin LA, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see CONTRAINDICATIONS]. |
| Intervention | Concomitant use of Ritalin LA with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. |
| Antihypertensive Drugs | |
| Clinical impact | Ritalin LA may decrease the effectiveness of drugs used to treat hypertension [see WARNINGS AND PRECAUTIONS]. |
| Intervention | Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. |
| Halogenated Anesthetics | |
| Clinical impact | Concomitant use of halogenated anesthetics and Ritalin LA may increase the risk of sudden blood pressure and heart rate increase during surgery. |
| Intervention | Avoid use of Ritalin LA in patients being treated with anesthetics on the day of surgery. |
| Risperidone | |
| Clinical impact | Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS) |
| Intervention | Monitor for signs of EPS |
Ritalin LA contains methylphenidate hydrochloride, a Schedule II controlled substance.
Ritalin LA has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see WARNINGS AND PRECAUTIONS]. Ritalin LA can be diverted for non-medical use into illicit channels or distribution.
Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.
Misuse and abuse of methylphenidate hydrochloride may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including Ritalin LA, can result in overdose and death [see OVERDOSAGE], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
Physical Dependence
Ritalin LA may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.
Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including Ritalin LA include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.
Tolerance
Ritalin LA may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
Included as part of the PRECAUTIONS section.
Ritalin LA has a high potential for abuse and misuse. The use of Ritalin LA exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Ritalin LA can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse And Dependence]. Misuse and abuse of CNS stimulants, including Ritalin LA, can result in overdose and death [see OVERDOSAGE], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
Before prescribing Ritalin LA, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store Ritalin LA in a safe place, preferably locked, and instruct patients to not give Ritalin LA to anyone else. Throughout Ritalin LA treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.
Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who are treated with CNS stimulants at the recommended ADHD dosage.
Avoid Ritalin LA use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.
CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 beats per minute). Some patients may have larger increases.
Monitor all Ritalin LA-treated patients for hypertension and tachycardia.
CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.
CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating Ritalin LA treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).
CNS stimulants, at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing Ritalin LA.
Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation).
Ritalin LA-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.
CNS stimulants, including Ritalin LA, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon were observed in post-marketing reports and at the therapeutic dosage of CNS stimulants in all agegroups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or the CNS stimulant.
Careful observation for digital changes is necessary during Ritalin LA treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for Ritalin LA-treated patients who develop signs or symptoms of peripheral vasculopathy.
CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.
Careful follow-up of weight and height in pediatric patients 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 patients over 36 months (to the ages of 10 to13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year had 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 development period.
Closely monitor growth (weight and height) in Ritalin LA-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.
There have been reports of angle closure glaucoma associated with methylphenidate treatment.
Although the mechanism is not clear, Ritalin LA-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.
There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see ADVERSE REACTIONS].
Prescribe Ritalin LA to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor Ritalin LA-treated patients with a history of abnormally increased IOP or open angle glaucoma.
CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see ADVERSE REACTIONS].
Before initiating Ritalin LA, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor Ritalin LA-treated patients for the emergence or worsening of tics or Tourette’s syndrome and discontinue treatment if clinically appropriate.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Educate patients and their families about the risks of abuse, misuse, and addiction of Ritalin LA, which can lead to overdose and death, and proper disposal of any unused drug [see WARNINGS AND PRECAUTIONS, Drug Abuse And Dependence, OVERDOSAGE]. Advise patients to store Ritalin LA in a safe place, preferably locked, and instruct patients to not give Ritalin LA to anyone else.
Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with Ritalin LA use. Instruct patients to contact a healthcare provider immediately if they develop symptoms, such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see WARNINGS AND PRECAUTIONS].
Instruct patients that Ritalin LA can cause elevations of their blood pressure and pulse rate [see WARNINGS AND PRECAUTIONS].
Advise patients that Ritalin LA, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see WARNINGS AND PRECAUTIONS].
Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct them to seek immediate medical attention in the event of priapism [see WARNINGS AND PRECAUTIONS].
Instruct patients beginning treatment with Ritalin LA about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.
Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking Ritalin LA. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see WARNINGS AND PRECAUTIONS].
Advise patients that Ritalin LA may cause slowing of growth and weight loss [see WARNINGS AND PRECAUTIONS].
Advise patients that IOP and glaucoma may occur during treatment with Ritalin LA [see WARNINGS AND PRECAUTIONS].
Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with Ritalin LA. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see WARNINGS AND PRECAUTIONS].
Advise patients to avoid alcohol while taking Ritalin LA. Consumption of alcohol while taking Ritalin LA may result in a more rapid release of the dose of methylphenidate [see CLINICAL PHARMACOLOGY].
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to Ritalin LA during pregnancy [see Use In Specific Populations].
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 2 times the MRHD of 60 mg/day given to children on a mg/m² basis. 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 increase 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 4 times the MRHD (children) on a mg/m² basis.
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, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. 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 10 times the maximum recommended dose of 60 mg/day given to adolescents on a mg/m² basis.
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including Ritalin LA during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhdmedications/.
Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drugassociated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations). No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m² basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the MRHD given to adolescents (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Fetal/Neonatal Adverse Reactions
CNS stimulants, such as Ritalin LA, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth-weight-infants have been reported in amphetamine-dependent mothers.
Animal Data
In embryo-fetal development 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. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on a mg/m² basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the MRHD given to adolescents on a mg/m² basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adolescents 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 (3 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 (6 times the MRHD of 60 mg/day given to adolescents 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 (approximately 2 times the MRHD given to adolescents on a mg/m² basis).
Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Ritalin LA and any potential adverse effects on the breastfed infant from Ritalin LA or from the underlying maternal condition.
Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.
The safety and effectiveness of Ritalin LA for the treatment of ADHD have been established in pediatric patients aged 6 to 12 years.
The safety and effectiveness of Ritalin LA in pediatric patients aged less than 6 years have not been established.
The long-term efficacy of methylphenidate in pediatric patients has not been established.
Growth should be monitored during treatment with stimulants, including Ritalin LA. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see WARNINGS AND PRECAUTIONS].
Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 60 mg/day given to children on a mg/m² basis.
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 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children 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 (8 times the MRHD given to children on a mg/m² basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m² basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
Ritalin LA has not been studied in the geriatric population.
Overdose of CNS stimulants is characterized by the following sympathomimetic effects:
Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of Ritalin LA should be considered when treating patients with overdose. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
Methylphenidate hydrochloride is a CNS stimulant. The mode of therapeutic action in ADHD is not known.
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. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.
A formal QT study has not been conducted in patients taking Ritalin LA.
The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of Ritalin, on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of dexmethylphenidate XR 40 mg (maximum recommended adult total daily dosage) in 75 healthy volunteers. Electrocardiograms were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident-exposure response relationship.
Ritalin LA produces a bi-modal plasma concentration-time profile (i.e., 2 distinct peaks approximately 4 hours apart) when administered orally to children diagnosed with ADHD and healthy adults.
No accumulation of methylphenidate is expected following multiple once daily oral dosing with Ritalin LA, however, there is a slight upward trend in the methylphenidate area under the curve and peak plasma concentrations (Cmax1 and Cmax2) after oral administration of Ritalin LA 20 mg and 40 mg capsules to adults.
The absolute oral bioavailability of methylphenidate in children was 22% ± 8% for d-methylphenidate and 5% ± 3% for l- methylphenidate. The relative bioavailability of Ritalin LA given once daily is comparable to the same total dose of Ritalin tablets given in 2 doses 4 hours apart in both children and 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 2 formulations, i.e., initial lag time (Tlag), first peak concentration (Cmax1), and time to the first peak (Tmax1), which is reached in 1 to 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 2 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 2 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 4).
Figure 1: Mean Plasma Concentration Time-profile of Methylphenidate After a Single Dose of Ritalin LA 40 mg and Ritalin 20 mg Given in Two Doses 4 Hours Apart
 |
Table 4: 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 Formulation dose | Children | Adult males | ||
| 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 4. - .3 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 | .2 7. - .6 3. | .3 8. - .9 3. | |
| AUC(0-∞) (ng/mL x h-1) | 102.4 ± 54.6 | 86.6 ± 64.0a | 37.8 ± 21.9 | 45.8 ± 10.0 |
| 40.5 - 261.6 | 43.3 - 301.44 | 14.3 - 85.3 | 34.0 - 61.6 | |
| t½ (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 | |
| aN = 15. | ||||
Effect Of Food
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.
Effect Of Alcohol
An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the Ritalin LA 40 mg capsule dosage form. At an alcohol concentration of 40% there was a 98% release of methylphenidate in the first hour. The results with the 40 mg capsule are considered to be representative of the other available capsule strengths.
Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2.65 ± 1.11 L/kg for dmethylphenidate and 1.80 ± 0.91 L/kg for l-methylphenidate.
The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate. 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 to 7.7 hours). In children the average half-life is about 2.5 hours, with a range of about 1.5 to 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 to 4 hours.
Metabolism
The absolute oral bioavailability of methylphenidate in children was 22% ± 8% for d-methylphenidate and 5% ± 3% for l- methylphenidate, suggesting pronounced presystemic metabolism. Biotransformation of methylphenidate by the carboxylesterase CES1A1 is rapid and extensive leading to the main, de-esterified metabolite α-phenyl-2-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. 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.
Excretion
After oral administration of an immediate release formulation of methylphenidate, 78% to 97% of the dose is excreted in the urine and 1% to 3% in the feces in the form of metabolites within 48 to 96 hours. Only small quantities (less than 1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60% to 86%), the remainder being accounted for by minor metabolite.
There were no apparent gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults when administered Ritalin LA.
There is insufficient experience with the use of Ritalin LA to detect ethnic variations in pharmacokinetics.
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.
Ritalin LA has not been studied in renally-impaired patients. Renal impairment 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.
Ritalin LA has not been studied in patients with hepatic impairment. Hepatic impairment 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.
Ritalin LA was evaluated in a randomized, double-blind, placebo-controlled, parallel group clinical study in which 134 children, ages 6 to 12 years, with DSM-IV diagnoses of ADHD received a single morning dose of Ritalin LA in the range of 10 to 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 [Mean (final score - baseline) = -10.7 points] over patients who received placebo [Mean (final score - baseline) = +2.8 points]. The lower the final score on the CADS-T scale from baseline, the less severe the disease is. 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*
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RITALIN LA®
(rit-ah-lin LA)
(methylphenidate hydrochloride) extended-release capsules for oral use
What is the most important information I should know about RITALIN LA?
RITALIN LA may cause serious side effects, including:
Your healthcare provider should check you or your child carefully for heart problems before starting RITALIN LA.
Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects.
Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child has any signs of heart problems, such as chest pain, shortness of breath, or fainting while taking RITALIN LA.
Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.
Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems while taking RITALIN LA, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.
What is RITALIN LA?
RITALIN LA is a central nervous system (CNS) stimulant prescription medicine. It is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). RITALIN LA may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.
RITALIN LA should be used as a part of a total treatment program for ADHD that may include counseling or other therapies.
It is not known if RITALIN LA is safe and effective in children under 6 years of age.
RITALIN LA is a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs. Keep RITALIN LA in a safe place to protect it from theft. Never give your RITALIN LA to anyone else because it may cause death or harm them. Selling or giving away RITALIN LA may harm others and is against the law.
Who should not take RITALIN LA?
RITALIN LA should not be taken if you or your child:
RITALIN LA may not be right for you or your child. Before starting RITALIN LA, tell your or your child’s healthcare provider about all health conditions (or a family history of), including:
Tell your healthcare provider about all of the medicines that you or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. RITALIN LA and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking RITALIN LA.
Your healthcare provider will decide whether RITALIN LA can be taken with other medicines.
Especially tell your healthcare provider if you or your child takes:
Know the medicines that you or your child takes. Keep a list of your medicines with you to show your healthcare provider and pharmacist.
Do not start any new medicine while taking RITALIN LA without talking to your healthcare provider first.
How should RITALIN LA be taken?
What are possible side effects of RITALIN LA?
Tell your healthcare provider if you or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes.
Call your healthcare provider right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking RITALIN LA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088.
How should I store RITALIN LA?
General information about the safe and effective use of RITALIN LA.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about RITALIN LA that is written for healthcare professionals. Do not use RITALIN LA for a condition for which it was not prescribed. Do not give RITALIN LA to other people, even if they have the same symptoms. It may harm them and it is against the law.
What are the ingredients in RITALIN LA?
Active ingredient: methylphenidate HCl
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).
This Medication Guide has been approved by the U.S. Food and Drug Administration.
