RITALIN- methylphenidate hydrochloride_tablet

Methylphenidate hydrochloride is a CNS stimulant. The mode of therapeutic action in ADHD and narcolepsy is not known. Methylphenidate is a racemic mixture comprised of the d- l-threo d-threo l-threo Cardiac Electrophysiology A formal QT study has not been conducted in patients taking Ritalin. The effect of dexmethylphenidate, the pharmacologically active d- Absorption The time to peak rate in children was 1. 4 hours) for the Ritalin. Distribution Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2. 11 L/kg for d-methylphenidate and 1. 91 L/kg for l Elimination The systemic clearance is 0. 12 L/h/kg for d-methylphenidate and 0. 28 L/h/kg for l Metabolism Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Excretion After oral administration, 78% to 97% of the dose is excreted in the urine and 1% to 3% in feces in the form of metabolites within 48 to 96 hours. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). Studies in Specific Populations Male and Female Patients No gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults are expected. Racial or Ethnic Groups There is insufficient experience with the use of Ritalin to detect ethnic variations in pharmacokinetics. Patients with Renal Impairment Ritalin 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. Patients with Hepatic Impairment Ritalin 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 is indicated for the treatment of: Ritalin is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorders (ADHD) and Narcolepsy ( 1.

2 Prior to treating patients with Ritalin, assess: for the presence of cardiac disease (i. , perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions ( 5. 2 the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating Ritalin [see Warnings and Precautions ( 5. 10 Pediatric Patients 6 years and Older Adults If paradoxical worsening of symptoms or other adverse reactions occur, reduce the dosage, or, if necessary, discontinue Ritalin. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

The following are discussed in more detail in other sections of the labeling: [see Boxed Warning, Warnings and Precautions ( 5. 3 [see Contraindications ( 4 [see Contraindications ( 4 7. 1 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 4 [see Warnings and Precautions ( 5. 5 [see Warnings and Precautions ( 5. 6 [see Warnings and Precautions ( 5. 7 [see Warnings and Precautions ( 5. 8 [see Warnings and Precautions ( 5. 9 [see Warnings and Precautions ( 5. 10 The following adverse reactions associated with the use of Ritalin and other methylphenidate products were identified in clinical trials, spontaneous reports, and literature. 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. Adverse Reactions Reported with Ritalin Infections and Infestations: Blood and the Lymphatic System Disorders: Immune System Disorders: Metabolism and Nutrition Disorders: Psychiatric Disorders: Nervous System Disorders: Eye Disorders: Cardiac Disorders: Respiratory, Thoracic, and Mediastinal Disorders: Gastrointestinal Disorders: Hepatobiliary Disorders: Skin and Subcutaneous Tissue Disorders: Musculoskeletal and Connective Tissue Disorders: Investigations: Vascular Disorders: Additional Adverse Reactions Reported with Other Methylphenidate-Containing Products The list below shows adverse reactions not listed for Ritalin that have been reported with other methylphenidate-containing products. Blood and Lymphatic Disorders: Immune System Disorders: Psychiatric Disorders: Nervous System Disorders: Eye Disorders: Cardiac Disorders: Respiratory, Thoracic, and Mediastinal Disorders: Gastrointestinal Disorders: Skin and Subcutaneous Tissue Disorders: Musculoskeletal, Connective Tissue, and Bone Disorders: Renal and Urinary Disorders: Reproductive System and Breast Disorders: General Disorders: Urogenital Disorders: 6 To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www. gov/medwatch.

[see Adverse Reactions ( 6 [see Drug Interactions ( 7. 1 4 4.

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including Ritalin, 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/adhd-medications/ Risk Summary Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated 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/m 2 (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. 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. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as Ritalin, 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. Data 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/m 2 2 2 2 2 2 Risk Summary 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. 7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1. 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 and any potential adverse effects on the breastfed infant from Ritalin or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. The safety and effectiveness of Ritalin for the treatment of ADHD have been established in pediatric patients aged 6 to 17 years. The safety and effectiveness of Ritalin in pediatric patients less than aged 6 years have not been established. The long-term efficacy of methylphenidate in pediatric patients has not been established. Long-Term Suppression of Growth Growth should be monitored during treatment with stimulants, including Ritalin. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5. 7 Juvenile Animal Toxicity Data 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/m 2 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/m 2 2 2 Ritalin has not been studied in the geriatric population.

Antihypertensive Drugs: 7. 1 Table 1 presents clinically important drug interactions with Ritalin. Table 1: Clinically Important Drug Interactions with Ritalin Monoamine Oxidase Inhibitors (MAOI) Clinical Impact Concomitant use of MAOIs and CNS stimulants, including Ritalin can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications ( 4 Intervention Concomitant use of Ritalin with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical Impact Ritalin may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions ( 5. 3 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 may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention Avoid use of Ritalin 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.

OVERDOSAGE
Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: Overdose Management Consider the possibility of multiple drug ingestion. 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.
NONCLINICAL TOXICOLOGY
Carcinogenesis 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 mg/m 2 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/m 2 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. Mutagenesis Methylphenidate was not mutagenic in the in vitro in vitro in vitro in vitro in vivo Impairment of Fertility No human data on the effect of methylphenidate on fertility are available. 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 10times the MRHD of 60 mg/day given to adolescents on a mg/m 2

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