Methylphenidate Hydrochloride (Page 4 of 6)
Methylphenidate hydrochloride in the extended-release tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the extended-release tablet compared to the Methylphenidate hydrochloride tablet, measured by the urinary excretion of Methylphenidate hydrochloride major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49% to 168%) in children and 101% (85% to 152%) in adults. The time to peak rate in children was 1.9 hours (0.3 to 4.4 hours) for the Methylphenidate hydrochloride tablets and 4.7 hours (1.3 to 8.2 hours) for the Methylphenidate hydrochloride extended-release tablets. An average of 67% of extended-release tablet dose was excreted in children as compared to 86% in adults.
Effect of Food
After a high-fat meal, both area under the curve (AUC) (by 25%) and Cmax (by 27 %) are higher. Time to Cmax (Tmax) is faster after a high-fat meal (median Tmax: 2.5 hours) as compared to without food (median Tmax: 3 hours).
Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2.65 ± 1.11 L/kg for d- methylphenidate 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.
Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity.
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%). The cumulative urinary excretion of alpha-phenyl-2-piperidine acetic acid are not significantly different for Methylphenidate hydrochloride extended-release tablets.
Studies in Specific Populations
Male and Female Patients
In a clinical study involving adult subjects who received Methylphenidate hydrochloride extended-release tablets, plasma concentrations of Methylphenidate hydrochloride tablets major metabolite appeared to be greater in females than in males. No gender differences were observed for Methylphenidate hydrochloride tablets plasma concentration in the same subjects.
Racial or Ethnic Groups
There is insufficient experience with the use of Methylphenidate hydrochloride tablets to detect ethnic variations in pharmacokinetics.
Patients with Renal Impairment
Methylphenidate hydrochloride tablets 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
Methylphenidate hydrochloride tablets 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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg/day given to children on 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.
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/m2 basis.
16 HOW SUPPLIED/STORAGE AND HANDLING
Methylphenidate hydrochloride tablets, USP are available as follows:
Tablets 5 mg- Yellow, round, flat faced beveled edge tablets, debossed “K” above “100” on one side and plain on other side.
Bottles of 100 NDC 10702-100-01
Tablets 10 mg- Pale green colored, round, biconvex tablets debossed “K” above bisect “101” on one side and plain on the other side.
Bottles of 100 NDC 10702-101-01
Tablets 20 mg- Light yellow, round, biconvex tablets debossed “K” above bisect “102” on one side and plain on the other side.
Bottles of 100 NDC 10702-102-01
Store at 20°C to 25°C (68°F to 77°F), excursions permitted 15°C and 30°C (59°F and 86°F). [see USP controlled room temperature].
Protect from light.
Dispense in tight, light-resistant container (USP).
Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired Methylphenidate hydrochloride tablets, USP by a medicine takeback program or by an authorized collector registered with the Drug Enforcement Administration. If no take-back program or authorized collector is available, mix Methylphenidate hydrochloride tablets, USP with an undesirable, nontoxic substance to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and discard Methylphenidate hydrochloride tablets, USP in the household trash.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Controlled Substance Status/High Potential for Abuse and Dependence
Advise patients that Methylphenidate hydrochloride tablets are controlled substances, and they can be abused and lead to dependence. Instruct patients that they should not give Methylphenidate hydrochloride tablets to anyone else. Advise patients to store Methylphenidate hydrochloride tablets in a safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired Methylphenidate hydrochloride tablets by a medicine take-back program if available [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.1, 9.2, 9.3), How Supplied/Storage and Handling (16)].
Serious Cardiovascular Risks
Advise patients that there is a potential serious cardiovascular risk including sudden death, myocardial infarction, stroke, and hypertension with Methylphenidate hydrochloride tablets 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 (5.2)].
Blood Pressure and Heart Rate Increases
Instruct patients that Methylphenidate hydrochloride tablets can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions (5.3)].
Advise patients that Methylphenidate hydrochloride tablets, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)].
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 (5.5)].
Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon]
Instruct patients 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 Methylphenidate hydrochloride tablets. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6)].
Suppression of Growth
Advise patients that Methylphenidate hydrochloride tablets may cause slowing of growth and weight loss [see Warnings and Precautions (5.7)].
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ADHD medications, including Methylphenidate hydrochloride tablets, during pregnancy [see Use in Specific Populations (8.1)].
110 Terry Drive
Newtown, PA 18940
Manufacturer’s code: 10702 Item ID #: 6209/05 Rev: 02/2022
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