Methylphenidate hydrochloride extended-release tablets, USP

Prior to treating patients with Methylphenidate hydrochloride extended-release tablets, assess:
• The risk for abuse, misuse, and addiction [see Warnings and Precautions (5.1)] .
• For the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)] .
• The risk for developing a manic episode (e.g., history of depressive symptoms or a family history of suicide, bipolar disorder, or depression) [see Warnings and Precautions (5.4)] .
• For a family history for tics or Tourette syndrome and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome [see Warnings and Precautions (5.10)]

In pediatric patients 6 years of age and older, start with an immediate-release methylphenidate product 5 mg orally twice daily. Subsequently, switch to methylphenidate hydrochloride extended-release tablets 10 mg once daily. May gradually increase the methylphenidate hydrochloride extended-release tablets dosage. The maximum recommended methylphenidate hydrochloride extended-release tablets dosage in pediatric patients 6 years of age and older is 60 mg per day.

In adult patients, the recommended oral dosage of methylphenidate hydrochloride extended-release tablets is 20 mg or 30 mg daily. The maximum recommended methylphenidate hydrochloride extended-release tablets dosage in adults is 60 mg per day.

Swallow methylphenidate hydrochloride extended-release tablets whole and do not crush or chew the extended-release tablets.

If paradoxical aggravation of ADHD or narcolepsy symptoms or methylphenidate hydrochloride extended-release tablets-associated adverse reactions occur, reduce the methylphenidate hydrochloride extended-release tablets dosage, or, if necessary, discontinue methylphenidate hydrochloride extended-release tablets. If improvement is not observed after appropriate dosage modification over a one-month period, discontinue methylphenidate hydrochloride extended-release tablets.

Must wait at least 14 days after stopping a monoamine oxidase (MAO) inhibitor before starting methylphenidate hydrochloride extended-release tablets [see Contraindications (4) and Drug Interactions (7)] .

Methylphenidate hydrochloride extended-release tablets has a high potential for abuse and misuse. The use of methylphenidate hydrochloride extended-release tablets exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction [see Drug Abuse and Dependence ( 9.1, 9.2)] . Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can result in overdose and death [see Overdosage (10)] , and this risk is increased with higher dosage or unapproved methods of administration, such as snorting or injection.

Before prescribing methylphenidate hydrochloride extended-release tablets, 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 methylphenidate hydrochloride extended-release tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride extended-release tablets to anyone else. Throughout methylphenidate hydrochloride extended-release tablets 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 were treated with CNS stimulants at the recommended ADHD dosage.

Prior to treating patients with methylphenidate hydrochloride extended-release tablets, assess for the presence of cardiac disease (e.g., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam). Avoid methylphenidate hydrochloride extended-release tablets use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

CNS stimulants may 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) [see Adverse Reactions (6)] . Some patients may have larger increases.

Monitor all methylphenidate hydrochloride extended-release tablets-treated patients for hypertension and tachycardia.

Exacerbation of Preexisting Psychosis in Patients with a Psychotic Disorder
CNS stimulants, including methylphenidate hydrochloride extended-release tablets, may exacerbate behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.

Induction of a Manic Episode in Patients with Bipolar Disorder
CNS stimulants, including methylphenidate hydrochloride extended-release tablets, may induce a manic or mixed mood episode in patients with bipolar disorder. Prior to initiating methylphenidate hydrochloride extended-release tablets treatment, screen patients for risk factors for developing a manic episode (e.g., history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).

New Psychotic or Manic Symptoms in Patients without a History of a Bipolar or Psychotic Disorder
CNS stimulants (including methylphenidate hydrochloride extended-release tablets), 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 with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing methylphenidate hydrochloride extended-release tablets.

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in adult and pediatric male patients [see Adverse Reactions (6)]. Although priapism was not reported with methylphenidate initiation, priapism occurred in patients treated with methylphenidate but developed after some time., often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation).

Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

Methylphenidate hydrochloride extended-release tablets-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

CNS stimulants, including methylphenidate hydrochloride extended-release tablets used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon [see Adverse Reactions (6)] . Signs and symptoms of these cases of peripheral vasculopathy were 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 postmarketing reports at different times and at a therapeutic dosage of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms of these cases of peripheral vasculopathy generally improved after CNS stimulant dosage reduction or discontinuation of drug.

During methylphenidate hydrochloride extended-release tablets treatment, carefully assess for digital changes. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate hydrochloride extended-release tablets-treated patients who develop signs or symptoms of peripheral vasculopathy.

Methylphenidate hydrochloride extended-release tablets are not approved for use and are not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4)] .

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 to 13 years), suggests that pediatric patients treated with methylphenidate (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.

Closely monitor growth (weight and height) in methylphenidate hydrochloride extended-release tablets-treated pediatric patients. 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, methylphenidate hydrochloride extended-release tablets-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 (6)] .

Prescribe methylphenidate hydrochloride extended-release tablets to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate hydrochloride extended-release tablets-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 [see Adverse Reactions (6)] . Worsening of Tourette's syndrome has also been reported.

Before initiating methylphenidate hydrochloride extended-release tablets, assess the family history for tics or Tourette' syndrome and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor methylphenidate hydrochloride extended-release tablets-treated patients for the emergence or worsening of tics or Tourette's syndrome, and discontinue methylphenidate hydrochloride extended-release tablets treatment if clinically appropriate.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD drugs, including Methylphenidate hydrochloride extended-release tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visit womensmentalhealth.org/adhd-medications

Risk Summary

Published studies and postmarketing reports on methylphenidate use during pregnancy have inconsistent findings about a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are 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 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 background risk of major birth defects and miscarriage in those with ADHD or narcolepsy 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.

Clinical Considerations

Fetal/Neonatal Adverse Reactions: CNS stimulants, such as Methylphenidate hydrochloride extended-release tablets, 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 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 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15times the MRHD given to adolescents on a mg/m ² 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/m ² 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/m ² 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/m ² 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 (~2 times the MRHD given to adolescents on a mg/m ² basis).

Risk Summary

Limited published literature, based on milk sampling from a small number of methylphenidate-treated lactating women, 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 Methylphenidate hydrochloride extended-release tablets and any potential adverse effects on the breastfed infant from Methylphenidate hydrochloride extended-release tablets or from the underlying maternal condition.

Clinical Considerations

Monitor breastfeeding infants of methylphenidate hydrochloride extended-release tablets-treated lactating women for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

The safety and effectiveness of methylphenidate hydrochloride extended-release tablets for the treatment of ADHD and narcolepsy have been established in pediatric patients 6 years of age and older. The safety and effectiveness of methylphenidate hydrochloride extended-release tablets have not been established in pediatric patients below the age of 6 years.

In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss.

Long-Term Suppression of Growth

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Growth (weight and height) should be monitored during treatment with CNS stimulants, including Methylphenidate hydrochloride extended-release tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their methylphenidate hydrochloride extended-release tablets 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 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/m ² 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/m ² 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/m ² basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

Methylphenidate hydrochloride tablet has not been studied in the geriatric population.

Methylphenidate hydrochloride extended-release tablets contain methylphenidate hydrochloride, a Schedule II controlled substance.

Methylphenidate hydrochloride extended-release tablets have a high potential for abuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1)] .

Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. 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.

Methylphenidate hydrochloride extended-release tablets has a high potential for misuse. 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. Misuse, like abuse, is often associated with higher doses and/or more frequent use of the drug, which may lead to adverse reactions similar to those seen in the context of abuse and substance use disorder.

Misuse and abuse of methylphenidate hydrochloride extended-release tablets 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 methylphenidate hydrochloride extended-release tablets, can result in overdose and death [see Overdosage (10)] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Physical Dependence
Methylphenidate hydrochloride extended-release tablets 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 dosage reduction of a drug.

Withdrawal signs and symptoms after abrupt discontinuation or dosage reduction following prolonged use of CNS stimulants including methylphenidate hydrochloride extended-release tablets included dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance
Methylphenidate hydrochloride extended-release tablets 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).

Overdose of CNS stimulants is characterized by the following sympathomimetic effects:

• Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop.
• CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur.
• Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop.
• Posterior reversible encephalopathy syndrome (PRES) symptoms including headache, altered mental status, hypertension, seizures, and visual disturbances including blindness have occurred in the setting of an amphetamine product overdose. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Diagnosis of PRES should be confirmed by radiological procedure (e.g., MRI).

Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of methylphenidate hydrochloride extended-release tablets should be considered when treating patients with overdose. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. If an overdose occurs, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD and narcolepsy is not known. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases 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. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of methylphenidate hydrochloride extended-release tablets have not been fully characterized.

Cardiac Electrophysiology

A formal QT study has not been conducted in patients who received Methylphenidate hydrochloride extended-release tablets.

The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of Methylphenidate hydrochloride tablets 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 (ECGs) 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 (CI) 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.

Absorption

Methylphenidate hydrochloride in methylphenidate hydrochloride 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 C _max (by 27%) are higher. Time to C _max (T _max) is faster after a high-fat meal (median T _max: 2.5 hours) as compared to without food (median T _max: 3 hours).

Distribution

Binding to plasma proteins is low (10% to 33%). The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.8 ± 0.91 L/kg for l-methylphenidate.

Elimination

The systemic clearance is 0.4 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate.

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%). 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's major metabolite appeared to be greater in females than in males. No gender differences were observed for Methylphenidate hydrochloride plasma concentration in the same subjects.

Racial or Ethnic Groups: There is insufficient experience with the use of Methylphenidate hydrochloride extended-release tablets to detect ethnic variations in pharmacokinetics.

Patients with Renal Impairment: Methylphenidate hydrochloride 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 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.

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 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/m ² 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.

Mutagenesis

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 (CHO) 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 10 times the MRHD of 60 mg/day given to adolescents on a mg/m ² basis.