PRINCIPAL DISPLAY PANEL - 20 mg Tablet Bottle Label

NDC 51407-528-01

Methylphenidate Hydrochloride Extended-Release Tablets, USP CII

20 mg

PHARMACIST: Dispense the enclosed Medication Guide to each patient

Rx Only

100 Tablets

1 INDICATIONS AND USAGE

Methylphenidate hydrochloride extended-release tablets are indicated for the treatment of:

• Attention Deficit Hyperactivity Disorders (ADHD) in pediatric patients 6 years and older and adults
• Narcolepsy

Limitations of Use

Pediatric patients younger than 6 years of age experience higher plasma exposure than patients 6 years and older at the same dose and higher rates of adverse reactions (e.g., weight loss) [see Use in Specific Populations (8.4)] .

4 CONTRAINDICATIONS

• Hypersensitivity to methylphenidate or other components of Methylphenidate hydrochloride extended-release tablets. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [ see Adverse Reactions (6)].
• Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [ see Drug Interactions (7.1)].

5 WARNINGS AND PRECAUTIONS

N/A

5.1 Potential for Abuse and Dependence

CNS stimulants, including Methylphenidate hydrochloride extended-release tablets other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Boxed Warning, Drug Abuse and Dependence (9.2, 9.3)].

5.2 Serious Cardiovascular Reactions

Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during Methylphenidate hydrochloride extended-release tablets treatment.

5.3 Blood Pressure and Heart Rate Increases

CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.

5.4 Psychiatric Adverse Reactions

Exacerbation of Preexisting Psychosis

CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.

Induction of a Manic Episode in Patients with Bipolar Disorder

CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating 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).

New Psychotic or Manic Symptoms

CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing Methylphenidate hydrochloride extended-release tablets. 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 in placebo-treated patients.

5.5 Priapism

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

5.6 Peripheral Vasculopathy, including Raynaud’s Phenomenon

CNS stimulants, including Methylphenidate hydrochloride extended-release tablets used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include 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 therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

5.7 Long-Term Suppression of Growth in Pediatric Patients

Methylphenidate hydrochloride extended-release tablets are not approved for use 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 consistently medicated pediatric patients (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 pediatric patients treated with CNS stimulants including Methylphenidate hydrochloride extended-release tablets. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

6 ADVERSE REACTIONS

The following are discussed in more detail in other sections of the labeling:

• Abuse and Dependence [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)]
• Known hypersensitivity to methylphenidate or other ingredients of Methylphenidate hydrochloride extended-release tablets [ see Contraindications (4)]
• Hypertensive crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see Contraindications (4), Drug Interactions (7.1)]
• Serious Cardiovascular Reactions [see Warnings and Precautions (5.2)]
• Blood Pressure and Heart Rate Increases [see Warnings and Precautions (5.3)]
• Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
• Priapism [see Warnings and Precautions (5.5)]
• Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions (5.6)]
• Long-term Suppression of Growth [see Warnings and Precautions (5.7)]

The following adverse reactions associated with the use of all Methylphenidate hydrochloride extended-release tablets 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 Methylphenidate hydrochloride extended-release tablets

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 pediatric patients

Psychiatric Disorders:insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood

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

Investigations:weight loss (adult ADHD patients)

Additional Adverse Reactions Reported with Other Methylphenidate-Containing Products

The list below shows adverse reactions not listed for Methylphenidate hydrochloride extended-release tablets 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 and libido changes

Nervous System Disorders:migraine

Eye Disorders:diplopia, mydriasis

Cardiac Disorders:sudden cardiac death, myocardial infarction, bradycardia, extrasystole

Vascular Disorders:peripheral coldness, Raynaud's phenomenon

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

MEDICATION GUIDE

Dispense with Medication Guide available at: https://granulespharma.com/product/methylphenidate-er-tab/ or Scan QR code MEDICATION GUIDE Methylphenidate Hydrochloride Extended-Release Tablets (meth" il fen' i date hye" droe klor' ide)

What is the most important information I should know about****Methylphenidate hydrochloride extended-release tablets? **Methylphenidate hydrochloride extended-release tablets is a federal controlled substance (CII) because it can be abused or lead to dependence.**Keep Methylphenidate hydrochloride extended-release tablets in a safe place to prevent misuse and abuse. Selling or giving away Methylphenidate hydrochloride extended-release tablets may harm others and is against the law. Tell your doctor if you or your child have ever abused or been dependent on alcohol, prescription medicines or street drugs. The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines: **1.**Heart-related problems: *sudden death in patients who have heart problems or heart defects *stroke and heart attack in adults *increased blood pressure and heart rate Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting Methylphenidate hydrochloride extended-release tablets. Your doctor should check you or your child’s blood pressure and heart rate regularly during treatment with Methylphenidate hydrochloride extended-release tablets. Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking****Methylphenidate hydrochloride extended-release tablets. **2.**Mental (Psychiatric) problems: All Patients *new or worse behavior and thought problems *new or worse bipolar illness *new or worse aggressive behavior or hostility *new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking****Methylphenidate hydrochloride extended-release tablets, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.

What is Methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride extended-release tablets is a central nervous system (CNS) stimulant prescription medicine.It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Methylphenidate hydrochloride extended-release tablets may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD. Methylphenidate hydrochloride extended-release tablets should be used as a part of a total treatment program for ADHD that may include counseling or other therapies. Methylphenidate hydrochloride extended-release tablets is also used in the treatment of a sleep disorder called narcolepsy. It is not known if****Methylphenidate hydrochloride extended-release tablets is safe and effective in children under 6 years of age.

Who should not take Methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride extended-release tablets should not be taken if you or your child: are allergic to methylphenidate hydrochloride, or any of the ingredients in Methylphenidate hydrochloride extended-release tablets. See the end of this Medication Guide for a complete list of ingredients in Methylphenidate hydrochloride extended-release tablets. are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI.

Methylphenidate hydrochloride extended-release tablets may not be right for you or your child. Before starting Methylphenidate hydrochloride extended- release tablets tell you or your child’s doctor about all health conditions (or a family history of) including: heart problems, heart defects, high blood pressure mental problems including psychosis, mania, bipolar illness, or depression circulation problems in fingers or toes if you are pregnant or plan to become pregnant. It is not known if Methylphenidate hydrochloride extended-release tablets will harm your unborn baby. There is a pregnancy registry for females who are exposed to ADHD medications, including Methylphenidate hydrochloride extended-release tablets, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to Methylphenidate hydrochloride extended-release tablets and their baby. If you or your child becomes pregnant during treatment with Methylphenidate hydrochloride extended-release tablets talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd­medications/. if you are breastfeeding or plan to breastfeed. Methylphenidate hydrochloride passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with Methylphenidate hydrochloride extended-release tablets. **Tell your doctor about all of the medicines that you or your child takes including prescription and over-the-counter medicines, vitamins, and herbal supplements.**Methylphenidate hydrochloride extended-release tablets 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 Methylphenidate hydrochloride extended-release tablets. Your doctor will decide whether Methylphenidate hydrochloride extended-release tablets can be taken with other medicines. Especially tell your doctor if you or your child takes: anti-depression medicines including MAOIs blood pressure medicines (anti-hypertensive) Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist. Do not start any new medicine while takingMethylphenidate hydrochloride extended-release tabletswithout talking to your doctor first.

How should****Methylphenidate hydrochloride extended-release tablets be taken? Take Methylphenidate hydrochloride extended-release tablets exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. Take Methylphenidate hydrochloride extended-release tablets 30 to 45 minutes before a meal. The effect of a dose of Methylphenidate hydrochloride extended-release tablets usually lasts about 8 hours. *Do not chew or crush**Methylphenidate hydrochloride extended-release tablets.**Swallow Methylphenidate hydrochloride extended-release tablets whole with water or other liquids. Tell your doctor if you or your child cannot swallow Methylphenidate hydrochloride extended-release tablets whole. A different medicine may need to be prescribed. From time to time, your doctor may stop Methylphenidate hydrochloride extended-release tablets treatment for a while to check ADHD symptoms. Your doctor may do regular checks of the blood, heart, and blood pressure while taking Methylphenidate hydrochloride extended-release tablets. Children should have their height and weight checked often while taking Methylphenidate hydrochloride extended-release tablets. Methylphenidate hydrochloride extended-release tablets treatment may be stopped if a problem is found during these check-ups. *In case of poisoning call your poison control center at 1-800-222-1222 right away or go to the nearest hospital emergency room.

What are the possible side effects of****Methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride extended-release tablets may cause serious side effects, including: What are possible side effects of****Methylphenidate hydrochloride extended- release tablets? See**“What is the most important information I should know about****Methylphenidate hydrochloride extended-release tablets?”**for information on reported heart and mental problems. ***painful and prolonged erections (priapism)**have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by a doctor immediately. *circulation problems in fingers and toes(Peripheral vasculopathy, including Raynaud’s phenomenon): fingers or toes may feel numb, cool, painful fingers or toes may change color from pale, to blue, to red Tell your doctor if you or your child have numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. *Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while takingMethylphenidate hydrochloride extended-release tablets. *slowing of growth (height and weight) in children Common side effects include: • fast heart beat • abnormal heartbeat (palpitations) • headache • trouble sleeping • nervousness • sweating a lot • decreased appetite • dry mouth • nausea • stomach pain 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****Methylphenidate hydrochloride extended-release tablets? Store Methylphenidate hydrochloride extended-release tablets in a safe place and in a tightly closed container at room temperature between 68°F to 77°F (20°C to 25°C). Protect from moisture. Dispose of remaining, unused, or expired Methylphenidate hydrochloride extended-release tablets by a medicine take-back program at authorized collection sites such as retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. If no take-back program or authorized collector is available, mix Methylphenidate hydrochloride extended-release tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away (discard) Methylphenidate hydrochloride extended-release tablets in the household trash. *KeepMethylphenidate hydrochloride extended-release tablets and all medicines out of the reach of children.

General information about the safe and effective use of****Methylphenidate hydrochloride extended-release tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or doctor for information about Methylphenidate hydrochloride extended-release tablets that is written for healthcare professionals. Do not use Methylphenidate hydrochloride extended- release tablets for a condition for which it was not prescribed. Do not give Methylphenidate hydrochloride extended-release tablets 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****Methylphenidate hydrochloride extended- release tablets? **Active ingredient:**methylphenidate hydrochloride **Inactive ingredients:**hypromellose, microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide and magnesium stearate. Manufactured by: Granules Pharmaceuticals Inc. < style="background-color: transparent;">Chantilly, VA 20151 Marketed by: GSMS, Inc. Camarillo, CA 93012 USA

This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 07/2025

16 HOW SUPPLIED/STORAGE AND HANDLING

Methylphenidate hydrochloride extended-release tablets, USP are available as follows:

10 mg: White to off white, round shaped, uncoated, tablets debossed with “FM4” on one side and plain on other side.

Bottles of 100 tablets NDC 51407-527-01

20 mg: White to off white, round shaped, uncoated, tablets debossed with “FM5” on one side and plain on other side.

Bottles of 100 tablets NDC 51407-528-01

NOTE: Methylphenidate hydrochloride extended-release tablets, USP are color-additive free.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

Protect from moisture.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure.

Disposal

Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired Methylphenidate hydrochloride extended-release 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 extended-release 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 extended-release 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 extended-release tablets are controlled substances, and they can be abused and lead to dependence. Instruct patients that they should not give Methylphenidate hydrochloride extended-release tablets to anyone else. Advise patients to store Methylphenidate hydrochloride extended-release 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 extended-release 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 extended-release 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 extended-release tablets can cause elevations of their blood pressure and pulse rate [ see Warnings and Precautions (5.3)] .

Psychiatric Risks

Advise patients that Methylphenidate hydrochloride extended-release 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)].

Priapism

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 extended-release 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 extended-release tablets may cause slowing of growth and weight loss [ see Warnings and Precautions (5.7)].

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ADHD medications, including Methylphenidate hydrochloride extended-release tablets, during pregnancy [see Use in Specific Populations (8.1)] .

The Medication Guide may also be obtained by calling 877-770-3183.

Print Medication Guides at:
https://granulespharma.com/product/methylphenidate-er-tab/

Manufactured by:

Granules Pharmaceuticals Inc.

Chantilly, VA 20151

Rev. 07/2025

Marketed by:
GSMS, Inc.
Camarillo, CA 93012 USA

8 USE IN SPECIFIC POPULATIONS

N/A

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, 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 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 2basis. 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.

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 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 2basis. 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 2basis). 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 2basis), 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 2basis). 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 2basis), 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 2basis).

8.2 Lactation

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 0.16% 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 for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

8.4 Pediatric Use

The safety and effectiveness of Methylphenidate hydrochloride extended-release tablets for the treatment of ADHD have been established in pediatric patients 6 to 17 years.

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 experienced higher systemic drug exposures than those observed in older children and adolescents at the same dose. Pediatric patients 4 to <6 years of age also experienced elevated rates of adverse reactions, including weight loss.

The long-term efficacy of Methylphenidate hydrochloride extended-release tablets in pediatric patients has not been established.

Long-Term Suppression of Growth

Growth should be monitored during treatment with stimulants, including Methylphenidate hydrochloride extended-release tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [ see Warnings andPrecautions (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 2basis.

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 2basis) 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 2basis). 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 2basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

8.5 Geriatric Use

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

2 DOSAGE AND ADMINISTRATION

N/A

2.1 Pretreatment Screening

Prior to treating pediatric patients and adults with central nervous system (CNS) stimulants, including Methylphenidate hydrochloride extended-release tablets, assess for the presence of cardiac disease (i.e., perform a careful history including family history of sudden death or ventricular arrhythmia, and physical examination) [see Warnings and Precautions (5.2)] .

Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically reevaluate the need for Methylphenidate hydrochloride extended- release tablets use [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuseand Dependence (9)].

2.2 General Dosing Information

Methylphenidate hydrochloride extended-release tablets have a duration of action of approximately 8 hours. Therefore, Methylphenidate hydrochloride extended-release tablets may be used in place of methylphenidate hydrochloride tablets when the 8-hour dosage of Methylphenidate hydrochloride extended- release tablets corresponds to the titrated 8-hour dosage of methylphenidate hydrochloride tablets. Methylphenidate hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed.

Pharmacological treatment of ADHD may be needed for extended periods. Periodically re-evaluate the long-term use of Methylphenidate hydrochloride extended-release tablets, and adjust dosage as needed.

2.3 Dose Reduction and Discontinuation

If paradoxical worsening of symptoms or other adverse reactions occur, reduce the dosage, or, if necessary, discontinue Methylphenidate hydrochloride extended-release tablets. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

3 DOSAGE FORMS AND STRENGTHS

• 10 mg extended-release tablets, white to off white, round shaped, uncoated, tablets debossed with “FM4” on one side and plain on other side.
• 20 mg extended-release tablets, white to off white, round shaped, uncoated, tablets debossed with “FM5” on one side and plain on other side.

11 DESCRIPTION

Methylphenidate hydrochloride extended-release tablets, USP contains methylphenidate hydrochloride a CNS stimulant. It is available as extended- release tablets of 10 mg and 20 mg strength for oral administration. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is:


Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77 g/mol.

Methylphenidate hydrochloride extended-release tablets, USP contains the following inactive ingredients: hypromellose, microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide and magnesium stearate.

FDA approved dissolution test differs from the USP dissolution test.

13 NONCLINICAL TOXICOLOGY

N/A

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

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/day. This dose is approximately 2 times the MRHD of 60 mg/kg/day given to children on mg/m 2basis. 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 2basis.

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 vitroAmes reverse mutation assay, in the in vitromouse lymphoma cell forward mutation assay, or in the in vitrochromosomal 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 vivoin 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 2basis.