Dexmethylphenidate Hydrochloride

DEXMETHYLPHENIDATE HYDROCHLORIDE- dexmethylphenidate hydrochloride tablet
Lupin Pharmaceuticals,Inc.

INDICATIONS AND USAGE

Dexmethylphenidate Hydrochloride is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) [see Clinical Studies (14)].

DOSAGE AND ADMINISTRATION

2.1 Pretreatment Screening

Prior to treating pediatric patients and adults with central nervous system (CNS) stimulants, including Dexmethylphenidate Hydrochloride tablet, assess 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].

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 Dexmethylphenidate Hydrochloride use [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].

2.2 Pediatric Patients with ADHD

Patients New to Methylphenidate

The recommended starting dose of Dexmethylphenidate Hydrochloride tablet for pediatric patients who are not currently taking racemic methylphenidate, or for patients who are on stimulants other than methylphenidate, is 5 mg daily (2.5 mg twice daily) with or without food.

Patients Currently on Methylphenidate

The recommended starting dose of Dexmethylphenidate Hydrochloride tablet for pediatric patients currently using methylphenidate is half the total daily dose of racemic methylphenidate.

Titration Schedule

The dose may be titrated weekly in increments of 2.5 to 5 mg to a maximum of 20 mg daily (10 mg twice daily). The dose should be individualized according to the needs and response of the patient.

Maintenance/Extended Treatment

Pharmacological treatment of ADHD may be needed for extended periods. Periodically reevaluate the long-term use of Dexmethylphenidate Hydrochloride and adjust dosage as needed.

2.3 Administration Instructions

Dexmethylphenidate Hydrochloride tablet is administered orally twice daily, at least 4 hours apart.

2.4 Dose Reduction and Discontinuation

If paradoxical aggravation of symptoms or other adverse reactions occur, reduce the dosage, or if necessary, discontinue Dexmethylphenidate Hydrochloride tablet. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

Dexmethylphenidate Hydrochloride tablets are as follows:

2.5 mg: blue, round, flat-faced, beveled-edge tablets, debossed with “862” on the one side and “n” on the other side

5 mg: yellow, round, flat-faced, beveled-edge tablets, debossed with “860” on the one side and “n” on the other side

10 mg: white, round, flat-faced, beveled-edge tablets, debossed with “861” on the one side and “n” on the other side

CONTRAINDICATIONS

Hypersensitivity to methylphenidate or other components of Dexmethylphenidate Hydrochloride tablets. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [see Adverse Reactions (6.1)].

Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MOAI, because of the risk of hypertensive crises [see Drug Interactions (7.1)].

WARNINGS AND PRECAUTIONS

Potential for Abuse and Dependence

CNS stimulants, including Dexmethylphenidate Hydrochloride, 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)].

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 Dexmethylphenidate Hydrochloride treatment.

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.

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 Dexmethylphenidate Hydrochloride tablet. 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.

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.

Peripheral Vasculopathy, Including Raynaud’s Phenomenon

CNS stimulants, including Dexmethylphenidate Hydrochloride tablet, 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 post-marketing 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.

Long-Term Suppression of Growth

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

Careful follow-up of weight and height in 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 Dexmethylphenidate Hydrochloride tablet, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

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 Dexmethylphenidate Hydrochloride tablet [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)]

1.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials Experience with Dexmethylphenidate Hydrochloride in Pediatric Patients with ADHD

The safety data in this section is based on data related to Dexmethylphenidate Hydrochloride exposure during the premarketing development program in a total of 696 participants in clinical trials (684 patients, 12 healthy adult subjects). These participants received Dexmethylphenidate Hydrochloride 5, 10, or 20 mg/day. The 684 ADHD patients (ages 6 to 17 years) were evaluated in 2 controlled clinical studies, 2 clinical pharmacology studies, and 2 open-label long-term safety studies.

Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice placebo): abdominal pain, fever, anorexia, and nausea

Adverse Reactions Leading to Discontinuation: Overall, 50 of 684 (7.3%) pediatric patients treated with Dexmethylphenidate Hydrochloride experienced an adverse reaction that resulted in discontinuation. The most common reasons for discontinuation were twitching (described as motor or vocal tics), anorexia, insomnia, and tachycardia (approximately 1% each).

Table 1 enumerates adverse reactions for two, placebo-controlled, parallel group studies in pediatric patients with ADHD taking Dexmethylphenidate Hydrochloride tablet doses of 5, 10, and 20 mg/day. The table includes only those reactions that occurred in patients treated with Dexmethylphenidate Hydrochloride tablet for which the incidence was at least 5% and twice the incidence among placebo-treated patients.

Table 1: Common Adverse Reactions in Pediatric Patients (6 to 17 years of age) with ADHD*

System Organ Class	Adverse Reactions	Dexmethylphenidate Hydrochloride tablet (N = 79)	Placebo (N = 82)
Body as a Whole	Abdominal Pain	15%	6%
	Fever	5%	1%
Digestive System	Anorexia	6%	1%
		9%	1%

* ADHD: Attention Deficit Hyperactivity Disorder

Postmarketing Experience

The following additional adverse reactions have been identified during post approval use of dexmethylphenidate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal: rhabdomyolysis

Immune System Disorders: hypersensitivity reactions such as angioedema, anaphylactic reactions

Adverse Reactions Reported with all Ritalin and Dexmethylphenidate Hydrochloride Formulations

The following adverse reactions associated with the use of all Ritalin and Dexmethylphenidate Hydrochloride formulations 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.

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 choreoatheetoid 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 with Ritalin and Dexmethylphenidate Hydrochloride formulations [see Adverse Reactions (6.2)] that have been reported with other methylphenidate products based on clinical trials data and post-marketing spontaneous reports.

Blood and Lymphatic Disorders: pancytopenia

Immune System Disorders: hypersensitivity reactions such as auricular swelling Psychiatric Disorders: affect lability, mania, disorientation, libido changes Nervous System Disorders: migraine

Eye Disorders: diplopia, mydriasis

Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole, supraventricular tachycardia, ventricular 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

Urogenital disorders: priapism