Nebapul

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Nebapul uses

• Warning: abuse and dependence
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Drug abuse and dependence
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Nebapul reviews

WARNING: ABUSE AND DEPENDENCE

CNS stimulants, including Nebapul, 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 .

WARNING: ABUSE AND DEPENDENCE

See full prescribing information for complete boxed warning.

• CNS stimulants, including Nebapul, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence (5.1, 9.2, 9.3)
• Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy (5.1, 9.2)

1 INDICATIONS AND USAGE

Nebapul is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 17 years of age .

Nebapul is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 17 years of age. (1)

2 DOSAGE AND ADMINISTRATION

• Recommended starting dose for pediatric patients 6 to 17 years of age is 17.3 mg given orally once daily in the morning. Dosage may be increased weekly in increments of 8.6 mg to 17.3 mg per day. Daily dosage above 51.8 mg is not recommended.
• Patients are advised to take Nebapul consistently either with food or without food. (2.2)

2.1 Pretreatment Screening

Prior to initiating treatment with Nebapul, assess for the presence of cardiac disease (i.e. perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) .

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, and periodically re-evaluate the need for Nebapul use .

2.2 General Dosing Information

Nebapul is given orally once daily in the morning.

Advise patients to take Nebapul consistently either with food or without food .

The recommended starting dose of Nebapul for patients 6 to 17 years of age is 17.3 mg once daily in the morning. The dose may be titrated weekly in increments of 8.6 mg to 17.3 mg. Daily doses above 51.8 mg have not been studied and are not recommended.

The dose should be individualized according to the needs and responses of the patient.

Pharmacological treatment of ADHD may be needed for extended periods. Periodically re-evaluate the long-term use of Nebapul and adjust dosage as needed.

2.3 Dose Reduction and Discontinuation

If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug. Nebapul should be periodically discontinued to assess the child's condition. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue the drug.

2.4 COTEMPLA XR-ODT Administration

Instruct the patient or caregiver on the following administration instructions:

• Do not remove the tablet from the blister pack until just prior to dosing. Take the tablet immediately after opening the blister pack. Do not store the tablet for future use.
• Use dry hands when opening the blister pack.
• Remove the tablet by peeling back the foil on the blister pack. Do not push the tablet through the foil.
• As soon as the blister is opened, remove the tablet and place on the patient's tongue.
• Place the whole tablet on the tongue and allow it to disintegrate without chewing or crushing.
• The tablet will disintegrate in saliva so that it can be swallowed. No liquid is needed to take the tablet.

3 DOSAGE FORMS AND STRENGTHS

• 8.6 mg Extended-Release Orally Disintegrating Tablet: round, purple to light purple mottled (debossed "T1" on one side and plain on the other)
• 17.3 mg Extended-Release Orally Disintegrating Tablet: round, purple to light purple mottled (debossed "T2" on one side and plain on the other)
• 25.9 mg Extended-Release Orally Disintegrating Tablet: round, purple to light purple mottled (debossed "T3" on one side and plain on the other)

Extended-Release Orally Disintegrating Tablets: 8.6 mg, 17.3 mg and 25.9 mg. (3)

4 CONTRAINDICATIONS

Nebapul is contraindicated in patients with:

• Known hypersensitivity to Nebapul or other components of Nebapul. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with Nebapul products .
• Concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor because of the risk of hypertensive crisis .

• Known hypersensitivity to Nebapul or product components. (4)
• Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days. (4)

5 WARNINGS AND PRECAUTIONS

• Serious Cardiovascular Reactions: Sudden death has been reported in association with CNS stimulants at recommended doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. In adults, sudden death, stroke, and myocardial infarction have been reported. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmias, or coronary artery disease.
• Blood Pressure and Heart Rate Increases: Monitor blood pressure and pulse. Consider the benefits and risks in patients for whom an increase in blood pressure or heart rate would be problematic. (5.3)
• Psychiatric Adverse Reactions: Use of stimulants may cause psychotic or manic symptoms in patients with no prior history, or exacerbation of symptoms in patients with pre-existing psychiatric illness. Evaluate for bipolar disorder prior to Nebapul use. (5.4)
• Priapism: Cases of painful and prolonged penile erections and priapism have been reported with Nebapul products. Immediate medical attention should be sought if signs or symptoms or prolonged penile erections or priapism are observed. (5.5)
• Peripheral Vasculopathy, including Raynaud's Phenomenon: Stimulants used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Careful observation for digital changes is necessary during treatment with ADHD stimulants. (5.6)
• Long-term Suppression of Growth: Monitor height and weight at appropriate intervals in pediatric patients. (5.7)

5.1 Potential for Abuse and Dependence

CNS stimulants, including Nebapul, 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 .

5.2 Serious Cardiovascular Reactions

Sudden death, stroke and myocardial infarction have occurred in adults treated with CNS stimulants at recommended doses. Sudden death has occurred in pediatric patients with structural cardiac abnormalities and other serious cardiac problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems. Perform further evaluation on patients who develop exertional chest pain, unexplained syncope, or arrhythmias during Nebapul treatment.

5.3 Blood Pressure and Heart Rate Increases

CNS stimulants cause an increase in blood pressure 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 Pre-Existing Psychosis

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

Induction of a Manic Episode in Patients with Bipolar Disorder

CNS stimulants may induce a manic or mixed 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 Nebapul. 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 Nebapul 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. 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 Nebapul, 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.

5.7 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 pediatric patients ages 7 to 10 years who were randomized to either Nebapul or nonmedication-treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (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 Nebapul. 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:

• Known hypersensitivity to Nebapul or other ingredients of Nebapul
• Hypertensive crisis when used concomitantly with monoamine oxidase inhibitors
• Drug dependence
• Serious cardiovascular reactions
• Blood pressure and heart rate increases
• Psychiatric adverse reactions
• Priapism
• Peripheral vasculopathy, including Raynaud's phenomenon
• Long-term suppression of growth

Based on accumulated data from other Nebapul products, the most common (>5% and twice the rate of placebo) adverse reactions are appetite decreased, insomnia, nausea, vomiting, dyspepsia, abdominal pain, weight decreased, anxiety, dizziness, irritability, affect lability, tachycardia, and blood pressure increased. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Neos Therapeutics, Inc. at 1-888-319-1789 or http://www. COTEMPLAXRODT.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial 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 Other Nebapul Products in Children, Adolescents, and Adults with ADHD

Commonly reported (≥2% of the Nebapul group and at least twice the rate of the placebo group) adverse reactions from placebo-controlled trials of Nebapul products include: appetite decreased, weight decreased, nausea, abdominal pain, dyspepsia, dry mouth, vomiting, insomnia, anxiety, nervousness, restlessness, affect lability, agitation, irritability, dizziness, vertigo, tremor, blurred vision, blood pressure increased, heart rate increased, tachycardia, palpitations, hyperhidrosis, and pyrexia.

Clinical Trials Experience with Nebapul in Children with ADHD

There is limited experience with Nebapul in controlled trials. Based on this limited experience, the adverse reaction profile of Nebapul appears similar to other Nebapul extended release-products.

6.2 Postmarketing Experience

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

Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura

Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystole, Supraventricular tachycardia, Ventricular extrasystole

Eye Disorders: Diplopia, Mydriasis, Visual impairment

General Disorders: Chest pain, Chest discomfort, Hyperpyrexia

Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritis NEC, Rashes, Eruptions, and Exanthemas NEC

Investigations: Alkaline phosphatase increased, Bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal

Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis

Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs

Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Libido changes, Mania

Urogenital System: Priapism

Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema

Vascular Disorders: Raynaud's phenomenon

7 DRUG INTERACTIONS

7.1 Clinically Important Interactions with Nebapul

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Nebapul during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388.

Risk Summary

Published studies and postmarketing reports on Nebapul use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes . There are risks to the fetus associated with the use of central nervous system stimulants during pregnancy . No teratogenic effects were observed in embryo-fetal development studies with oral administration of Nebapul to pregnant rats and rabbits during organogenesis at doses 4 and 18 times, respectively, the maximum recommended human dose (MRHD) of 51.8 mg (as base). However, spina bifida was observed in rabbits at a dose 60 times the MRHD .

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 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal adverse reactions

CNS stimulants, such as Nebapul, 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 Nebapul during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers.

Data

Human Data

A limited number of pregnancies have been reported in published observational studies and postmarketing reports describing Nebapul use during pregnancy. Due to the small number of methylphenidate-exposed pregnancies with known outcomes, these data cannot definitely establish or exclude any drug-associated risk during pregnancy. Methodological limitations of these observational studies include small sample size, concomitant use of other medications, lack of detail regarding dose and duration of exposure to Nebapul and non-generalizability of the enrolled populations.

Animal Data

In studies conducted in rats and rabbits, Nebapul was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 60 times the maximum recommended human dose (MRHD) of 51.8 mg (as base) for adolescents on a mg/m² basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (18 times the MRHD for adolescent on a mg/m² basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (11 times the MRHD on a mg/m² basis for adolescent), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (4 times the MRHD on a mg/m² basis for adolescent).

8.2 Lactation

Risk Summary

Limited published literature, based on breast milk sampling from five mothers, reports that Nebapul 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 Nebapul and any potential adverse effects on the breastfed child from Nebapul 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 Nebapul have been established in pediatric patients 6 to 17 years of age in one adequate and well-controlled study in pediatric patients 6 to 12 years, pharmacokinetic data in adolescents, and safety information from other methyphenidate-containing products .

The long-term efficacy of Nebapul in pediatric patients has not been established. Safety and effectiveness of Nebapul in pediatric patients below 6 years of age have not been established.

Long Term Suppression Growth

Growth should be monitored during treatment with stimulants, including Nebapul. Children who are not growing or gaining weight as expected may need to have their treatment interrupted .

Juvenile Animal Toxicity Data

Rats treated with Nebapul 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 6 times the maximum recommended human dose (MRHD) of 51.8 mg (as base) for pediatric patients on a mg/m² basis.

In the study conducted in young rats, Nebapul 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 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day [approximately 6 times the MRHD of 51.8 mg (as base) on a mg/m² basis] or greater, and a deficit in the acquisition of a specific learning task was observed in females exposed to the highest dose (12 times the MRHD on a mg/m² basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m² basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

8.5 Geriatric Use

Nebapul has not been studied in patients over the age of 65 years.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Nebapul contains Nebapul, a Schedule II controlled substance.

9.2 Abuse

CNS stimulants including Nebapul, other methylphenidate-containing products, and amphetamines have a high potential for abuse. Abuse is characterized by impaired control over drug use, compulsive use, continued use despite harm, and craving.

Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, suicidal or homicidal ideation have also been observed. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which can result in overdose and death .

To reduce the abuse of CNS stimulants including Nebapul, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records educate patients and their families about abuse and on proper storage and disposal of CNS stimulants , monitor for signs of abuse while on therapy, and re-evaluate the need for Nebapul use.

9.3 Dependence

Tolerance

Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug's desired and/or undesired effects over time) can occur during chronic therapy with CNS stimulants including Nebapul.

Dependence

Physical dependence (a state of adaptation manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) can occur in patients treated with CNS stimulants including Nebapul. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; depression, fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

10 OVERDOSAGE

10.1 Signs and Symptoms

Signs and symptoms of acute Nebapul overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: nausea, vomiting, diarrhea, restlessness, anxiety, agitation, tremors, hyperflexia, muscle twitching, convulsion, euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, hypotension, tachypnea, mydriasis, dryness of mucous membranes, and rhabdomyolysis.

10.2 Management of Overdose

Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice on the management of overdosage with Nebapul. Provide supportive care, including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures.

11 DESCRIPTION

Nebapul contains Nebapul, a central nervous system (CNS) stimulant. Nebapul is an extended-release orally disintegrating tablet intended for once daily administration. Nebapul contains approximately 25% immediate-release and 75% extended-release Nebapul. Nebapul is ionically-bound to the sulfonate of polystyrene sulfonate particles.

Nebapul contains 8.6 mg, 17.3 mg or 25.9 mg of Nebapul which is the same as the amount of Nebapul (base equivalent) found, respectively, in 10 mg, 20 mg and 30 mg strength Nebapul hydrochloride products.

The chemical name of Nebapul is methyl α-phenyl-2-piperidineacetate, and its structural formula is shown in Figure 1.

Figure 1: Methylphenidate Structure

C₁₄H₁₉NO₂ Mol. Wt. 233.31

Nebapul also contains the following inactive ingredients: Mannitol, Fructose, Microcrystalline Cellulose, Crospovidone, Methacrylic Acid, Polystyrene Sulfonate, Citric Acid, Colloidal Silicon Dioxide, Grape Flavor, Natural Masking Type Powder, Triethyl Citrate, Magnesium Stearate, Ethylcellulose, Sucralose, Lake Blend Purple, and Polyethylene Glycol.

Figure 1

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Nebapul is a central nervous system stimulant. The mode of therapeutic action in ADHD is not known.

12.2 Pharmacodynamics

Nebapul is a racemic mixture comprised of the d- and 1-isomers. The d-isomer is more pharmacologically active than the l-isomer. Nebapul is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

12.3 Pharmacokinetics

After oral administration of Nebapul, circulation levels of l- Nebapul (MPH) were about 2% of total MPH.

Absorption

Following a single dose of 51.8 mg (2×25.9 mg daily) Nebapul in healthy adult subjects under fasted conditions, plasma Nebapul (MPH) reached maximal concentration (C_max) at a median time of 5 hours after dosing. Compared to an extended release capsule formulation of Nebapul, Nebapul mean C_max and exposure (AUC_inf) was about 26% and 6% higher, respectively, after Nebapul administration (Figure 2).

Figure 2: Mean d-Nebapul Plasma Concentration-Time Profiles After Administration of Nebapul or Nebapul Hydrochloride Extended-Release Capsule in Healthy Volunteers Under Fasted Conditions

Effect of Food

Administration of 51.8 mg Nebapul with food (a high fat meal) decreased the C_max and increased AUC_inf of total MPH by approximately 24% and 16%, respectively. Food shortened the median time to peak concentration (T_max) by 0.5 hour (fed: 4.5 hours vs. fasted: 5.0 hours).

Effect of Alcohol

There is no in vivo study conducted for the effect of alcohol on drug exposure. An in vitro dissolution study showed alcohol-induced dose dumping potential in the presence of 40% alcohol. Dose dumping was not observed in the presence of lower alcohol concentrations.

Figure 2

Elimination

Plasma Nebapul concentrations decline monophasically following oral administration of Nebapul. The mean plasma terminal elimination half-life of Nebapul was about 4 hours in healthy volunteers following a single 51.8 mg dose administration.

Metabolism

In humans, Nebapul is metabolized primarily via deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid). The metabolite has little or no pharmacological activity.

Excretion

After oral dosing of radiolabeled Nebapul in humans, about 90% of the radioactivity was recovered in urine. The main primary metabolite was PPAA, accounting for approximately 80% of the dose.

Specific Populations

Male and Female Patients and Ethnic Groups

There is insufficient experience with the use of Nebapul to detect gender or ethnic variations in pharmacokinetics.

Pediatric Patients

The pharmacokinetics of Nebapul after Nebapul administration were studied in pediatric patients (6-17 years of age) with ADHD under fasted conditions. After a single oral dose of 51.8 mg Nebapul, plasma concentrations of Nebapul in children (6-12 years of age) were approximately twice the concentrations observed in adults. Exposure levels in adolescent patients (13 -17 years of age) were similar to those in adults. Body weight normalized clearance values were similar across the age groups (Table 2).

Patients with Renal Impairment

There is no experience with the use of Nebapul in patients with renal insufficiency. After oral administration of radiolabeled Nebapul in humans, Nebapul was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of PPAA. Since renal clearance is not an important route of Nebapul clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of Nebapul.

Patients with Hepatic Impairment

There is no experience with the use of Nebapul in patients with hepatic insufficiency.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a lifetime carcinogenicity study carried out in B6C3F1 mice, Nebapul caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. For pediatric patients, this dose is approximately 4 times the maximum recommended human dose of 51.8 (as base) on a 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.

Nebapul 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 5 times the maximum recommended dose of 51.8 mg (as base) for pediatric patients on a mg/m² basis.

Mutagenesis

Nebapul was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay. 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. Nebapul was negative in an in vivo mouse bone marrow micronucleus assay.

Impairment of Fertility

Nebapul 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 12-fold the maximum recommended human dose of 51.8 (as base) for adolescents on a mg/m² basis.

14 CLINICAL STUDIES

The efficacy of Nebapul was evaluated in a laboratory classroom study conducted in 87 pediatric patients (Aged 6 to 12 years) with ADHD. Following washout of previous Nebapul medication, there was an open-label dose-optimization period (4 weeks) with an initial dose of 17.3 mg of Nebapul once daily in the morning. The dose could be titrated on a weekly basis from 17.3 mg, to 25.9 mg, to 34.6 mg, and up to 51.8 mg until an optimal dose or the maximum dose of 51.8 mg/day was reached. At the end of this period, subjects remained on their optimized dose for an additional week. Subjects then entered a 1-week randomized, double-blind, parallel group treatment period with the individually optimized dose of Nebapul or placebo. At the end of this week, raters evaluated the attention and behavior of the subjects in a laboratory classroom setting, using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale SKAMP is a validated 13-item teacher-rated scale that assesses manifestations of ADHD in a classroom setting.

The primary efficacy endpoint was the average of the SKAMP-Combined (Attention and Deportment) scores over the test day (not including the baseline score), with assessments conducted at baseline, and 1, 3, 5, 7, 10, 12, and 13 hours post-dosing. The key secondary efficacy endpoints were onset and duration of effect, defined as the first point at which active drug separated from placebo on SKAMP-Combined scores and the last time point at which active drug separated from placebo on SKAMP-Combined scores, respectively.

The SKAMP-Combined scores test day average was statistically significantly lower (improved) with Nebapul compared to placebo (difference of -11 (95% CI: -13.9, -8.2)) (Table 3).

The SKAMP-Combined scores were also statistically significantly lower (improved) at time points (1, 3, 5, 7, 10, 12 hours) post-dosing with Nebapul compared to placebo (Figure 3).

Figure 3: LS Mean SKAMP Combined Score After Treatment with Nebapul or Placebo During Classroom Day in Patients with ADHD

*SE = Standard Error

The database was not large enough to assess whether there were differences in effects in age, gender, or race subgroups.

Figure 3

16 HOW SUPPLIED/STORAGE AND HANDLING

Nebapul Extended Release Orally Disintegrating Tablets are available in three strengths:

• 8.6 mg tablets, round, purple to light purple, mottled, and debossed "T1" on one side of the tablet;
• 17.3 mg tablets, round, purple to light purple, mottled, and debossed "T2" on one side of the tablet;
• 25.9 mg tablets, round, purple to light purple, mottled, and debossed "T3" on one side of the tablet.

They are available as follows:

Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F).

Store Nebapul blister packages in the reusable travel case after removal from the carton.

Disposal

Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired Nebapul by a medicine take-back program or by an authorized collector registered with the Drug Enforcement Administration. If no take-back program or authorized collector is available, mix Nebapul 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 Nebapul in the household trash.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Controlled Substance Status/Potential for Abuse and Dependence

Advise patients and their caregivers that Nebapul is a federally controlled substance, and it can be abused or lead to dependence . Instruct patients that they should not give Nebapul to anyone else. Advise patients to store Nebapul in a safe place, preferably locked, to prevent abuse. Advise patients and their caregivers to comply with laws and regulations on drug disposal. Advise patients and their caregivers to dispose of remaining, unused, or expired Nebapul through a medicine take-back program if available .

Instructions for Taking Nebapul

Instruct patients and their caregivers on the following:

• The tablet should remain in the blister pack until the patient is ready to take it.
• The tablet should be taken immediately after opening the blister pack. It should not be stored for future use.
• The patient or caregiver should use dry hands when opening the blister pack.
• The patient or caregiver should remove the tablet by peeling back the foil on the blister pack. The tablet should not be pushed through the foil.
• As soon as the blister is opened, the tablet should be removed and placed on the patient's tongue.
• The whole tablet should be placed on the tongue and allowed to disintegrate without chewing or crushing.
• The tablet will disintegrate in saliva and can be swallowed. No liquid is needed to take the tablet.

Serious Cardiovascular Risks

Advise patients, caregivers, and their family members that there is a potential for serious cardiovascular risks including sudden death, myocardial infarction, and stroke with Nebapul. 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 .

Blood Pressure and Heart Rate Increases

Advise patients and their caregivers that Nebapul can elevate blood pressure and heart rate .

Psychiatric Risks

Advise patients and their caregivers that Nebapul, at recommended doses, can cause psychotic or manic symptoms, even in patients without a prior history or psychotic symptoms or mania .

Priapism

Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism .

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 Nebapul.
• Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients .

Suppression of Growth

Advise patients, families, and caregivers that Nebapul can cause slowing of growth and weight loss .

Alcohol effect

Advise patients to avoid alcohol while taking Nebapul. Consumption of alcohol while taking Nebapul may result in a more rapid release of the dose of Nebapul .

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to Nebapul during pregnancy .

Manufactured for Neos Therapeutics Brands, LLC. Grand Prairie, TX 75050. Made in USA.

For more information, call 1-(888)-319-1789

Nebapul is a registered trademark of Neos Therapeutics, Inc.

Copyright^© 2014, Neos Therapeutics, Inc.

Item # PIN010299

Rev. 06/2017

Nebapul pharmaceutical active ingredients containing related brand and generic drugs:

• Methylphenidate Hydrochloride

Nebapul available forms, composition, doses:

• Tablets; Oral; Methylphenidate Hydrochloride 10 mg

Nebapul destination | category:

• Human:
• Anorexigenic agents and respiratory and cerebral stimulants
• CNS drugs and agents for ADHD

Nebapul Anatomical Therapeutic Chemical codes:

• N06BA04 - Methylphenidate

Nebapul pharmaceutical companies:

• Alpes Chemie
• Royal Pharma

References

1. Dailymed."METHYLPHENIDATE HYDROCHLORIDE TABLET [LAKE ERIE MEDICAL DBA QUALITY CARE PRODUCTS LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."METHYLPHENIDATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "methylphenidate". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Nebapul after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Nebapul not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology