Safety and Tolerability

BOXED WARNING

WARNING: ABUSE AND DEPENDENCE

CNS stimulants, including Quillivant XR, 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.

CONTRAINDICATIONS

  • Quillivant XR is contraindicated:
  • In patients known to be hypersensitive to methylphenidate or other components of Quillivant XR. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported
  • During treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days following discontinuation of treatment with an MAOI because of the risk of hypertensive crisis

WARNINGS AND PRECAUTIONS

Potential for Abuse and Dependence

  • CNS stimulants, including Quillivant XR, 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

Serious Cardiovascular Reactions

  • Stroke and myocardial infarction have occurred in adults treated with CNS stimulants at recommended doses. Sudden death has occurred in children and adolescents with structural cardiac abnormalities and other serious cardiac problems, and in adults taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac problems
  • Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during treatment with Quillivant XR

Blood Pressure and Heart Rate Increases

  • CNS stimulants cause an increase in blood pressure (mean increase approximately 2-4 mm Hg) and heart rate (mean increase approximately 3-6 bpm). Some individuals may have larger increases. Monitor all patients for hypertension and tachycardia

Psychiatric Adverse Reactions

  • CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic 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 (eg, comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression)
  • CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (eg, hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing Quillivant XR. 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 Quillivant XR, 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 of digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (eg, 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 pediatric patients ages 7 to 10 years who were randomized to either methylphenidate 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 pediatric patients (ie, 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 Quillivant XR. Patients who are not growing or gaining weight as expected may need to have their treatment interrupted

TOLERABILITY

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 methylphenidate products in children, adolescents, and adults with ADHD

Commonly reported (≥2% of the methylphenidate group and at least twice the rate of the placebo group) adverse reactions from placebo-controlled trials of methylphenidate 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 Quillivant XR in children and adolescents with ADHD

There is limited experience with Quillivant XR in controlled trials. Based on this limited experience, the adverse reaction profile of Quillivant XR appears similar to other methylphenidate extended-release products. The most common (≥2% in the Quillivant XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted in 45 ADHD patients (ages 6-12 years) are described in the table below.

USE IN SPECIFIC POPULATIONS

Pregnancy

  • CNS stimulant medications, such as Quillivant XR, 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

Lactation

  • The developmental and health benefits of breastfeeding should be considered along with a mother’s clinical need for Quillivant XR and any potential adverse effects on the breastfed infant from Quillivant XR or from the underlying maternal condition

BOXED WARNING

WARNING: ABUSE AND DEPENDENCE

CNS stimulants, including QuilliChew ER, 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.

CONTRAINDICATIONS

  • QuilliChew ER is contraindicated:
  • In patients known to be hypersensitive to methylphenidate or other components of QuilliChew ER. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported
  • During treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days following discontinuation of treatment with an MAOI because of the risk of hypertensive crisis

WARNINGS AND PRECAUTIONS

Potential for Abuse and Dependence

  • CNS stimulants, including QuilliChew ER, 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

Serious Cardiovascular Reactions

  • Stroke and myocardial infarction have occurred in adults treated with CNS stimulants at recommended doses. Sudden death has occurred in children and adolescents with structural cardiac abnormalities and other serious cardiac problems, and in adults taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac problems
  • Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during treatment with QuilliChew ER

Blood Pressure and Heart Rate Increases

  • CNS stimulants cause an increase in blood pressure (mean increase approximately 2-4 mm Hg) and heart rate (mean increase approximately 3-6 bpm). Some individuals may have larger increases. Monitor all patients for hypertension and tachycardia

Psychiatric Adverse Reactions

  • CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic 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 (eg, comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression)
  • CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (eg, hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing QuilliChew ER. 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 QuilliChew ER, 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 of digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (eg, 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 pediatric patients ages 7 to 10 years who were randomized to either methylphenidate 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 pediatric patients (ie, 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 QuilliChew ER. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted

Risks in Patients with Phenylketonuria

  • Phenylalanine can be harmful to patients with phenylketonuria (PKU). QuilliChew ER extended-release chewable tablets contain phenylalanine, a component of aspartame. Each 20 mg, 30 mg, and 40 mg extended-release chewable tablet contains 3 mg, 4.5 mg, and 6 mg phenylalanine, respectively. Before prescribing QuilliChew ER in patients with PKU, consider the combined daily amount of phenylalanine from all sources, including QuilliChew ER

TOLERABILITY

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 practice.

Clinical Trials Experience with Other Methylphenidate Products in Pediatric Patients and Adults with ADHD

Commonly reported (≥2% of the methylphenidate group and at least twice the rate of the placebo group) adverse reactions from placebo-controlled trials of methylphenidate 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 QuilliChew ER in Pediatric Patients with ADHD

There is limited experience with QuilliChew ER in controlled trials. The safety data in this section are based on data from a laboratory classroom study conducted in 90 pediatric subjects (ages 6 to 12 years) with ADHD. The study consisted of a 6-week dose optimization period, followed by a randomized, double-blind, parallel group treatment period with the individually optimized dose of QuilliChew ER or placebo. The most common (≥2% in the QuilliChew ER group and greater than placebo) adverse reactions reported in the double-blind, randomized, placebo-controlled treatment period in patients optimized to doses of QuilliChew ER 20 to 60 mg/day are described in the table below.

USE IN SPECIFIC POPULATIONS

Pregnancy

  • CNS stimulant medications, such as QuilliChew ER, 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

Lactation

  • The developmental and health benefits of breastfeeding should be considered along with a mother’s clinical need for QuilliChew ER and any potential adverse effects on the breastfed infant from QuilliChew ER or from the underlying maternal condition