Prescribing information for Tris Pharma’s products

These highlights do not include all the information needed to use DYANAVEL^® XR safely and effectively. See full prescribing information for DYANAVEL^® XR.

DYANAVEL XR (amphetamine) extended-release oral suspension, CII

DYANAVEL XR (amphetamine) extended-release tablets, for oral use, CII

Initial U.S. Approval: 1960

Dosage and Administration (2.3, 2.4)     11/2021

Warnings and Precautions (5.5)     11/2021

DYANAVEL XR is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older (1)

• Recommended starting dosage is 2.5 mg or 5 mg once daily in the morning (2.2)
• Dosage may be increased in increments of 2.5 mg to 10 mg per day every 4 to 7 days up to a maximum daily dose of 20 mg (2.2)
• May be taken with or without food (2.3)
• Extended-release oral suspension: Shake bottle before administering (2.3)
• Extended-release tablets: May be chewed or swallowed whole (2.3)
• DYANAVEL XR oral suspension can be substituted with DYANAVEL XR tablets on a milligram per milligram basis (2.4)
• Do not substitute for other amphetamine products on a milligram-per-milligram basis, because of different amphetamine salt compositions and differing pharmacokinetic profiles (2.4)

• Extended-release oral suspension: containing 2.5 mg amphetamine base equivalents per mL (3)
• Extended-release tablets: 5 mg (functionally scored), 10 mg, 15 mg, 20 mg (3)

• Known hypersensitivity to amphetamine products or other ingredients in DYANAVEL XR (4)
• Use of monoamine oxidase inhibitor (MAOI) or within 14 days of the last MAOI dose (4, 7.1)

• Serious Cardiovascular Reactions: Sudden death has been reported in association with CNS stimulant treatment at recommended doses in pediatric patients 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 arrhythmia, or coronary artery disease (5.2)
• Blood Pressure and Heart Rate Increases: Monitor blood pressure and pulse. Consider benefits and risks before use in patients for whom blood pressure increases may be problematic (5.3)
• Psychiatric Adverse Reactions: May cause psychotic or manic symptoms in patients with no prior history, or exacerbation of symptoms in patients with pre-existing psychosis. Evaluate for bipolar disorder prior to stimulant use (5.4)
• Long-Term Suppression of Growth: Monitor height and weight in pediatric patients during treatment (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)
• Serotonin Syndrome: Increased risk when co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue DYANAVEL XR and initiate supportive treatment (5.7).

Most common adverse reactions observed with amphetamine products: dry mouth, anorexia, weight loss, abdominal pain, nausea, insomnia, restlessness, emotional lability, dizziness, tachycardia (6.1)

Most common adverse reactions observed with amphetamine products: dry mouth, anorexia, weight loss, abdominal pain, nausea, insomnia, restlessness, emotional lability, dizziness, tachycardia (6.1)

• Acidifying and Alkalinizing Agents: Agents that alter urinary pH can alter blood levels of amphetamine. Acidifying agents can decrease amphetamine blood levels, while alkalinizing agents can increase amphetamine blood levels. Adjust DYANAVEL XR dosage accordingly (7.1)

• Pregnancy: May cause fetal harm (8.1)
• Lactation: Breastfeeding not recommended (8.2)

Revised: 02/2022

DYANAVEL XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older [see Clinical Studies (14)].

Prior to initiating treatment with DYANAVEL XR, 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 re-evaluate the need for DYANAVEL XR use [see Warnings and Precautions (5.1), and Drug Abuse and Dependence (9)].

The recommended starting dosage is 2.5 mg or 5 mg once daily in the morning. The dosage may be increased in increments of 2.5 mg to 10 mg per day every 4 to 7 days based on clinical response. The maximum recommended dosage is 20 mg once daily.

Pharmacological treatment of ADHD may be needed for extended periods. Healthcare providers should periodically re-evaluate the long-term use of DYANAVEL XR, and adjust dosage as needed.

Administer DYANAVEL XR orally once daily in the morning with or without food.

DYANAVEL XR Extended-Release Oral Suspension.

Instruct patients to read the “Instructions for Use” for complete administration instructions.

• Ensure that the bottle adapter is firmly inserted into the bottle and do not remove once inserted.
• Shake the bottle of DYANAVEL XR extended-release oral suspension well before every administration.
• Use with the oral dosing dispenser provided by the pharmacist.

DYANAVEL XR Extended-Release Tablets

• May be chewed or swallowed whole [see Clinical Pharmacology (12.3)].
• The 5 mg extended-release tablet is functionally scored and may be divided into equal halves (2.5 mg) at the score line.

DYANAVEL XR extended-release oral suspension can be substituted with DYANAVEL XR extended-release tablets on a milligram-per-milligram basis [see Clinical Pharmacology (12.3)].

If switching from other amphetamine products, discontinue that treatment, and titrate with DYANAVEL XR using the above titration schedule.

Do not substitute for other amphetamine products on a milligram-per-milligram basis, because of different amphetamine salt compositions and differing pharmacokinetic profiles [see Description (11), Clinical Pharmacology (12.3)].

Agents that alter urinary pH can impact urinary excretion and alter blood levels of amphetamine. Acidifying agents (e.g., ascorbic acid) decrease blood levels, while alkalinizing agents (e.g., sodium bicarbonate) increase blood levels. Adjust DYANAVEL XR dosage accordingly [see Drug Interactions (7.1)].

DYANAVEL XR (amphetamine) extended-release oral suspension:

• Extended-release oral suspension contains 2.5 mg amphetamine base equivalents per mL.

DYANAVEL XR (amphetamine) extended-release tablets:

• 5 mg: Off-white, speckled, caplet shaped tablet with ‘5’ debossed on one side and functionally scored on the other side
• 10 mg: Off-white, speckled, diamond shaped tablet with ‘10’ debossed on one side and plain on the other side
• 15 mg: Off-white, speckled, triangle shaped tablet with ‘15’ debossed on one side and plain on the other side
• 20 mg: Off-white, speckled, oval shaped tablet with ‘20’ debossed on one side and plain on the other side

All strengths are expressed in terms of amphetamine base equivalents.

DYANAVEL XR is contraindicated:

• In patients known to be hypersensitive to amphetamine, or other components of DYANAVEL XR. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products [see Adverse Reactions (6)].
• Patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis [see Warnings and Precautions (5.7), Drug Interactions (7.1)].

CNS stimulants, including DYANAVEL XR, other amphetamine-containing products, and methylphenidate, 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)].

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 structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during DYANAVEL XR treatment.

CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Monitor all patients for potential tachycardia and hypertension.

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 Illness

CNS stimulants may induce a mixed or manic episode in patients with bipolar disorder. 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 prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing DYANAVEL XR. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in 0.1% of CNS stimulant-treated patients compared to 0% in placebo-treated patients.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including DYANAVEL XR.

Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted [see Use in Specific Populations (8.4)].

Stimulants, including DYANAVEL 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 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.

Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort [see Drug Interactions (7.1)]. The co-administration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to DYANAVEL XR. In these situations, consider an alternative nonserotonergic drug or an alternative drug that does not inhibit CYP2D6 [see Drug Interactions (7.1)].

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Concomitant use of DYANAVEL XR with MAOI drugs is contraindicated [see Contraindications (4)].

Discontinue treatment with DYANAVEL XR and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment. If concomitant use of DYANAVEL XR with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate DYANAVEL XR with lower doses, monitor patients for the emergence of serotonin syndrome during drug initiation or titration, and inform patients of the increased risk for serotonin syndrome.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Drug Dependence [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)]
• Hypersensitivity to amphetamine, or other components of DYANAVEL XR [see Contraindications (4)]
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) and 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)]
• Long-Term Suppression of Growth [see Warnings and Precautions (5.5)]
• Peripheral Vasculopathy, including Raynaud’s phenomenon [see Warnings and Precautions (5.6)]
• Serotonin Syndrome [see Warnings and Precautions (5.7)]

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 Amphetamine Products in Pediatric Patients and Adults with ADHD

Cardiovascular: Palpitations, tachycardia, elevation of blood pressure, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use.

Central Nervous System: Psychotic episodes at recommended doses, overstimulation, restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, tics, aggression, anger, logorrhea.

Eye Disorders: Vision blurred, mydriasis.

Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects.

Allergic: Urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

Endocrine: Impotence, changes in libido.

Skin: Alopecia.

Clinical Trials Experience with DYANAVEL XR in Pediatric Patients with ADHD

There is limited experience with DYANAVEL XR in controlled trials. Based on this limited experience, the adverse reaction profile of DYANAVEL XR appears similar to other amphetamine extended-release products. The most common (≥2% in the DYANAVEL XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted with DYANAVEL XR extended-release oral suspension in 108 patients with ADHD (aged 6 to 12 years) were: epistaxis, allergic rhinitis, and upper abdominal pain.

The following adverse reactions have been identified during post approval use of other amphetamine 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.

Allergic: urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis have been reported

Cardiovascular: palpitations, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use

Central Nervous System: restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, aggression, anger, logorrhea, and paresthesia (including formication)

Endocrine: impotence, changes in libido, frequent or prolonged erections

Eye Disorders: vision blurred, mydriasis

Gastrointestinal: unpleasant taste, constipation, intestinal ischemia, and other gastrointestinal disturbances

Musculoskeletal, Connective Tissue, and Bone Disorders: rhabdomyolysis

Psychiatric Disorders: dermatillomania, bruxism

Skin: alopecia

Vascular Disorders: Raynaud’s phenomenon

Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DYANAVEL XR during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-andresearch-programs/pregnancyregistry/othermedications/.

Risk Summary

There are limited published data on the use of amphetamines in pregnant women. These data are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. Adverse pregnancy outcomes, including premature delivery and low birth weight, have been seen in infants born to mothers dependent on amphetamines. No effects on morphological development were observed in embryofetal development studies with oral administration of amphetamine to rats and rabbits during organogenesis at doses that are approximately 3 and 16 times, respectively, the maximum recommended human dose (MRHD) of 20 mg/day (as base equivalents) on a mg/m² basis, given to adults. However, long-term neurochemical and behavioral effects have been reported in published animal developmental studies using clinically relevant doses of amphetamine [see Data]. 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

Amphetamines, such as DYANAVEL XR, may cause vasoconstriction, including vasoconstriction of placental blood vessels, and may increase the risk for intrauterine growth restriction. In addition, amphetamines can stimulate uterine contractions increasing the risk of premature delivery. Premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Monitor infants born to mothers taking amphetamines for symptoms of withdrawal, such as feeding difficulties, irritability, agitation, and excessive drowsiness.

Data

Animal Data

Amphetamine (d- to l- enantiomer ratio of 3:1) had no apparent effects on embryofetal morphological development or survival when orally administered to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 6 and 16 mg/kg/day, respectively. These doses are approximately 3 and 16 times, respectively, the MRHD of 20 mg/day (as base equivalents) on a mg/m² basis, given to adults. Fetal malformations and death have been reported in mice following parenteral administration of d-amphetamine doses of 50 mg/kg/day (approximately 12 times the MRHD) given to adults on a mg/m² basis or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity.

A number of studies in rodents indicate that prenatal or early postnatal exposure to amphetamine (d- or d, l-), at doses similar to those used clinically, can result in long-term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function.

Risk Summary

Based on limited case reports in published literature, amphetamine (d- or d, l-) is present in human milk, at relative infant doses of 2% to 13.8% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.9 and 7.5. There are no reports of adverse effects on the breastfed infant and no effects on milk production. However, long term neurodevelopmental effects on infants from stimulant exposure are unknown. Because of the potential for serious adverse reactions in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with DYANAVEL XR.

Risk Summary

Safety and effectiveness have been established in pediatric patients with ADHD ages 6 to 17 years [see Adverse Reactions (6.1), Clinical Pharmacology (12), and Clinical Studies (14)]. Safety and efficacy in pediatric patients younger than 6 years with ADHD have not been established.

Long-Term Growth Suppression

Growth should be monitored during treatment with stimulants, including DYANAVEL XR, and pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.5)].

DYANAVEL XR has not been studied in the geriatric population.

DYANAVEL XR contains amphetamine, a Schedule II controlled substance.

DYANAVEL XR, is a CNS stimulant that contains amphetamine which has a high potential for abuse. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Both abuse and misuse may lead to addiction, and some individuals may develop addiction even when taking DYANAVEL XR as prescribed.

Signs and symptoms of amphetamine abuse may 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. Individuals who abuse amphetamines may use unapproved routes of administration which can result in overdose and death [see Overdosage (10)].

To reduce the abuse of DYANAVEL XR, 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 DYANAVEL XR use.

Tolerance

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance may occur during the chronic therapy of CNS stimulants including DYANAVEL XR.

Dependence

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation, a significant dose reduction of a drug, or administration of an antagonist and may occur in patients treated with CNS stimulants including DYANAVEL XR. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice for treatment of overdosage. Individual patient response to amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses.

Manifestations of amphetamine overdose include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia, and rhabdomyolysis. Fatigue and depression usually follow the central nervous system stimulation. Other reactions include arrhythmias, hypertension or hypotension, circulatory collapse, nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma.

DYANAVEL XR (amphetamine) extended-release oral suspension and DYANAVEL XR (amphetamine) extended-release tablets contain amphetamine, a CNS stimulant, in a 3.2:1 ratio of d- to l-amphetamine.

There are three active ingredients: amphetamine (complexed with sodium polystyrene sulfonate), dextroamphetamine sulfate and amphetamine aspartate. The dosage strengths are expressed in terms of amphetamine base.

DYANAVEL XR contains both immediate-release and extended-release components.

DYANAVEL XR extended-release oral suspension 2.5 mg/mL:

• Each 1 mL contains 2 mg of amphetamine (in a 3.2 to 1 ratio of d- to l-amphetamine complexed with sodium polystyrene sulfonate), and 0.5 mg amphetamine (present as 0.5 mg of amphetamine aspartate and 0.3 mg of dextroamphetamine sulfate).

DYANAVEL XR extended-release tablets:

• Each 5 mg strength tablet contains 4 mg of amphetamine (in a 3.2 to 1 ratio of d- to l-amphetamine complexed with sodium polystyrene sulfonate), and 1 mg of amphetamine (present as 1 mg of amphetamine aspartate and 0.7 mg of dextroamphetamine sulfate).
• Each 10 mg strength tablet contains 8 mg of amphetamine (in a 3.2 to 1 ratio of d- to l-amphetamine complexed with sodium polystyrene sulfonate), and 2 mg of amphetamine (present as 2 mg amphetamine aspartate and 1.4 mg dextroamphetamine sulfate).
• Each 15 mg strength tablet contains 12 mg of amphetamine (in a 3.2 to 1 ratio of d- to l-amphetamine complexed with sodium polystyrene sulfonate), and 3 mg of amphetamine (present as 3 mg amphetamine aspartate and 2 mg dextroamphetamine sulfate).
• Each 20 mg strength tablet contains 16 mg of amphetamine (in a 3.2 to 1 ratio of d- to l-amphetamine complexed with sodium polystyrene sulfonate), and 4 mg of amphetamine (present as 4 mg amphetamine aspartate and 2.7 mg dextroamphetamine sulfate).

DYANAVEL XR extended-release oral suspension and DYANAVEL XR extended-release tablets are intended for oral administration.

DYANAVEL XR extended-release oral suspension: anhydrous citric acid, bubblegum flavor, glycerin, methylparaben, modified starch, polysorbate 80, povidone, polyvinyl acetate, propylparaben, sodium lauryl sulfate, sodium polystyrene sulfonate, sucralose, triacetin and xanthan gum.

DYANAVEL XR extended-release tablets: bubblegum flavor, crospovidone, guar gum, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl acetate, povidone, silicon dioxide, sodium polystyrene sulfonate, sucralose, talc, triacetin and xanthan gum.

Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in ADHD is not known.

Amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

Absorption

Extended-Release Oral Suspension

Following a single 18.8 mg dose of DYANAVEL XR extended-release oral suspension in 29 healthy adult subjects under fasting conditions in a crossover study, the median (range) time to peak plasma concentrations (T_max) for both d- to l- isomers of amphetamine were 4 (2 to 7) hours after dosing. Peak concentrations (C_max) of d- to l-amphetamine were 102% and 106%, respectively, of the C_max of immediate-release (IR) mixed amphetamine salts (MAS) tablets. The relative bioavailability of DYANAVEL XR compared with an equal dose of IR MAS tablets is 106% for d- and 111% for l-amphetamine.

Following a single 18.8 mg dose of DYANAVEL XR extended-release oral suspension in 28 healthy adult subjects in a crossover study under fasting conditions, the median (range) time to peak plasma concentrations (T_max) were about 4 (2 to 7) hours and 5 (3 to 7) hours for d- and l-amphetamine, respectively. Peak concentration (C_max) was 93% and 94%, respectively, of the C_max of extended release (ER) MAS capsules. The relative bioavailability of DYANAVEL XR compared with an equal dose of ER MAS capsules is 94% for both d- and l-amphetamine.

Extended-Release Tablet

Following a single 20 mg dose of DYANAVEL XR extended-release tablets (swallowed whole) to 36 healthy adults under fasted conditions in a crossover study, the median (range) time to peak plasma concentration (T_max) for both d- and l-amphetamine, were 5.0 (2 to 9) hours after dosing. Peak concentrations (C_max) for both d- and l-amphetamine, were 101% of the C_max of DYANAVEL XR oral suspension. The relative bioavailability of DYANAVEL XR tablets compared with an equal dose of DYANAVEL XR oral suspension, for d- and l-amphetamine, were 105% and 106%, respectively.

Dyanavel XR extended-release tablets chewed or swallowed whole under fasted conditions did not significantly affect exposure and T_max.

Effect of Food

Extended-Release Oral Suspension

Ingestion of 18.8 mg of DYANAVEL XR extended-release oral suspension with a high-fat meal increased the average C_max of both isomers of DYANAVEL XR by about 2%, decreased the AUC of d- and l-amphetamine by 5.7% and 7.4%, respectively. A delay of T_max by approximately 1 hour was observed for both isomers. Extended-Release Tablet

Ingestion of 20 mg DYANAVEL XR extended-release tablets with a high-fat meal decreased the average C_max of both isomers of amphetamine by about 3%, decreased AUC of d- and l-amphetamine by about 4.0% and 7.3%, respectively. Median T_max was not delayed for either isomer.

Elimination

The mean plasma terminal elimination half-lives of d- and l-amphetamine were 12.4 hours and 15.1 hours, respectively, following a single 18.8 mg dose of DYANAVEL XR extended-release oral suspension.

The mean plasma terminal elimination half-lives of d- and l-amphetamine were 13.5 hours and 17.3 hours, respectively, following a single 20 mg dose of DYANAVEL XR extended-release tablets.

Metabolism

Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain A or B carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxy-amphetamine are both active and each is subsequently oxidized to form 4-hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid. Although the enzymes involved in amphetamine metabolism have not been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy-amphetamine.

Because CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility.

Excretion

With normal urine pH, approximately half of an administered dose of amphetamine is recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30%-40% of the dose is recoverable in urine as amphetamine itself.

Specific Populations

Pediatric Patients

Following a single 10 mg dose of DYANAVEL XR extended-release oral suspension in pediatric subjects with ADHD (aged 6 to 12 years) under fasting conditions, peak plasma concentrations of d- and l-amphetamine occurred at a median time of 3.9 and 4.5 hours after dosing, respectively. The mean plasma terminal elimination half-lives of d- and l-amphetamine were 10.4 hours and 12.1 hours, respectively.

Patients with Hepatic or Renal Impairment

No specific studies have been conducted to evaluate the effect of renal impairment or hepatic impairment on the PK after DYANAVEL XR administration. However, urinary recovery of amphetamine has been reported to range from 1% to 75%, depending on urinary pH, with the remaining fraction of the dose hepatically metabolized. Consequently, both hepatic and renal dysfunctions have the potential to inhibit the elimination of amphetamine and result in prolonged exposures.

Drug Interaction Studies

CYP Enzymes

In vitro experiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites. However, because of the probability of auto-inhibition and the lack of information on the concentration of these metabolites relative to in vivo concentrations, no predications regarding the potential for amphetamine or its metabolites to inhibit the metabolism of other drugs by CYP isozymes in vivo can be made.

Urine pH Modulators

Because amphetamine has a pKa of 9.9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pH results in less ionization and reduced renal elimination; acidic pH and high flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion. In addition, any decrease in amphetamine’s metabolism that might occur due to drug interactions or genetic polymorphisms is more likely to be clinically significant when renal elimination is decreased [see Drug Interactions (7.1)].

Alcohol Effect

There is no in vivo study conducted for the effect of alcohol on drug exposure. An in vitro dissolution study on DYANAVEL XR extended-release oral suspension showed alcohol-induced dose dumping potential in the presence of 40% alcohol. A similar study on the DYANAVEL XR extended-release tablets showed no alcohol-induced dose dumping in the presence of 40% alcohol. Dose dumping was not observed in the presence of 5%, 10%, or 20% alcohol concentrations for either product.

Carcinogenesis

No evidence of carcinogenicity was found in studies in which d, l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats. These doses are approximately 7, 5, and 2 times, respectively, the maximum recommended human dose of 20- mg/day (as base equivalents) given to adults, on a mg/m² basis.

Mutagenesis

Amphetamine, in the enantiomer ratio (d- to l- ratio of approximately 3:1), was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli component of the Ames test in vitro. d, l-Amphetamine (1:1 enantiomer ratio) has been reported to produce a positive response in the mouse bone marrow micronucleus test, an equivocal response in the Ames test, and negative responses in the in vitro sister chromatid exchange and chromosomal aberration assays.

Impairment of Fertility

Amphetamine, in the enantiomer ratio (d- to l- ratio of approximately 3:1), did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day [approximately 10 times the maximum recommended human dose of 20 mg/day (as base equivalents) given to adults on a mg/m² basis].

Acute administration of high doses of amphetamine (d- or d, l-) has been shown to produce long-lasting neurotoxic effects, including irreversible nerve fiber damage, in rodents. The significance of these findings to humans is unknown.

The efficacy of DYANAVEL XR extended-release oral suspension was evaluated in a laboratory classroom study conducted in 108 pediatric patients (aged 6 to 12 years) with ADHD. The study began with an open-label dose optimization period (5 weeks) with an initial DYANAVEL XR dose of 2.5 or 5 mg once daily in the morning. The dose could be titrated weekly in increments of 2.5 to 10 mg until an optimal dose or the maximum dose of 20 mg/day was reached. Subjects then entered a 1-week randomized, doubleblind treatment with the individually optimized dose of DYANAVEL XR or placebo. At the end of the week, school teachers and raters evaluated the attention and behavior of the subjects in a laboratory classroom using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale. SKAMP is a 13-item teacher-rated scale that assesses manifestations of ADHD in a classroom setting. Each item is rated on a 7-point impairment scale.

The primary efficacy endpoint was change from pre-dose in the SKAMP-Combined score at 4 hours post-dosing. The key secondary efficacy parameters were onset and duration of clinical effect. The change scores from pre-dose SKAMP-Combined scores at post-dose time points (1, 2, 4, 6, 8, 10, 12 and 13 hours) were used to evaluate the key secondary efficacy parameters. Results from the double-blind, placebo-controlled week of the study are summarized in Table 3 and Figure 3. SKAMP-Combined change scores from pre-dose demonstrated a statistically significant improvement at all time points (1, 2, 4, 6, 8, 10, 12, 13 hours) post-dosing with DYANAVEL XR compared to placebo.

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.

^a Difference (drug minus placebo) in least-squares mean change from pre-dose.

DYANAVEL XR (amphetamine) extended-release oral suspension: The concentration is 2.5 mg/mL amphetamine base equivalents and is supplied as light beige to tan viscous suspension with bubblegum flavor in bottles of 464 mL (NDC 24478-102-01).

The product is provided in a carton. Each carton also contains four oral dispensers and four bottle adapters.

DYANAVEL XR (amphetamine) extended-release tablets: Supplied in bottles (that contain a desiccant) with child-resistant closure as 5 mg, 10 mg, 15 mg, and 20 mg strengths.

• 5 mg DYANAVEL XR extended-release tablet is functionally scored and is available as an off-white, speckled, caplet shaped tablet with 5 debossed on one side and scored on the other side, supplied in bottles of 30 (NDC 24478-106-01).
• 10 mg DYANAVEL XR extended-release tablet is available as an off-white, speckled, diamond shaped tablet with 10 debossed on one side and plain on the other side, supplied in bottles of 30 (NDC 24478-108-01).
• 15 mg DYANAVEL XR extended-release tablet is available as an off-white, speckled, triangle shaped tablet with 15 debossed on one side and plain on the other side, supplied in bottles of 30 (NDC 24478-109-01).
• 20 mg DYANAVEL XR extended-release tablet is available as an off-white, speckled, oval shaped tablet with 20 debossed on one side and plain on the other side, supplied in bottles of 30 (NDC 24478-110-01).

Dispense in a tight container with child-resistant closure.

Store at 20° to 25°C (68° to 77°F); excursions permitted from 15º to 30ºC (59º to 86ºF) [see USP Controlled Room Temperature].

DYANAVEL XR extended-release oral suspension: The pharmacist should insert the bottle adapter firmly into the neck of the bottle and provide the oral dosing dispenser to the patient when dispensing this product.

Disposal

Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired DYANAVEL XR 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 DYANAVEL XR 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 DYANAVEL XR in the household trash.

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Controlled Substance Status/Potential for Abuse, Misuse, and Dependence

Advise patients that DYANAVEL XR is a federally controlled substance because it can be abused or lead to dependence. Advise patients to store DYANAVEL XR 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 DYANAVEL XR by a medicine take-back program if available [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].

Dosage and Administration Instructions

Provide the following instructions on administration to the patient [see Dosage and Administration (2.3)]:

Serious Cardiovascular Risks

Advise patients and their caregivers of serious cardiovascular risk (including sudden death, myocardial infarction, stroke, and hypertension) with DYANAVEL XR. 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 and their caregivers that DYANAVEL XR can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions (5.3)].

Psychiatric Risks

Advise patients and their caregivers that DYANAVEL XR, at recommended doses, may cause psychotic or manic symptoms, even in patients without a prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)].

Long-Term Suppression of Growth

Advise patients and their caregivers that DYANAVEL XR may cause slowing of growth and weight loss [see Warnings and Precautions (5.5)].

Circulation Problems in Fingers and Toes [Peripheral vasculopathy, including Raynaud’s phenomenon]

Instruct patients and their caregivers beginning treatment with DYANAVEL XR 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 and their caregivers to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.

Instruct patients and their caregivers to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking DYANAVEL XR. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6)].

Serotonin Syndrome

Caution patients and their caregivers about the risk of serotonin syndrome with concomitant use of DYANAVEL XR and other serotonergic drugs including SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others such as linezolid [see Contraindications (4), Warnings and Precautions (5.7) and Drug Interactions (7.1)]. Advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.

Concomitant Medications

Advise patients and their caregivers to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs because there is a potential for interactions [see Drug Interactions (7.1)].

Pregnancy Registry

Advise patients and their caregivers that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DYANAVEL XR during pregnancy [see Use in Specific Populations (8.1)].

Pregnancy

Advise patients and their caregivers to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with DYANAVEL XR.

Advise patients of the potential fetal effects from the use of DYANAVEL XR during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise women not to breastfeed if they are taking DYANAVEL XR [see Use in Specific Populations (8.2)].

Alcohol

Advise patients to avoid alcohol while taking DYANAVEL XR. Consumption of alcohol while taking DYANAVEL XR may result in a more rapid release of the dose of amphetamine [see Clinical Pharmacology (12.3)].

Manufactured by:

Monmouth Junction, NJ 08852

LB8684

Rev. 00

May 2022

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 05/2022

QuilliChew ER is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). (1)

• QuilliChew ER may be taken with or without food. (2.1)
• For patients 6 years and above, recommended starting dose is 20 mg given orally once daily in the morning. Dosage may be titrated weekly in increments of 10 mg, 15 mg or 20 mg per day. Daily dosage above 60 mg is not recommended. (2.1)

• Extended-release chewable tablets: 20 mg and 30 mg of methylphenidate hydrochloride (HCl), functionally scored (3)
• Extended-release chewable tablets: 40 mg of methylphenidate HCl, not scored (3)

• Known hypersensitivity to methylphenidate or product components. (4.1)
• Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days. (4.2, 7.1)

• 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. (5.2)
• 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 CNS 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 QuilliChew ER use. (5.4)
• Priapism: Cases of painful and prolonged penile erections and priapism have been reported with methylphenidate products. Immediate medical attention should be sought if signs or symptoms of prolonged penile erections or priapism are observed. (5.5)
• Peripheral Vasculopathy, including Raynaud’s Phenomenon: CNS 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)
• Risks in Phenylketonurics: QuilliChew ER extended-release chewable tablets contain phenylalanine, a component of aspartame. (5.8)

Based on accumulated data from other methylphenidate 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. (6.1)

• Antihypertensive drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. (7)

Revised: 6/2021

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

Prior to treating children, adolescents, and adults with CNS stimulants including QuilliChew ER, 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 re-evaluate the need for QuilliChew ER use [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].

The recommended starting dose of QuilliChew ER for patients 6 years and above is 20 mg once daily orally in the morning. The dose may be titrated up or down weekly in increments of 10 mg, 15 mg or 20 mg. The 10 mg and 15 mg doses can each be achieved by breaking in half the functionally scored 20 mg and 30 mg tablets, respectively. Daily doses above 60 mg have not been studied and are not recommended. As with any CNS stimulant, during titration of QuilliChew ER, the prescribed dose should be adjusted, if necessary, until a well-tolerated, therapeutic dose is achieved.

Pharmacological treatment of ADHD may be needed for extended periods. Health care providers should periodically re-evaluate the long-term use of QuilliChew ER, and adjust dosage as needed.

QuilliChew ER should be orally administered once daily in the morning with or without food [see Clinical Pharmacology (12.3)].

If switching from other methylphenidate products, discontinue that treatment, and titrate with QuilliChew ER using the above titration schedule.

Do not substitute for other methylphenidate products on a milligram-per-milligram basis, because of different methylphenidate base compositions and differing pharmacokinetic profiles [see Description (11), Clinical Pharmacology (12.3)].

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

Extended-release chewable tablets:

20 mg equivalent of methylphenidate HCl available as a speckled, off-white, capsule-shaped coated tablet, debossed with “NP 12” on one side and functionally scored on the other side.

30 mg equivalent of methylphenidate HCl available as a speckled, light pink color, capsule- shaped coated tablet, debossed with “NP 13” on one side and functionally scored on the other side.

40 mg equivalent of methylphenidate HCl available as a speckled, dark pink to peach color, capsule-shaped coated tablet, debossed with “NP 14” on one side and plain (not scored) on the other side.

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 in patients treated with other methylphenidate products [see Adverse Reactions (6.2)].

QuilliChew ER is contraindicated during concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (MAOI), because of the risk of hypertensive crisis [see Drug Interactions (7.1)].

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 [see Drug Abuse and Dependence (9.2, 9.3)].

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.

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.

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 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.

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.

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 (e.g., rheumatology referral) may be appropriate for certain patients.

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 (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 QuilliChew ER. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

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.

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

• Known hypersensitivity to methylphenidate products or other ingredients of QuilliChew ER [see Contraindications (4.1)]
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4.2), Drug Interactions (7.1)]
• Drug Dependence [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)]
• 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)]
• Risks in Phenylketonuria [see Warnings and Precautions (5.8)]

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 QuilliChew ER in Children with ADHD

There is limited experience with QuilliChew ER in controlled trials. The safety data in this section is 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 phase in patients optimized to doses of QuilliChew ER 20 to 60 mg/day are described in Table 1.

The following adverse reactions have been identified during post approval use of methylphenidate 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

Hepatobiliary Disorders: Severe hepatocellular injury

Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus 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

Do not administer QuilliChew ER concomitantly with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment. Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.

QuilliChew ER may decrease the effectiveness of drugs used to treat hypertension. Monitor blood pressure and adjust the dosage of the hypertensive drug as needed [see Warnings and Precautions (5.3)].

Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/.

There are limited published studies and small case series that report on the use of methylphenidate in pregnant women; however, the data are insufficient to inform any drug-associated risks. There are clinical considerations [see Clinical Considerations]. No teratogenic effects were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses 2 and 11 times, respectively, the maximum recommended human dose (MRHD). However, spina bifida was observed in rabbits at a dose 40 times the MRHD [see Data].

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.

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.

Data

In 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. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m² basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD 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 (7 times the MRHD on a mg/m² basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m² basis).

Limited published literature 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 CNS stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the 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.

Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

The safety and effectiveness of QuilliChew ER have been established in pediatric patients ages 6 to 17 years. Use of QuilliChew ER in these age groups is based on one adequate and well-controlled clinical study in pediatric patients 6 to 12 years old, pharmacokinetic data in adolescents and adults, and safety information from other methylphenidate-containing products. The long-term efficacy of methylphenidate in pediatric patients has not been established [see Clinical Pharmacology (12), Clinical Studies (14)]. Safety and efficacy in pediatric patients below the age of 6 years have not been established.

Growth should be monitored during treatment with CNS stimulants, including QuilliChew ER. Children who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7)].

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 6 times the maximum recommended human dose (MRHD) on a mg/m² basis.

In the 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 6 times the maximum recommended human dose [MRHD] 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.

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

QuilliChew ER contains methylphenidate, a Schedule II controlled substance.

CNS stimulants including QuilliChew ER, 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 [see Overdosage (10)].

To reduce the abuse of CNS stimulants including QuilliChew ER, 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 [see How Supplied/Storage and Handling (16.1, 16.2)], monitor for signs of abuse while on therapy, and re-evaluate the need for QuilliChew ER use.

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 QuilliChew ER.

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 QuilliChew ER. Withdrawal symptoms after abrupt cessation following prolonged highdosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice on the management of overdosage with methylphenidate.

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

QuilliChew ER (methylphenidate hydrochloride extended-release chewable tablets) is available in three dosage strengths - 20 mg, 30 mg and 40 mg. The dosage strengths are expressed in terms of methylphenidate hydrochloride equivalents; however only 15% of methylphenidate is present as methylphenidate hydrochloride salt. The remaining 85% is present as methylphenidate ionically-bound to the sulfonate groups of sodium polystyrene sulfonate particles. QuilliChew ER contains approximately 30% immediate-release and 70% extended-release methylphenidate.

The QuilliChew ER extended-release chewable tablets are cherry flavored.

Methylphenidate HCl is a central nervous system (CNS) stimulant. The chemical name is methyl α- phenyl-2-piperidineacetate hydrochloride, and its structural formula is shown in Figure 1.

C₁₄H₁₉NO₂•HCI Mol.         Wt. 269.77

Methylphenidate HCl is a white, odorless 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.

QuilliChew ER also contains the following inactive ingredients: aspartame [see Warnings and Precautions (5.8)], cherry flavor, citric acid, crospovidone, D&C red #30 (for 30 mg strength), D&C red #7 (for 40 mg strength), guar gum, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl acetate, polyvinyl alcohol, povidone, silicon dioxide, sodium polystyrene sulfonate, talc, triacetin, xanthan gum.

Methylphenidate HCl is a central nervous system (CNS) stimulant.

Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l‑isomer. The mode of therapeutic action in ADHD is not known. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.

Following a single oral dose of 40 mg QuilliChew ER under fasting conditions, plasma methylphenidate reached maximal concentration (C_max) at a median time of 5 hours after dosing. Compared to an immediate-release formulation of methylphenidate chewable tablet (40 mg in 2 equal doses of 20 mg, 6 hours apart), methylphenidate mean peak concentration and exposure (AUC_inf) was about 20% and 11% lower, respectively, after single dose administration of 40 mg QuilliChew ER (Figure 2).

High-fat meal had no effect on the time to peak concentration, and increased C max and systemic exposure (AUC_inf) of methylphenidate by about 20% and 4%, respectively, after a single dose administration of 40 mg QuilliChew ER.

Plasma methylphenidate concentrations decline monophasically following oral administration of QuilliChew ER. The mean plasma terminal elimination half-life of methylphenidate was about 5.2 hours in healthy volunteers following a single 40 mg dose administration.

In humans, methylphenidate is metabolized primarily via de-esterification to alpha-phenyl-piperidine acetic acid (PPAA). The metabolite has little or no pharmacologic activity.

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

At 40% alcohol concentration, there was about 90% release methylphenidate from QuilliChew ER 40 mg tablet within half an hour. The results with the 40 mg chewable tablet strength are considered representative of the other available tablet strengths.

There is insufficient experience with the use of QuilliChew ER to detect gender variations in pharmacokinetics.

There is insufficient experience with the use of QuilliChew ER to detect ethnic variations in pharmacokinetics.

There are no specific pediatric pharmacokinetic studies for QuilliChew ER. However, the pharmacokinetics of methylphenidate in pediatric patients 6 to 17 years old are not expected to be significantly different from adults following QuilliChew ER administration.

There is no experience with the use of QuilliChew ER in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate 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 methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of QuilliChew ER.

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

In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 4 times the maximum recommended human dose 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.

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 5 times the maximum recommended human dose on a mg/m² basis.

Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in 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. Methylphenidate was negative in an in vivo mouse bone marrow micronucleus assay.

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 of up to 160 mg/kg/day, approximately 8-fold the maximum recommended human dose on a mg/m² basis.

The efficacy of QuilliChew ER was evaluated in a laboratory classroom study conducted in 90 pediatric subjects (ages 6 to 12 years) with ADHD. Patients in the trial met DSM-IV criteria for ADHD. The study began with a 6-week open-label dose optimization period with an initial QuilliChew ER dose of 20 mg. Patients were instructed to chew each dose once daily in the morning. The dose could be titrated weekly in increments of 10 to 20 mg until a therapeutic dose or the maximum dose of 60 mg/day was reached.

Eighty-six of the 90 enrolled subjects then entered a 1-week randomized, double-blind, parallel group treatment period with the individually optimized dose of QuilliChew ER or placebo. The intent-to-treat (ITT) population consisted of 85 randomized subjects who received at least 1 dose of double-blind study drug and had at least 1 post-Baseline assessment of the primary efficacy variable. At the end of the double-blind treatment period, the laboratory classroom raters and teachers evaluated the attention and behavior of the subjects, throughout the day using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale. The SKAMP rating scale is a validated 13-item teacher-rated scale that assesses manifestations of ADHD in a classroom setting.

The SKAMP-Combined score, measured at 0.75, 2, 4, 8, 10, 12, and 13 hours post-dose during the laboratory classroom day at the end of the double-blind treatment period, was used to assess the primary and the key secondary efficacy parameters. The primary efficacy endpoint was the average of treatment effects across all the time points as specified above during the classroom day. The key secondary efficacy parameters were onset and duration of clinical effect.

QuilliChew ER was statistically significantly superior to placebo with respect to the primary endpoint (Table 2). QuilliChew ER also showed improvement over placebo at 0.75, 2, 4, and 8 hours post-dosing. Efficacy results at each time point are summarized in Figure 3.

N: number of patients; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.

^aLeast-Squares Mean Difference (drug minus placebo).

ITT: intent-to-treat

LS means from post-dose time-points were obtained from a repeated measures mixed model with terms for center, hour, treatment and treatment by hour interaction. For the pre-dose time-point, arithmetic means and standard errors are displayed.

QuilliChew ER is supplied as extended-release chewable tablets in 20 mg, 30 mg and 40 mg strengths.

The 20 mg strength extended-release chewable tablet is available as a speckled, off-white, capsule-shaped coated tablet, debossed with “NP 12” on one side and functionally scored on the other side.

The 30 mg strength extended-release chewable tablet is available as a speckled, light pink color, capsule-shaped coated tablet, debossed with “NP 13” on one side and functionally scored on the other side.

The 40 mg strength extended-release chewable tablet is available as a speckled, dark pink to peach color, capsule-shaped coated tablet, debossed with “NP 14” on one side and plain on the other side (not scored).

The product is supplied in bottles of 100.

Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF). [See USP Controlled Room Temperature.]

Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired QuilliChew ER 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 QuilliChew ER 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 QuilliChew ER in the household trash.

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

Advise patients and their caregivers that QuilliChew ER is a federally controlled substance, and it can be abused and lead to dependence [see Drug Abuse and Dependence (9.1, 9.2, 9.3)].

Instruct patients that they should not give QuilliChew ER to anyone else. Advise patients to store QuilliChew ER 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 QuilliChew ER through a medicine take-back program if available [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)].

Advise patients that QuilliChew ER should be taken by mouth once daily in the morning with or without food.

Advise patients, caregivers, and family members that there is a potential for serious cardiovascular risks including sudden death, myocardial infarction, and stroke with QuilliChew ER use. Instruct patients to contact a health care 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)].

Advise patients that QuilliChew ER can elevate blood pressure and heart rate [see Warnings and Precautions (5.3)].

Advise patients that QuilliChew ER, at recommended doses, can cause psychotic or manic symptoms, even in patients without a prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)].

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 [see Warnings and Precautions (5.5)].

• Instruct patients beginning treatment with QuilliChew ER 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 QuilliChew ER.
• Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6)].

Advise patients, families, and caregivers that QuilliChew ER can cause slowing of growth and weight loss [see Warnings and Precautions (5.7)].

Advise patients to avoid alcohol while taking QuilliChew ER extended-release chewable tablets. Consumption of alcohol while taking QuilliChew ER may result in a more rapid release of the dose of methylphenidate [see Clinical Pharmacology (12.3)].

Advise patients with phenylketonuria that QuilliChew ER extended-release chewable tablets contain phenylalanine, a component of aspartame [see Warnings and Precautions (5.8)].

This product’s label may have been updated. For current full prescribing information, please visit www.trispharma.com.

Distributed by:

Manufactured by:

Tris Pharma, Inc.

Monmouth Junction, NJ 08852

LB8533

QUILLIVANT XR is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). (1)

• Before administering the dose, vigorously shake bottle for at least 10 seconds. (2.2)
• May be taken with or without food. (2.3)
• For patients 6 years and above, recommended starting dose is 20 mg given orally once daily in the morning. Dosage may be increased weekly in increments of 10 mg to 20 mg per day. Daily dosage above 60 mg is not recommended. (2.2)
• Reconstitution instructions for the pharmacist: Tap bottle until powder flows freely. Remove bottle cap, add specified amount of water for reconstitution. Insert bottle adapter into neck of bottle. Replace bottle cap. Shake with vigorous back and forth motion for at least 10 seconds to prepare suspension. (2.6)

• Extended-release oral suspension (after reconstitution with water): 25 mg per 5 mL (5 mg per mL). (3)

• Known hypersensitivity to methylphenidate or product components. (4.1)
• Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days. (4.2, 7.1)

• 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. (5.2)
• 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 CNS 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 QUILLIVANT XR use. (5.4)
• Priapism: Cases of painful and prolonged penile erections and priapism have been reported with methylphenidate products. Immediate medical attention should be sought if signs or symptoms of prolonged penile erections or priapism are observed. (5.5)
• Peripheral Vasculopathy, including Raynaud’s Phenomenon: CNS 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)

Based on accumulated data from other methylphenidate 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. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Tris Pharma, Inc. at 732-940-0358 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• Antihypertensive drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. (7)

Revised: 6/2021

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

Prior to treating children, adolescents, and adults with CNS stimulants including QUILLIVANT XR, 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 re-evaluate the need for QUILLIVANT XR use [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].

Before administering the dose, VIGOROUSLY SHAKE the bottle of QUILLIVANT XR for at least 10 seconds, to ensure that the proper dose is administered.

The recommended starting dose of QUILLIVANT XR for patients 6 years and above is 20 mg once daily in the morning. The dose may be titrated weekly in increments of 10 mg to 20 mg. Daily doses above 60 mg have not been studied and are not recommended. As with any CNS stimulant, during titration of QUILLIVANT XR, the prescribed dose should be adjusted, if necessary, until a well‑tolerated, therapeutic dose is achieved.

Pharmacologic treatment of ADHD may be needed for extended periods. Health care providers should periodically re-evaluate the long-term use of QUILLIVANT XR, and adjust dosage as needed.

Patients should be advised to avoid alcohol while taking QUILLIVANT XR [see Clinical Pharmacology (12.3)].

QUILLIVANT XR should be orally administered once daily in the morning with or without food [see Clinical Pharmacology (12.3)].

If switching from other methylphenidate products, discontinue that treatment, and titrate with QUILLIVANT XR using the above titration schedule.

Do not substitute for other methylphenidate products on a milligram-per-milligram basis, because of different methylphenidate base compositions and differing pharmacokinetic profiles [see Description (11), Clinical Pharmacology (12.3)].

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

QUILLIVANT XR is supplied as a powder for oral suspension which must be reconstituted with water prior to dispensing. Preparation instructions: Tap bottle until powder flows freely. Remove bottle cap, and add specified amount of water to the bottle (see Table 1 below). Fully insert bottle adapter into neck of bottle [see Instructions for Use, Figures F and G]. Replace bottle cap. Shake with vigorous back and forth motion for at least 10 seconds to prepare suspension.

Store reconstituted QUILLIVANT XR at 25ºC (77ºF); excursions permitted from 15º to 30ºC (59º to 86ºF). Dispense in original packaging (bottle in carton) with bottle adapter inserted and with enclosed oral dosing dispenser. QUILLIVANT XR is stable for up to 4 months after reconstitution.

Extended-release oral suspension (after reconstitution with water): 25 mg per 5 mL (5 mg per mL).

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 in patients treated with other methylphenidate products [see Adverse Reactions (6.2)].

QUILLIVANT XR is contraindicated during treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (MAOI), because of the risk of hypertensive crisis [see Drug Interactions (7.1)].

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 [see Drug Abuse and Dependence (9.2, 9.3)].

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.

CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mm Hg) and heart rate (mean increase approximately 3 to 6 bpm).

Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.

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 (e.g., 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 (e.g., 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.

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.

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 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 of digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

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 (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 QUILLIVANT XR. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

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

• Known hypersensitivity to methylphenidate products or other ingredients of QUILLIVANT XR [see Contraindications (4)]
• Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4), Drug Interactions (7.1)]
• Drug Dependence [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)]
• 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)]

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.

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.

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 to 12 years) were affect lability, excoriation, initial insomnia, tic, decreased appetite, vomiting, motion sickness, eye pain, and rash.

The following adverse reactions have been identified during post approval use of methylphenidate 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

Hepatobiliary Disorders: Severe hepatocellular injury

Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus 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

Do not administer QUILLIVANT XR concomitantly with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment. Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.

QUILLIVANT XR may decrease the effectiveness of drugs used to treat hypertension. Monitor blood pressure and adjust the dosage of the hypertensive drug as needed [see Warnings and Precautions (5.3)].

Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/.

There are limited published studies and small case series that report on the use of methylphenidate in pregnant women; however, the data are insufficient to inform any drug-associated risks. There are clinical considerations [see Clinical Considerations]. No teratogenic effects were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses 2 and 11 times, respectively, the maximum recommended human dose (MRHD). However, spina bifida was observed in rabbits at a dose 40 times the MRHD [see Data].

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.

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.

In 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. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m² basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD 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 (7 times the MRHD on a mg/m² basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m² basis).

Limited published literature 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 CNS stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the 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.

Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

The safety and effectiveness of QUILLIVANT XR have been established in pediatric patients ages 6 to 17 years. Use of QUILLIVANT XR in pediatric patients 6 to 12 years of age is supported by one adequate and well-controlled study [see Clinical Studies (14)]. Use in 12 to 17 year old’s is supported by the adequate and well-controlled studies of QUILLIVANT XR in younger pediatric patients and additional pharmacokinetic data in adolescents, along with safety information from other methylphenidate‑containing products. The long-term efficacy of methylphenidate in pediatric patients has not been established. Safety and efficacy in pediatric patients below the age of 6 years have not been established.

Growth should be monitored during treatment with CNS stimulants, including QUILLIVANT XR. Children who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7)].

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 6 times the maximum recommended human dose (MRHD) on a mg/m² basis.

In the 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 6 times the maximum recommended human dose [MRHD] 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.

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

QUILLIVANT XR contains methylphenidate, a Schedule II controlled substance.

CNS stimulants including QUILLIVANT XR, 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 [see Overdosage (10)].

To reduce the abuse of CNS stimulants including QUILLIVANT XR, 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 QUILLIVANT XR use.

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 QUILLIVANT XR.

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 QUILLIVANT XR. Withdrawal symptoms after abrupt cessation following prolonged highdosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice on the management of overdosage with methylphenidate.

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

QUILLIVANT XR is a powder that, after reconstitution with water, forms an extended-release oral suspension formulation of methylphenidate intended for once daily oral administration. QUILLIVANT XR contains approximately 20% immediate-release and 80% extended-release methylphenidate. After reconstitution, QUILLIVANT XR is available in a 25 mg per 5 mL (5 mg per mL) extended-release oral suspension.

Methylphenidate HCl is a central nervous system (CNS) stimulant. The chemical name is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is shown in Figure 1.

Methylphenidate HCl is a white, odorless 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.

QUILLIVANT XR also contains the following inactive ingredients: sodium polystyrene sulfonate, povidone, triacetin, polyvinyl acetate, sucrose, anhydrous trisodium citrate, anhydrous citric acid, sodium benzoate, sucralose, poloxamer 188, corn starch, xanthan gum, talc, banana flavor, and silicon dioxide.

Methylphenidate HCl is a central nervous system (CNS) stimulant.

Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l‑isomer. The mode of therapeutic action in ADHD is not known. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.

Following a single, 60 mg oral dose of QUILLIVANT XR in 28 healthy adult subjects in a crossover study under fasting conditions, d-methylphenidate (d-MPH) mean (± SD) peak plasma concentrations of 13.6 (± 5.8) ng/mL occurred at a median time of 5 hours after dosing (Figure 2). The relative bioavailability of QUILLIVANT XR compared to Methylphenidate IR oral solution (2x30 mg, q6h) is 95%.

The single dose pharmacokinetics of d-MPH under fed conditions are summarized (Table 3) from studies in children and adolescents with ADHD, and healthy adults following an oral dose of 60 mg QUILLIVANT XR.

^* Breakfast was given 30 min prior to drug administration

^† total MPH measured in children (9 to 12 years old) and adolescents (13 to 15 years old), l-MPH <2% of d-MPH in circulation

^‡ data presented as median (range)

In a study in adult volunteers to investigate the effects of a high-fat meal on the bioavailability of QUILLIVANT XR at a dose of 60 mg, the presence of food reduced the time to peak concentration by approximately 1 hour (fed: 4 hours vs. fasted: 5 hours). Overall, a high-fat meal increased the average C_max of QUILLIVANT XR by about 28% and the AUC by about 19%. These changes are not considered clinically significant.

Following a single 60 mg oral dose of QUILLIVANT XR in 28 healthy adult subjects under fasting conditions, the mean plasma terminal elimination half-life of d-methylphenidate was 5.6 (± 0.8) hours.

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

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

An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from QUILLIVANT XR Oral Suspension. At alcohol concentrations of 5% and 10%, there was no effect of alcohol on the release characteristics of methylphenidate. At 20% alcohol concentration, there was on average a 20% increase in drug exposure [see Dosage and Administration (2.2)].

There is insufficient experience with the use of QUILLIVANT XR to detect gender variations in pharmacokinetics.

There is insufficient experience with the use of QUILLIVANT XR to detect ethnic variations in pharmacokinetics.

The pharmacokinetics of methylphenidate after QUILLIVANT XR administration were studied in pediatric patients with ADHD between 9 and 15 years of age. After a single oral dose of 60 mg QUILLIVANT XR, plasma concentrations of methylphenidate in children (9 to 12 years old; n=3) were approximately twice the concentrations observed in adults. The plasma concentrations in adolescent patients (13 to 15 years old; n=4) were similar to those in adults.

There is no experience with the use of QUILLIVANT XR in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate 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 methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of QUILLIVANT XR.

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

In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. This dose is approximately 4 times the maximum recommended human dose 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.

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 5 times the maximum recommended human dose on a mg/m² basis.

Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in 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. Methylphenidate was negative in an in vivo mouse bone marrow micronucleus assay.

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 of up to 160 mg/kg/day, approximately 8-fold the maximum recommended human dose on a mg/m² basis.

The efficacy of QUILLIVANT XR was evaluated in a laboratory classroom study conducted in 45 pediatric patients (ages 6 to 12 years) with ADHD. Patients in the trial met Diagnostic and Statistical Manual of Mental Diseases, 4th edition (DSM-IV^®) criteria for ADHD. The study began with an open-label dose optimization period (4 to 6 weeks) with an initial QUILLIVANT XR dose of 20 mg once daily in the morning. The dose could be titrated weekly in increments of 10 or 20 mg until a therapeutic dose or the maximum dose of 60 mg/day was reached. At the end of the dose optimization period, approximately 5% of subjects were receiving 20 mg/day; 39%, 30 mg/day; 31%, 40 mg/day; 10%, 50 mg/day; and 15%, 60 mg/day. Subjects then entered a 2-week randomized, double-blind, crossover treatment with the individually optimized dose of QUILLIVANT XR or placebo. At the end of each week, school teachers and raters evaluated the attention and behavior of the subjects in a laboratory classroom using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale. The primary efficacy endpoint was the SKAMP-Combined score at 4 hours post-dosing. The key secondary efficacy endpoints were the SKAMP-Combined scores at 0.75, 2, 8, 10, and 12 hours post-dosing. Results from the first double-blind, placebo-controlled week of the study are summarized in Figure 3. SKAMP-Combined scores were statistically significantly lower (improved) at all time points (0.75, 2, 4, 8, 10, 12 hours) post-dosing with QUILLIVANT XR compared to placebo.

QUILLIVANT XR is supplied as powder that, after reconstitution with water, forms an extended-release oral suspension. The product is supplied in a carton. Each carton also contains one bottle, one oral dosing dispenser, and one bottle adapter.

The product must be reconstituted only by the pharmacist and not by the patient or caregiver. After reconstitution, the product is a light beige to tan viscous suspension containing 25 mg per 5 mL (5 mg per mL) of methylphenidate hydrochloride.

Bottles of 300 mg powder (to prepare 60 mL suspension) NDC 24478-321-02

Bottles of 600 mg powder (to prepare 120 mL suspension) NDC 24478-322-04

Bottles of 750 mg powder (to prepare 150 mL suspension) NDC 24478-323-05

Bottles of 900 mg powder (to prepare 180 mL suspension) NDC 24478-324-06

Store at 25ºC (77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF). [See USP Controlled Room Temperature.]

Dispense in original container.

Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired QUILLIVANT XR 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 QUILLIVANT XR 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 QUILLIVANT XR in the household trash.

Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Advise patients and their caregivers that QUILLIVANT XR is a federally controlled substance, and it can be abused and lead to dependence [see Drug Abuse and Dependence (9.1, 9.2, 9.3)]. Instruct patients that they should not give QUILLIVANT XR to anyone else. Advise patients to store QUILLIVANT XR 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 QUILLIVANT XR through a medicine take-back program if available [see Warnings and Precautions (5.1), Abuse and Dependence (9.2, 9.3)].

Provide the following instructions on administration to the patient or caregiver:

• The pharmacist should provide this medicine in its original packaging (bottle within carton) with the bottle adapter fully inserted and the accompanying oral dosing dispenser. Use only with the oral dosing dispenser provided with this product.
• Check and make sure that the QUILLIVANT XR bottle contains liquid medicine. If QUILLIVANT XR is in powder form, do not use it. Return it to your pharmacist.
• VIGOROUSLY SHAKE the bottle of QUILLIVANT XR for at least 10 seconds before each dose, to ensure that the proper dose is administered.
• Remove the bottle cap. Confirm that the bottle adapter has been inserted into top of the bottle.
• Insert the tip of the oral dosing dispenser provided with this product into the bottle adapter.
• Turn bottle upside down and withdraw prescribed amount of QUILLIVANT XR into the oral dosing dispenser.
• Remove filled oral dosing dispenser from bottle and dispense QUILLIVANT XR directly into mouth.
• Replace bottle cap and store bottle as directed.
• Wash oral dosing dispenser after each use (components are dishwasher-safe).

Advise patients, caregivers, and family members that there is a potential for serious cardiovascular risks including sudden death, myocardial infarction, and stroke with QUILLIVANT XR use. Instruct patients to contact a health care 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)].

Advise patients that QUILLIVANT XR can elevate blood pressure and heart rate [see Warnings and Precautions (5.3)].

Advise patients that QUILLIVANT XR, at recommended doses, can cause psychotic or manic symptoms, even in patients without a prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)].

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 [see Warnings and Precautions (5.5)].

• Instruct patients beginning treatment with QUILLIVANT XR 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 QUILLIVANT XR.
• Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

Advise patients, families, and caregivers that QUILLIVANT XR can cause slowing of growth and weight loss [see Warnings and Precautions (5.7)].

Patients should be advised to avoid alcohol while taking QUILLIVANT XR Oral Suspension. Consumption of alcohol while taking QUILLIVANT XR may result in a more rapid release of the dose of methylphenidate [see Clinical Pharmacology (12.3)].

This product’s label may have been updated. For current full prescribing information, please visit www.trispharma.com

Distributed by:

Manufactured by:

Tris Pharma, Inc.

Monmouth Junction, NJ 08852

LB8529 Rev. 01 06/2021

Distributed by:

Manufactured by:

Tris Pharma, Inc.

Monmouth Junction, NJ 08852

LB8529 Rev. 01 06/2021