"The US Food and Drug Administration (FDA) has approved the amphetamine Dyanavel XR (Tris Pharma Inc), a once-daily extended-release oral liquid, for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children aged 6 years "...
Potential For Abuse And Dependence
CNS stimulants, including QUILLIVANT XR, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Drug Abuse and Dependence].
Serious Cardiovascular Reactions
Stroke and myocardial infarction have occurred in adults treated with CNS stimulants at recommended doses. Sudden death has occurred in children and adolescents with structural cardiac abnormalities and other serious cardiac problems, and in adults taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during treatment with QUILLIVANT XR.
Blood Pressure And Heart Rate Increases
CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.
Psychiatric Adverse Reactions
Exacerbation Of 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 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.
Peripheral Vasculopathy, Including Raynaud's Phenomenon
CNS stimulants, including QUILLIVANT XR, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in 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.
Long-Term Suppression Of Growth
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 QUILLIVANT XR. Careful follow-up of weight and height in children 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 children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development.
Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth; however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with CNS stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide)
Information On The Medication Guide
Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with QUILLIVANT XR, and counsel them on its appropriate use. A patient Medication Guide is available for QUILLIVANT XR. Instruct patients, their families, and their caregivers to read the Medication Guide, and assist them in understanding its contents. Give patients, their families, and their caregivers the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is attached to the prescribing information.
Instructions For Using The Enclosed Oral Dosing Dispenser
Provide the following instructions on administration to the patient or caregiver:
- Use only with the oral dosing dispenser provided with this product
- 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).
Controlled Substance Status/Potential For Abuse and Dependence
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]. 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 and Abuse and Dependence].
Serious Cardiovascular Risks
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 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].
Blood Pressure And Heart Rate Increases
Advise patients that QUILLIVANT XR can elevate blood pressure and heart rate [see WARNINGS AND PRECAUTIONS].
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].
Suppression Of Growth
Advise patients, families, and caregivers that QUILLIVANT XR can cause slowing of growth and weight loss [see WARNINGS AND PRECAUTIONS].
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].
Circulation Problems In Fingers And Toes [Peripheral Vasculopathy, including Raynaud's Phenomenon]
- 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.
Instruct patients to inform their healthcare provider if they become pregnant or intend to become pregnant during treatment with QUILLIVANT XR. Advise patients of the potential fetal effects from the use of QUILLIVANT XR during pregnancy [see Use In Specific Populations].
Advise nursing mothers to discontinue breastfeeding or discontinue QUILLIVANT XR [see Use in Specific Populations].
For The Pharmacist
Dispense a Medication Guide to patients receiving a QUILLIVANT XR prescription.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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. The genotoxic potential of methylphenidate has not been evaluated in an in vivo assay.
Impairment Of Fertility
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.
Use In Specific Populations
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 2-4% and 15-20%, respectively.
Fetal/Neonatal Adverse Reactions
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 adequate and well-controlled studies [see Clinical Studies]. Use in 12 to 17 year olds 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.
Long Term Suppression Of Growth
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].
Juvenile Animal Data
Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 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 13-14), 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.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 5/25/2016
Additional Quillivant XR Information
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