Included as part of the "PRECAUTIONS" Section
Potential For Abuse And Dependence
CNS stimulants, including APTENSIO 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 BOX WARNING and Drug Abuse And Dependence].
Serious Cardiovascular Events
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 APTENSIO XR treatment.
Blood Pressure And Heart Rate Increases
CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.
Psychiatric Adverse Reactions
Exacerbation Of Pre-Existing Psychosis
CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.
Induction Of A Manic Episode In Patients With Bipolar Disorder
CNS stimulants may induce a manic or mixed 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 APTENSIO 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
Stimulants, including APTENSIO 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.
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 APTENSIO XR.
Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated 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.
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 stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.
Patient Counseling Information
Advise patients to read the FDA-approved patient labeling (Medication Guide).
Controlled Substance Status/High Potential For Abuse And Dependence
Advise patients that APTENSIO XR is a controlled substance, and it can be abused and lead to dependence. Instruct patients that they should not give APTENSIO XR to anyone else. Advise patients to store APTENSIO 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 APTENSIO XR by a medicine take-back program if available [see BOX WARNING, WARNINGS AND PRECAUTIONS, Drug Abuse And Dependence].
Dosage And Administration Instructions
Advise patients that APTENSIO XR can be taken with or without food and that they should establish a routine pattern of taking APTENSIO XR with regard to meals. For patients who take APTENSIO XR sprinkled over applesauce, the contents of the entire capsule should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. When initiating treatment with APTENSIO XR, provide dosage escalation and administration instructions [see DOSAGE AND ADMINISTRATION].
Serious Cardiovascular Risks
Advise patients that there is a potential serious cardiovascular risk including sudden death, myocardial infarction, stroke, and hypertension with APTENSIO 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
Instruct patients that APTENSIO XR can cause elevations of their blood pressure and pulse rate [see WARNINGS AND PRECAUTIONS].
Advise patients that APTENSIO XR, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see WARNINGS AND PRECAUTIONS].
Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct them 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 APTENSIO 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 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 APTENSIO XR. Further clinical evaluation (e.g. rheumatology referral) may be appropriate for certain patients [see WARNINGS AND PRECAUTIONS].
Suppression Of Growth
Advise patients that APTENSIO XR may cause slowing of growth and weight loss [see WARNINGS AND PRECAUTIONS].
Advise patients to avoid alcohol while taking APTENSIO XR. Consumption of alcohol while taking APTENSIO XR may result in a more rapid release of the dose of methylphenidate [see CLINICAL PHARMACOLOGY].
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 18week Continuous Breeding study. The study was conducted at doses of up to 160 mg/kg/day, approximately 8fold the maximum recommended human dose on a mg/m2 basis.
Use In Specific Population
Limited published studies report on the use of methylphenidate in pregnant women; however, the data are insufficient to inform any drug-associated risks. No teratogenic effects were observed in embryo-fetal development studies with oral administration of methylphenidate to 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. A decrease in pup body weight was observed in a preand post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 4 times the MRHD [see Data]. The background risk of major birth defects and miscarriage for the indicated population are unknown. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.
Fetal/Neonatal Adverse Reactions
CNS stimulants, such as APTENSIO 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). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre-and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2 basis).
Limited published literature, based on breast milk sampling from five mothers, 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. However, long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for APTENSIO XR and any potential adverse effects on the breastfed infant from APTENSIO XR or from the underlying maternal condition.
Monitor breastfeeding infants for adverse reactions, such as agitation, anorexia, and reduced weight gain.
The safety and effectiveness of APTENSIO XR in pediatric patients under six years have not been evaluated.
The safety and effectiveness of APTENSIO XR have been established in pediatric patients ages 6 to 17 years in two adequate and well-controlled clinical trials [see Clinical Studies]. The long-term efficacy of methylphenidate in pediatric patients has not been established.
Long Term Suppression Of Growth
Growth should be monitored during treatment with stimulants, including APTENSIO XR. Pediatric patients 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.
Clinical trials of APTENSIO XR did not include any patients aged 65 years and over. In general, dose selection for an elderly patient start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.