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Adzenys ER

WARNINGS

Included as part of the “PRECAUTIONS” Section

PRECAUTIONS

Potential For Abuse Or Dependence

CNS stimulants, including ADZENYS ER, 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 BOX WARNING, Drug Abuse And Dependence].

Serious Cardiovascular Reactions

Sudden death, stroke, and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in children and adolescents 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 ADZENYS ER treatment.

Blood Pressure And Heart Rate Increases

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

Psychiatric Adverse Events

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 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 has a history of depressive symptoms or a family history of suicide, bipolar disorder, and 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 ADZENYS ER. 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.

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 ADZENYS ER.

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

Peripheral Vasculopathy, Including Raynaud’s Phenomenon

Stimulants, including ADZENYS 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 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

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]. The co-administration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to ADZENYS ER. In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6 [see DRUG INTERACTIONS].

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 ADZENYS ER with MAOI drugs is contraindicated [see CONTRAINDICATIONS].

Discontinue treatment with ADZENYS ER and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of ADZENYS ER with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate ADZENYS ER 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.

Potential For Overdose Due To Medication Errors

Medication errors, including substitution and dispensing errors, between ADZENYS ER and other amphetamine products could occur, leading to possible overdosage. To avoid substitution errors and overdosage, do not substitute for other amphetamine products on a milligram-permilligram basis because of different amphetamine salt compositions and differing pharmacokinetic profiles [see DOSAGE AND ADMINISTRATION].

Potential For Intestinal Necrosis

Cases of intestinal necrosis, including some deaths, have been reported with the concomitant use of sodium polystyrene sulfonate and sorbitol, two of the inactive ingredients in ADZENYS ER. In these cases, patients were administered sodium polystyrene sulfonate to treat hyperkalemia at doses greater than 200 times the amount present in Adzenys ER. However, no absolute safe levels for the interaction of sodium polystyrene sulfonate and sorbitol have been established.

Patient Counseling Information

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

Controlled Substance Status/Potential For Abuse, Misuse, And Dependence

Advise patients that ADZENYS ER is a federally controlled substance because it can be abused or lead to dependence. Advise patients to store ADZENYS 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 ADZENYS ER by a medicine take-back program if available [see BOX WARNING, WARNINGS AND PRECAUTIONS , Drug Abuse And Dependence].

Dosage And Administration Instructions

Provide the following instructions on administration to the patient:

  • Use with an oral dosing device or other suitable measuring device.
  • Shake the bottle of ADZENYS ER before each dose.
  • Measure the appropriate dose as prescribed by the physician.
  • Use the filled oral dosing device or measuring device to dispense ADZENYS ER directly into mouth.
  • Replace bottle cap and store bottle as directed.
  • Wash oral dosing device or measuring device after each use.
Serious Cardiovascular Risks

Advise patients of serious cardiovascular risk (including sudden death, myocardial infarction, stroke, and hypertension) with ADZENYS ER. 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 ADZENYS ER can cause elevations of their blood pressure and pulse rate and they should be monitored for such effects [see WARNINGS AND PRECAUTIONS].

Psychiatric Risks

Advise patients that ADZENYS ER at recommended doses, may cause psychotic or manic symptoms even in patients without prior history of psychotic symptoms or mania [see WARNINGS AND PRECAUTIONS].

Long-Term Suppression Of Growth

Advise patients, family members, and caregivers that ADZENYS ER may cause slowing of growth including weight loss [see WARNINGS AND PRECAUTIONS].

Circulation Problems In fingers And Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon]

Instruct patients beginning treatment with ADZENYS ER about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and in 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 ADZENYS ER.

Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see WARNINGS AND PRECAUTIONS].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with concomitant use of ADZENYS ER 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, WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. 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 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].

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADZENYS ER during pregnancy [see Use In Specific Populations].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become
pregnant during treatment with ADZENYS ER. Advise patients of the potential fetal effects from the use of ADZENYS ER during pregnancy [see Use In Specific Populations].

Lactation

Advise patients not to breastfeed if they are taking ADZENYS ER [see Use In Specific Populations].

Alcohol

Advise patients to avoid alcohol while taking ADZENYS ER. Consumption of alcohol while
taking ADZENYS ER may result in a more rapid release of the dose of amphetamine [see CLINICAL PHARMACOLOGY].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

No evidence of carcinogenicity was found in studies in which d,l-amphetamine sulfate (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 3, 2, and 1 (equivalent) times, respectively, the maximum recommended human dose of 18.8 mg/day (as base) given to children on a mg/m2 basis.

Mutagenesis

Amphetamine, in the enantiomer ratio (d-to l-ratio of 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 3:1, did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day [approximately 12.4 times the maximum recommended human dose of 12.5 mg/day (as base) given to adolescents on a mg/m2 basis].

Use In Specific Populations

Pregnancy

Pregnancy Exposure Registry

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

Risk Summary

The limited available data from published literature and postmarketing reports on the use of prescription amphetamine in pregnant women are insufficient to inform a drug-associated risk for 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 (see Clinical Considerations).

No effects on morphological development were observed in embryo-fetal development studies with oral administration of amphetamine to rats and rabbits during organogenesis at doses 4 and 20 times, respectively, the maximum recommended human dose (MRHD) of 12.5 mg/day (as base) given to adolescents, on a mg/m2 basis. However, in a pre-and post-natal development study, amphetamine (d-to l-ratio of 3:1) administered orally to pregnant rats during gestation and lactation caused a decrease in pup survival and a decrease in pup body weight that correlated with a delay in developmental landmarks at clinically relevant doses of amphetamine. In addition, adverse effects on reproductive performance were observed in pups whose mothers were treated with amphetamine. Long-term neurochemical and behavioral effects have also been reported in published animal developmental studies using clinically relevant doses of amphetamine (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal adverse reactions

Amphetamines, such as ADZENYS ER, cause vasoconstriction and thereby may decrease placental perfusion. In addition, amphetamines can stimulate uterine contractions increasing the risk of premature delivery. Infants born to amphetamine dependent mothers have an increased risk of premature delivery and low birth weight.

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 administered orally 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 4 and 20 times, respectively, the MRHD of 12.5 mg/day (as base) given to adolescents, on a mg/m2 basis. Fetal malformations and death have been reported in mice following parenteral administration of d-amphetamine doses of 50 mg/kg/day (approximately 15 times the MRHD given to adolescents on a mg/m2 basis) or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity.

A study was conducted in which pregnant rats received daily oral doses of amphetamine (d-to lenantiomer ratio of 3:1) of 2, 6, and 10 mg/kg from gestation day 6 to lactation day 20. These doses are approximately 1, 4, and 6 times the MRHD of 12.5 mg/day (as base) given to adolescents, on a mg/m2 basis. All doses caused hyperactivity and decreased weight gain in the dams. A decrease in pup survival was seen at all doses. A decrease in pup body weight was seen at 6 and 10 mg/kg which correlated with delays in developmental landmarks, such as preputial separation and vaginal opening. Increased pup locomotor activity was seen at 10 mg/kg on day 22 postpartum but not at 5 weeks postweaning. When pups were tested for reproductive performance at maturation, gestational weight gain, number of implantations, and number of delivered pups were decreased in the group whose mothers had been given 10 mg/kg.

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.

Lactation

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. Long term neurodevelopmental effects on infants from stimulant exposure are unknown. It is possible that large dosages of amphetamine might interfere with milk production, especially in women whose lactation is not well established. Because of the potential for serious adverse reactions in nursing infants, advise patients that breastfeeding is not recommended during treatment with ADZENYS ER.

Pediatric Use

Safety and effectiveness have been established in pediatric patients with ADHD ages 6 to 17 years of age in three adequate and well-controlled clinical trials of up to 4 weeks in duration [see ADVERSE REACTIONS , CLINICAL PHARMACOLOGY, Clinical Studies]. Safety and efficacy in pediatric patients younger than 6 years of age with ADHD have not been established.

Long-Term Growth Suppression

Growth should be monitored during treatment with stimulants, including ADZENYS ER, and children who are not growing or gaining weight as expected may need to have their treatment interrupted [see WARNINGS AND PRECAUTIONS].

Juvenile Animal Toxicity Data

Juvenile rats treated with mixed amphetamine salts early in the postnatal period through sexual maturation demonstrated transient changes in motor activity. Learning and memory was impaired at approximately 10 times the maximum recommended human dose (MRHD) given to children on a mg/m2 basis. No recovery was seen following a drug free period. A delay in sexual maturation was observed at a dose approximately 10 times the MRHD given to pediatric patients on a mg/m2 basis, although there was no effect on fertility.

In a juvenile developmental study, rats received daily oral doses of amphetamine (d to l enantiomer ratio of 3:1) of 2, 6, or 20 mg/kg on days 7-13 of age; from day 14 to approximately day 60 of age these doses were given twice daily for total daily doses of 4, 12, or 40 mg/kg. The latter doses are approximately 1, 3, and 10 times the MRHD of 18.8 mg/day (as base) given to children on a mg/m2 basis. Post-dosing hyperactivity was seen at all doses; motor activity measured prior to the daily dose was decreased during the dosing period but the decreased motor activity was largely absent after an 18 day drug-free recovery period. Performance in the Morris water maze test for learning and memory was impaired at the 40 mg/kg dose, and sporadically at the lower doses, when measured prior to the daily dose during the treatment period; no recovery was seen after a 19 day drug-free period. A delay in the developmental milestones of vaginal opening and preputial separation was seen at 40 mg/kg but there was no effect on fertility.

Geriatric Use

Clinical studies of ADZENYS ER did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should 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.

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