|
This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or
standards of non-Merck sources.
Special Alerts
Medications for ADHD: AHA Clarification of Cardiovascular Screening Recommendation - May 2008
In an effort to reduce the rate of sudden cardiac death especially in pediatric patients receiving stimulant medications for the treatment of attention-deficit/hyperactivity disorder (ADHD), the American Heart Association (AHA) has issued a statement in April 2008 recommending that all children diagnosed with ADHD who may be candidates for stimulant medications have a thorough cardiovascular assessment prior to initiation of drug therapy. The AHA scientific statement was issued by the Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. On May 16, 2008, the AHA issued a clarification of the recommendations due to the language regarding ECG recommendations and subsequent interpretations.
These recommendations are based on the Food and Drug Administration (FDA) reports of serious cardiovascular adverse events (including sudden death) in patients (both children and adults) taking usual doses of stimulant medications. Most of these patients were found to have underlying structural heart disease (eg, hypertrophic obstructive cardiomyopathy). In 2006, these reports prompted the FDA to recommend labeling changes of these medications to include warnings about cardiovascular events and to develop patient medication guides to be distributed with each prescription.
Stimulant medications theoretically increase cardiovascular risk due to potential effects on blood pressure elevation and increased heart rate. These effects have generally been considered clinically insignificant in most children, however, may be detrimental in certain patients with underlying cardiovascular disease. None of the medications have been shown to cause heart conditions or proven to have caused sudden cardiac death.
The committee suggests that patients needing the following ADHD medications receive a thorough cardiovascular assessment: Methylphenidate, amphetamine, dextroamphetamine, atomoxetine, clonidine, guanfacine, desipramine, imipramine, bupropion, and modafinil.
According to the clarified AHA recommendations, this assessment should include a combination of thorough medical history, family history, and physical examination with the intent to identify risk factors for sudden death. Although not mandatory, physicians should consider obtaining an ECG.
Patients already maintained on ADHD medications should not stop taking their medication. Instead, patients or their caregivers should contact their healthcare provider. It is reasonable that these patients undergo a similar cardiovascular assessment without interruption of therapy.
Press releases and clarified recommendations from the AHA note that the intent of this statement is not to reduce appropriate use of these medications, but to provide physicians with useful tools to identify heart conditions in children with ADHD in order to make more informed prescribing decisions. ECG testing is recommended as one option to be used as part of a combination screening process. They do suggest that a lack of ECG testing should not necessarily mean that treatment not be initiated.
The clarified statement has been endorsed by the American Academy of Child and Adolescent Psychiatry, the American College of Cardiology, Children and Adults with Attention-Deficit/Hyperactivity Disorder, and the National Initiative for Children's Healthcare Quality.
For more information, refer to:
http://americanheart.mediaroom.com/index.php?s=43&item=422
http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.189473/DC1
http://americanheart.mediaroom.com/index.php?s=43&item=398
http://www.fda.gov/medwatch/safety/2007/safety07.htm
http://www.fda.gov/bbs/topics/NEWS/2007/NEW01568.html
Nissen SE, “ADHD Drugs and Cardiovascular Risk,” N Engl J Med, 2006, 354(14):1445-48.
“Practice Parameter for the Assessment and Treatment of Children and Adolescents With Attention-Deficit/Hyperactivity Disorder,” J Am Acad Child Adolesc Psychiatry, 2007, 46(7):894-921.
Vetter VL, Elia J, Erickson CH, et al, “Cardiovascular Monitoring of Children and Adolescents With Heart Disease Receiving Stimulant Drugs. A Scientific Statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing,” Circulation, 2008, 117:2407-23.
Wilens TE, Prince JB, Spencer TJ, et al, “Stimulants and Sudden Death: What is a Physician to do?” Pediatrics, 2006, 118(3):1215-19.
Modafinil: Updated Warnings to Labeling - December, 2007
Shire Canada Inc, in conjunction with Health Canada has issued a “Dear Healthcare Professional” letter regarding updates to the warnings section of the Canadian labeling for modafinil (Alertec®). Similar updates to the U.S. labeling were prompted by a MedWatch alert from the U.S. Food and Drug Administration (FDA) in October, 2007. Updates include warnings regarding the association of modafinil use and life-threatening skin reactions such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) in adult and pediatric patients. In addition, hypersensitivity reactions including anaphylaxis, angioedema, and multiorgan hypersensitivity (including at least one fatality) have been reported. Patients should be advised to promptly discontinue modafinil use and seek medical treatment with the onset of rash or any signs or symptoms suggesting angioedema or anaphylaxis.
Psychiatric symptoms, including new onset symptoms (eg, anxiety, mania, hallucinations) have also been reported in adult and pediatric patients. Patients with a history of psychosis, depression, or mania should use modafinil cautiously. Discontinuation of therapy should be considered with the onset of psychiatric symptoms.
Modafinil is not approved for use in pediatric patients <16 years of age (U.S. labeling) or <18 years of age (Canadian labeling).
For further information, refer to the following websites:
U.S.: http://www.fda.gov/medwatch/safety/2007/safety07.htm#provigil
Canada: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2007/alertec_hpc-cps_e.html
Pronunciation
(moe DAF i nil)
U.S. Brand Names
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy and shift work sleep disorder (SWSD); adjunctive therapy for obstructive sleep apnea/hypopnea syndrome (OSAHS)
Use: Unlabeled/Investigational
Attention-deficit/hyperactivity disorder (ADHD); treatment of fatigue in MS and other disorders
Restrictions
C-IV
Pregnancy Risk Factor
C
Pregnancy Considerations
Embryotoxic effects have been observed in some, but not all animal studies. There are no adequate and well-controlled studies in pregnant women; use only when the potential risk of drug therapy is outweighed by the drug's benefits. Efficacy of steroidal contraceptives may be decreased; alternate means of contraception should be considered during therapy and for 1 month after modafinil is discontinued.
Lactation
Excretion in breast milk unknown/use caution
Contraindications
Hypersensitivity to modafinil, armodafinil, or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• CNS effects: May impair the ability to engage in potentially hazardous activities. The degree of sleepiness should be reassessed frequently; some patients may not return to a normal level of wakefulness.
• Dermatologic effects (severe): Serious and life-threatening rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with modafinil. Although initially reported in children during clinical trials, postmarketing cases have occurred in both children and adults. Most cases have occurred within the first 5 weeks of therapy; however, rare cases have occurred after long-term use. No risk factors have been identified to predict occurrence or severity. Patients should be advised to discontinue at first sign of rash.
• Hypersensitivity reactions: Rare cases of multiorgan hypersensitivity reactions in association with modafinil use and lone cases of angioedema and anaphylactoid reactions with armodafinil have been reported. Signs and symptoms are diverse, reflecting the involvement of specific organs. Patients typically present with fever and rash associated with organ-system dysfunction. Patients should be advised to report any signs and symptoms related to these effects; discontinuation of therapy is recommended.
Disease-related concerns:
• Cardiovascular disease: Use is not recommended in patients with a history of angina, cardiac ischemia, recent history of myocardial infarction, left ventricular hypertrophy, or patients with mitral valve prolapse who have developed mitral valve prolapse syndrome with previous CNS stimulant use. Increase monitoring in patients with hypertension; additional therapy may be necessary.
• Hepatic impairment: Use with caution in patients with hepatic impairment. Dosage reduction is recommended.
• Psychiatric disorders: Use with caution in patients with pre-existing psychosis or bipolar disorder (may induce mixed/manic episode). May exacerbate symptoms of behavior and thought disorder in psychotic patients; new onset psychosis or mania may occur with stimulant use; observe for symptoms of aggression, hostility, or suicidal ideation.
• Renal impairment: Use with caution in patients with renal impairment.
• Sleep disorders: Appropriate use: For use following complete evaluation of sleepiness and in conjunction with other standard treatments (eg, CPAP). The degree of sleepiness should be reassessed frequently; some patients may not return to a normal level of wakefulness.
• Tourette's syndrome: Use with caution in patients with Tourette's syndrome; stimulants may unmask tics.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children <16 years of age (U.S. labeling) or <18 years of age (Canadian labeling).
Adverse Reactions
>10%:
Central nervous system: Headache (34%, dose related)
Gastrointestinal: Nausea (11%)
1% to 10%:
Cardiovascular: Chest pain (3%), hypertension (3%), palpitation (2%), tachycardia (2%), vasodilation (2%), edema (1%)
Central nervous system: Nervousness (7%), dizziness (5%), depression (2%), anxiety (5%; dose related), insomnia (5%), somnolence (2%), chills (1%), agitation (1%), confusion (1%), emotional lability (1%), vertigo (1%)
Dermatologic: Rash (1%; includes some severe cases requiring hospitalization)
Gastrointestinal: Diarrhea (6%), dyspepsia (5%), xerostomia (4%), anorexia (4%), constipation (2%), flatulence (1%), mouth ulceration (1%), taste perversion (1%)
Genitourinary: Abnormal urine (1%), hematuria (1%), pyuria (1%)
Hematologic: Eosinophilia (1%)
Hepatic: LFTs abnormal (2%)
Neuromuscular & skeletal: Back pain (6%), paresthesia (2%), dyskinesia (1%), hyperkinesia (1%), hypertonia (1%), neck rigidity (1%), tremor (1%)
Ocular: Amblyopia (1%), eye pain (1%), vision abnormal (1%)
Respiratory: Pharyngitis (4%), rhinitis (7%), lung disorder (2%), asthma (1%), epistaxis (1%)
Miscellaneous: Diaphoresis
Postmarketing and/or case reports: Agranulocytosis, anaphylactic reaction, angioedema, DRESS syndrome, erythema multiforme, hypersensitivity syndrome (multiorgan), mania, psychosis, Stevens-Johnson syndrome, toxic epidermal necrolysis
Metabolism/Transport Effects
Substrate of CYP3A4 (major); Inhibits CYP1A2 (weak), 2A6 (weak), 2C9 (weak), 2C19 (strong), 2E1 (weak), 3A4 (weak); Induces CYP1A2 (weak), 2B6 (weak), 3A4 (weak)
Drug Interactions
Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
CYP2C19 Substrates: CYP2C19 Inhibitors (Strong) may decrease the metabolism of CYP2C19 Substrates. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Maraviroc: CYP3A4 Inducers may decrease the serum concentration of Maraviroc. Risk D: Consider therapy modification
Oral Contraceptive (Estrogens): Modafinil may decrease the serum concentration of Oral Contraceptive (Estrogens). Risk D: Consider therapy modification
Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid or limit ethanol.
Food: Delays absorption, but does not affect bioavailability.
Mechanism of Action
The exact mechanism of action is unclear, it does not appear to alter the release of dopamine or norepinephrine, it may exert its stimulant effects by decreasing GABA-mediated neurotransmission, although this theory has not yet been fully evaluated; several studies also suggest that an intact central alpha-adrenergic system is required for modafinil's activity; the drug increases high-frequency alpha waves while decreasing both delta and theta wave activity, and these effects are consistent with generalized increases in mental alertness
Pharmacodynamics/Kinetics
Modafinil is a racemic compound (10% d-isomer and 90% l-isomer at steady state) whose enantiomers have different pharmacokinetics
Distribution: Vd: 0.9 L/kg
Protein binding: 60%, primarily to albumin
Metabolism: Hepatic; multiple pathways including CYP3A4
Half-life elimination: Effective half-life: 15 hours; Steady-state: 2-4 days
Time to peak, serum: 2-4 hours
Excretion: Urine (as metabolites, <10% as unchanged drug)
Dosage
Oral:
Children: ADHD (unlabeled use): 50-100 mg once daily
Adults:
ADHD (unlabeled use): 100-300 mg once daily
Narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS): Initial: 200 mg as a single daily dose in the morning
Shift work sleep disorder (SWSD): Initial: 200 mg as a single dose taken ?1 hour prior to start of work shift
Note: Doses of 400 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that this dose confers additional benefit
Elderly: Elimination of modafinil and its metabolites may be reduced as a consequence of aging and as a result, consider initiating dose at 100 mg once daily.
Dosing adjustment in renal impairment: Safety and efficacy have not been established in severe renal impairment.
Dosing adjustment in hepatic impairment: Dose should be reduced to one-half of that recommended for patients with normal liver function.
Monitoring Parameters
Levels of sleepiness; blood pressure in patients with hypertension
When used for the treatment of ADHD, thoroughly evaluate for cardiovascular risk. Monitor heart rate, blood pressure, and consider obtaining ECG prior to initiation (Vetter, 2008).
Patient Education
Take exactly as prescribed; do not exceed recommended dosage without consulting prescriber. Avoid drinking alcohol. Do not share medication with anyone else. Void before taking medication. You may experience headache, nervousness, confusion, or dizziness (use caution when driving or engaging in tasks requiring alertness until response to drug is known); diarrhea (yogurt or buttermilk may help); or dry mouth or sore mouth, loss of appetite, or vomiting (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). If you have diabetes, monitor glucose levels closely. Report chest pain or palpitations; respiratory difficulty; excessive insomnia, CNS agitation, depression, or memory disturbances; rash; vision changes; changes in urinary pattern or ejaculation disturbances; or persistent joint pain or stiffness. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.
Geriatric Considerations
Clearance of modafinil may be reduced in the elderly. Safety and effectiveness in persons >65 years of age have not been established. In the limited number of elderly patients studied, the incidence of adverse events was similar to younger patients.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation), oral ulceration, gingivitis, and taste perversion.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Use vasoconstrictor with caution. Patients may experience heart palpitations and increased heart rate when taking modafinil.
Mental Health: Child/Adolescent Considerations
Eleven children with attention-deficit/hyperactivity disorder (ADHD) 5-15 years of age received modafinil for an average of 4.6 weeks (Rugino, 2001).
Rugino TA and Copley TC, “Effects of Modafinil in Children With Attention-Deficit/Hyperactivity Disorder: An Open-Label Study,” J Am Acad Child Adolesc Psychiatry, 2001, 40(2):230-5.
Nursing: Physical Assessment/Monitoring
Assess effectiveness and interactions of other medications, especially those that are metabolized by P450 enzymes. Note that modafinil has potential for abuse; caution patient about inappropriate or overuse. Perform careful cardiovascular assessment prior to initiating therapy. Assess knowledge/teach patient appropriate use, adverse symptoms to report. and interventions to reduce side effects.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Provigil®: 100 mg, 200 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Provigil)
100 mg (30): $222.12
200 mg (30): $311.34
References
Broughton, RJ, “Randomized, Double-Blind, Placebo-Controlled Crossover Trial of Modafinil in the Treatment of Excessive Daytime Sleepiness in Narcolepsy,” Neurology, 1997, 49(2):444-451.
Grozinger M, “Interaction of Modafinil and Clomipramine as Comedication in a Narcoleptic Patient,” Clin Neuropharmacol, 1998, 21(2):127-129.
Rugino TA and Copley TC, “Effects of Modafinil in Children With Attention-Deficit/Hyperactivity Disorder: An Open-Label Study,” J Am Acad Child Adolesc Psychiatry, 2001, 40(2):230-5.
Taylor FB and Russo J, “Efficacy of Modafinil Compared to Dextroamphetamine for the Treatment of Attention Deficit Hyperactivity Disorder in Adults,” J Child Adolesc Psychopharmacol, 2000, 10(4):311-20.
U.S. Modafinil in Narcolepsy Multicenter Study Group, “Randomized Trial of Modafinil for the Treatment of Pathological Somnolence in Narcolepsy,” Ann Neurol, 1998, 43(1):88-97.
Vetter VL, Elia J, Erickson CH, et al, “Cardiovascular Monitoring of Children and Adolescents With Heart Disease Receiving Stimulant Drugs. A Scientific Statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing,” Circulation, 2008, 117:2407-23.
Wong, YN, “Single-Dose Pharmacokinetics of Modafinil and Methylphenidate Given Alone or in Combination in Healthy Male Volunteers,” J Clin Pharmacol, 1998, 38(3):276-282.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
Content last modified August 2008
| 
