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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.
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section and/or refer to product labeling for additional detail.
Medication Safety Issues
Sound-alike/look-alike issues:
Imipramine may be confused with amitriptyline, desipramine, Norpramin®
Pronunciation
(im IP ra meen)
U.S. Brand Names
Index Terms
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of depression; treatment of nocturnal enuresis in children
Use: Unlabeled/Investigational
Analgesic for certain chronic and neuropathic pain; panic disorder; attention-deficit/hyperactivity disorder (ADHD)
Restrictions
An FDA-approved medication guide concerning the use of antidepressants in children, adolescents, and young adults must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm. Dispense to parents or guardians of children and adolescents receiving this medication.
Pregnancy Risk Factor
D
Lactation
Enters breast milk/not recommended (AAP rates “of concern”)
Contraindications
Hypersensitivity to imipramine (cross-reactivity with other dibenzodiazepines may occur) or any component of the formulation; concurrent use of MAO inhibitors (within 14 days); in a patient during acute recovery phase of MI; pregnancy
Warnings/Precautions
Boxed warnings:
• Suicidal thinking/behavior: See “Major psychiatric warnings” below.
Major psychiatric warnings:
• [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ?65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1-2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Imipramine is FDA approved for the treatment of nocturnal enuresis in children ?6 years of age.
• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.
• May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. Imipramine is not FDA approved for the treatment of bipolar depression.
Concerns related to adverse effects:
• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. The degree of anticholinergic blockade produced by this agent is high relative to other antidepressants.
• Hematologic effects: TCAs may rarely cause bone marrow suppression; monitor for any signs of infection and obtain CBC if symptoms (eg, fever, sore throat) evident.
• Orthostatic hypotension: May cause orthostatic hypotension (risk is very high relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).
• Photosensitization: Has been associated with photosensitization; avoid excessive exposure to sunlight.
• Sedation: May cause sedation, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). The degree of sedation is high relative to other antidepressants.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities); the risk of conduction abnormalities with this agent is high relative to other antidepressants.
• Diabetes: Use with caution in patients with diabetes mellitus; may alter glucose regulation.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment.
• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.
• Thyroid dysfunction: Use with caution in patients with hyperthyroidism or those receiving thyroid supplementation due to concerns of pro-arrhythmogenesis.
Concurrent drug therapy issues:
• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.
Special populations:
• Elderly: Use with caution in the elderly.
Other warnings/precautions:
• Discontinuation of therapy: Recommended to discontinue prior to elective surgery requiring general anesthesia. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.
• ECG monitoring: Baseline and periodic assessment recommended with use of higher dosages; should also be considered in elderly patients and/or patients with pre-existing cardiovascular disease.
• Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.
Adverse Reactions
Reported for tricyclic antidepressants in general. Frequency not defined.
Cardiovascular: Arrhythmia, CHF, ECG changes, heart block, hypertension, MI, orthostatic hypotension, palpitation, stroke, tachycardia
Central nervous system: Agitation, anxiety, confusion, delusions, disorientation, dizziness, drowsiness, fatigue, hallucination, headache, hypomania, insomnia, nightmares, psychosis, restlessness, seizure
Dermatologic: Alopecia, itching, petechiae, photosensitivity, purpura, rash, urticaria
Endocrine & metabolic: Breast enlargement, galactorrhea, gynecomastia, increase or decrease in blood sugar, increase or decrease in libido, SIADH
Gastrointestinal: Abdominal cramps, anorexia, black tongue, constipation, diarrhea, epigastric disorders, ileus, nausea, stomatitis, taste disturbance, vomiting, weight gain/loss, xerostomia
Genitourinary: Impotence, testicular swelling, urinary retention
Hematologic: Agranulocytosis, eosinophilia, thrombocytopenia
Hepatic: Cholestatic jaundice, transaminases increased
Neuromuscular & skeletal: Ataxia, extrapyramidal symptoms, incoordination, numbness, paresthesia, peripheral neuropathy, tingling, tremor, weakness
Ocular: Blurred vision, disturbances of accommodation, mydriasis
Otic: Tinnitus
Miscellaneous: Diaphoresis, falling, hypersensitivity (eg, drug fever, edema)
Metabolism/Transport Effects
Substrate of CYP1A2 (minor), 2B6 (minor), 2C19 (major), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C19 (weak), 2D6 (moderate), 2E1 (weak)
Drug Interactions
Acetylcholinesterase Inhibitors (Central): Anticholinergics may diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Risk C: Monitor therapy
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Alpha-/Beta-Agonists (Direct-Acting): Tricyclic Antidepressants may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Exceptions: Dipivefrin. Risk D: Consider therapy modification
Alpha1-Agonists: Tricyclic Antidepressants may enhance the vasopressor effect of Alpha1-Agonists. Risk D: Consider therapy modification
Alpha2-Agonists: Tricyclic Antidepressants may diminish the antihypertensive effect of Alpha2-Agonists. Exceptions: Apraclonidine; Brimonidine. Risk D: Consider therapy modification
Altretamine: May enhance the orthostatic effect of Tricyclic Antidepressants. Risk C: Monitor therapy
Amphetamines: Tricyclic Antidepressants may enhance the stimulatory effect of Amphetamines. Tricyclic Antidepressants may also potentiate the cardiovascular effects of Amphetamines. Risk C: Monitor therapy
Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Paliperidone. Risk C: Monitor therapy
Aspirin: Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy
Barbiturates: May increase the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification
Beta2-Agonists: Tricyclic Antidepressants may enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy
BuPROPion: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy
CarBAMazepine: May increase the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy
Cimetidine: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy
Cinacalcet: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy
CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C19 Inhibitors (Moderate): May decrease the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C19 Inhibitors (Strong): May decrease the metabolism of CYP2C19 Substrates. Risk D: Consider therapy modification
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification
CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Risk C: Monitor therapy
Desmopressin: Tricyclic Antidepressants may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy
Dexmethylphenidate: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy
DULoxetine: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
Lithium: May enhance the neurotoxic effect of Tricyclic Antidepressants. Risk C: Monitor therapy
MAO Inhibitors: May enhance the serotonergic effect of Tricyclic Antidepressants. This may cause serotonin syndrome. Risk X: Avoid combination
Methylphenidate: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy
Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
NSAID (COX-2 Inhibitor): Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of NSAID (COX-2 Inhibitor). Risk C: Monitor therapy
NSAID (Nonselective): Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of NSAID (Nonselective). Risk C: Monitor therapy
Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification
Propoxyphene: May enhance the CNS depressant effect of Tricyclic Antidepressants. Risk C: Monitor therapy
Protease Inhibitors: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
QuiNIDine: Tricyclic Antidepressants may enhance the QTc-prolonging effect of QuiNIDine. QuiNIDine may decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification
Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination
St Johns Wort: May increase the metabolism of Tricyclic Antidepressants. The risk of serotonin syndrome may theoretically be increased. Risk D: Consider therapy modification
Sulfonylureas: Cyclic Antidepressants may enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the formation of highly potent active metabolites. Risk D: Consider therapy modification
Terbinafine: May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Thioridazine: CYP2D6 Inhibitors may decrease the metabolism of Thioridazine. Risk X: Avoid combination
TraMADol: Tricyclic Antidepressants may enhance the neuroexcitatory and/or seizure-potentiating effect of TraMADol. Risk C: Monitor therapy
Valproic Acid: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Tricyclic Antidepressants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS depression).
Herb/Nutraceutical: St John's wort may decrease imipramine levels. Avoid valerian, St John's wort, SAMe, kava kava (may increase risk of serotonin syndrome and/or excessive sedation).
Mechanism of Action
Traditionally believed to increase the synaptic concentration of serotonin and/or norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane. However, additional receptor effects have been found including desensitization of adenyl cyclase, down regulation of beta-adrenergic receptors, and down regulation of serotonin receptors.
Pharmacodynamics/Kinetics
Onset of action: Peak antidepressant effect: Usually after ?2 weeks
Absorption: Well absorbed
Distribution: Crosses placenta
Metabolism: Hepatic, primarily via CYP2D6 to desipramine (active) and other metabolites; significant first-pass effect
Half-life elimination: 6-18 hours
Excretion: Urine (as metabolites)
Dosage
Oral:
Children:
Depression (unlabeled use): 1.5 mg/kg/day with dosage increments of 1 mg/kg every 3-4 days to a maximum dose of 5 mg/kg/day in 1-4 divided doses; monitor carefully especially with doses ?3.5 mg/kg/day
Enuresis: ?6 years: Initial: 25 mg at bedtime, if inadequate response still seen after 1 week of therapy, increase by 25 mg/day; dose should not exceed 2.5 mg/kg/day or 50 mg at bedtime if 6-12 years of age or 75 mg at bedtime if ?12 years of age
Adjunct in the treatment of cancer pain (unlabeled use): Initial: 0.2-0.4 mg/kg at bedtime; dose may be increased by 50% every 2-3 days up to 1-3 mg/kg/dose at bedtime
Adolescents: Depression: Initial: 25-50 mg/day; increase gradually; maximum: 100 mg/day in single or divided doses
Adults: Depression:
Outpatients: Initial: 75 mg/day; may increase gradually to 150 mg/day. May be given in divided doses or as a single bedtime dose; maximum: 200 mg/day
Inpatients: Initial: 100-150 mg/day; may increase gradually to 200 mg/day; if no response after 2 weeks, may further increase to 250-300 mg/day. May be given in divided doses or as a single bedtime dose; maximum: 300 mg/day.
Elderly: Depression: Initial: 25-50 mg at bedtime; may increase every 3 days for inpatients and weekly for outpatients if tolerated to a recommended maximum of 100 mg/day.
Monitoring Parameters
Monitor blood pressure and pulse rate prior to and during initial therapy; ECG in older adults, with high doses, and/or in patients with pre-existing cardiovascular disease; evaluate mental status, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased); blood levels are useful for therapeutic monitoring
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); ensure PR interval ?200 ms, QRS duration ?120 ms, and QTc ?460 ms.
Reference Range
Therapeutic: Imipramine and desipramine: 150-250 ng/mL (SI: 530-890 nmol/L); desipramine: 150-300 ng/mL (SI: 560-1125 nmol/L); Toxic: >500 ng/mL (SI: 446-893 nmol/L); utility of serum level monitoring controversial
Patient Education
Take exactly as directed; do not increase dose or frequency. It may take 2-3 weeks to achieve desired results. Take in the evening. Avoid alcohol, caffeine, and other prescription or OTC medications not approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, lightheadedness, impaired coordination, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, altered taste, dry mouth (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); diarrhea (buttermilk, yogurt, or boiled milk may help); postural hypotension (use caution when climbing stairs or changing position from lying or sitting to standing); or urinary retention (void before taking medication). Report persistent insomnia; muscle cramping or tremors; chest pain, palpitations, rapid heartbeat, swelling of extremities, or severe dizziness; unresolved urinary retention; rash or skin irritation; yellowing of eyes or skin; pale stools/dark urine; worsening of condition; and suicide ideation. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate contraceptive measures. Breast-feeding is not recommended.
Geriatric Considerations
Orthostatic hypotension is a concern with this agent, especially in patients taking other medications that may affect blood pressure. May precipitate arrhythmias in predisposed patients; may aggravate seizures. A less anticholinergic antidepressant may be a better choice. Data from a clinical trial comparing fluoxetine to tricyclics suggests that fluoxetine is significantly less effective than nortriptyline in hospitalized elderly patients with unipolar major affective disorder, especially those with melancholia and concurrent cardiovascular diseases.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation). Long-term treatment with TCAs, such as imipramine, increases the risk of caries by reducing salivation and salivary buffer capacity. In a study by Rundergren, et al, pathological alterations were observed in the oral mucosa of 72% of 58 patients; 55% had new carious lesions after taking TCAs for a median of 51/2 years. Current research is investigating the use of the salivary stimulant pilocarpine to overcome the xerostomia from imipramine.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Use with caution; epinephrine and levonordefrin have been shown to have an increased pressor response in combination with TCAs. Imipramine is one of the drugs confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, levonordefrin [Neo-Cobefrin®]) be used with caution.
Mental Health: Comment
Tricyclic antidepressants may be classified as tertiary (amitriptyline, doxepin, clomipramine, imipramine, trimipramine) or secondary amines (nortriptyline, desipramine, protriptyline). The tertiary amines are not recommended to treat depression in the elderly. If a TCA is used in the elderly, it should be a secondary amine. The tertiary amines are commonly used in low dosages for various conditions associated with pain. A 1-week supply at maximum dosage taken as a single ingestion is potentially fatal.
Plasma concentrations correlate with clinical response. A linear relationship exists.
Nursing: Physical Assessment/Monitoring
Assess other medications patient may be taking for effectiveness and interactions. Perform careful cardiovascular assessment prior to initiating therapy. Assess results of laboratory tests, therapeutic effectiveness, and adverse reactions at beginning of therapy and periodically with long-term use. Assess CNS status and clinical worsening, and be alert for suicidal ideation. Taper dosage slowly when discontinuing (allow 3-4 weeks between discontinuing and starting another antidepressant), if possible. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, as pamoate: 75 mg, 100 mg, 125 mg, 150 mg
Tofranil-PM®: 75 mg, 100 mg, 125 mg, 150 mg
Tablet, as hydrochloride: 10 mg, 25 mg, 50 mg
Tofranil®): 10 mg, 25 mg, 50 mg
Pricing: U.S. (www.drugstore.com)
Capsules (Imipramine Pamoate)
75 mg (30): $333.02
Capsules (Tofranil-PM)
75 mg (30): $459.98
100 mg (30): $399.98
125 mg (30): $479.58
150 mg (30): $473.08
Tablets (Imipramine HCl)
50 mg (30): $17.64
Tablets (Tofranil)
25 mg (30): $155.99
50 mg (30): $128.24
References
“American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk,” Pediatrics, 2001, 108(3):776-89.
“American Academy of Pediatrics Subcommittee on Attention-Deficit/Hyperactivity Disorder and Committee on Quality Improvement. Clinical Practice Guidelines: Treatment of the School-Aged Child With Attention-Deficit/Hyperactivity Disorder,” Pediatrics, 2001, 108(4):1033-44.
Berde C, Ablin A, Glazer J, et al, “American Academy of Pediatrics Report of the Subcommittee on Disease-Related Pain in Childhood Cancer,” Pediatrics, 1990, 86(5 Pt 2):818-25.
Boakes AJ, Laurence DR, Teoh PC, et al, “Interactions Between Sympathomimetic Amines and Antidepressant Agents in Man,” Br Med J, 1973, 1(849):311-5.
Callaham M and Kassel D, “Epidemiology of Fatal Tricyclic Antidepressant Ingestion: Implications for Management,” Ann Emerg Med, 1985, 14(1):1-9.
Fouron JC and Chicoine R, “EKG Changes in Fatal Imipramine (Tofranil®) Intoxication,” Pediatrics, 1971, 48(5):777-81.
Frommer DA, Kulig KW, Marx JA, et al, “Tricyclic Antidepressant Overdose,” JAMA, 1987, 257(4):521-6.
Hagerman GA and Hanashiro PK, “Reversal of Tricyclic Antidepressant-Induced Cardiac Conduction Abnormalities by Phenytoin,” Ann Emerg Med, 1981, 10(2):82-6.
Mitchell JR, “Guanethidine and Related Agents. III Antagonism by Drugs Which Inhibit the Norepinephrine Pump in Man,” J Clin Invest, 1970, 49(8):1596-604.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
Nies A, Robinson DS, Friedman MS, et al, “Relationship Between Age and Tricyclic Antidepressant Plasma Levels,” Am J Psychiatry, 1977, 134:790-3.
Pass SE and Simpson RW, “Discontinuation and Reinstitution of Medications During the Perioperative Period,” Am J Health Syst Pharm, 2004, 61(9):899-912.
Roose SP, Glassman AH, Attia E, et al, “Comparative Efficacy of Selective Serotonin Reuptake Inhibitors and Tricyclics in the Treatment of Melancholia,” Am J Psychiatry, 1994, 151(12):1735-9.
Sener EK, Gabe S, and Henry JA, “Response to Glucagon in Imipramine Overdose,” J Toxicol Clin Toxicol, 1995, 33(1):51-3.
Svedmyr N, “The Influence of a Tricyclic Antidepressive Agent (Protriptyline) on Some of the Circulatory Effects of Noradrenaline and Adrenalin in Man,” Life Sci, 1968, 7(1):77-84.
Tran P, Panacek EA, Rhee KJ, et al, “Is Norepinephrine More Efficacious Than Dopamine in Reversing Hypotension Caused by Cyclic Antidepressant Overdose?” Ann Emerg Med, 1995, 25(1):128-30.
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.
International Brand Names
Lexi-Comp.com
Last full review/revision September 2008
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