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Antidepressants, Tricyclic (Systemic)

This monograph includes information on the following:

1) Amitriptyline
2) Amoxapine
3) Clomipramine
4) Desipramine
5) Doxepin
6) Imipramine
7) Nortriptyline
8) Protriptyline
9) Trimipramine

VA CLASSIFICATION
Amitriptyline
Primary: CN601
Secondary: GU900; CN103; GA309; CN900

Amoxapine
Primary: CN601

Clomipramine
Primary: CN601
Secondary: CN900; CN103

Desipramine
Primary: CN601
Secondary: CN103; CN900

Doxepin
Primary: CN601
Secondary: CN900; DE890; CN103 ; GA309

Imipramine
Primary: CN601
Secondary: GU900; CN900; CN103

Nortriptyline
Primary: CN601
Secondary: CN103; CN900

Protriptyline
Primary: CN601
Secondary: CN900

Trimipramine
Primary: CN601
Secondary: GA309; CN103


Commonly used brand name(s): Anafranil3; Apo-Amitriptyline1; Apo-Imipramine6; Apo-Trimip9; Asendin2; Aventyl7; Elavil1; Endep1; Impril6; Levate1; Norfranil6; Norpramin4; Novo-Doxepin5; Novo-Tripramine9; Novopramine6; Novotriptyn1; Pamelor7; Pertofrane4; Rhotrimine9; Sinequan5; Surmontil9; Tipramine6; Tofranil6; Tofranil-PM6; Triadapin5; Triptil8; Vivactil8.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:

Note: All of the tricyclic antidepressants have similar pharmacologic actions; however, clinical uses among specific agents may vary because of actual pharmacokinetic differences, availability of specific testing, differences in side effects {201}0, and/or availability of clinical-use data.



Antidepressant—Amitriptyline; Amoxapine; Clomipramine; Desipramine; Doxepin; Imipramine; Nortriptyline; Protriptyline; Trimipramine;

Antienuretic—Amitriptyline; Imipramine Hydrochloride;

Antiobsessive-compulsive agent—Clomipramine;

Antipanic agent—Clomipramine; Desipramine{200}9; Doxepin; Imipramine{200}8; Nortriptyline{200}7{200}6{200}5;

Antineuralgic—Amitriptyline; Clomipramine{200}4{200}3; Desipramine; Doxepin; Imipramine; Nortriptyline; Trimipramine{200}2;

Antiulcer agent—Amitriptyline; Doxepin; Trimipramine;

Antinarcolepsy adjunct—Imipramine; Protriptyline{200}1;

Anticataplectic—Clomipramine; Desipramine; Imipramine; Protriptyline;

Antibulimic—Amitriptyline; Clomipramine{200}0; Desipramine; Imipramine;

Antipruritic—Doxepin;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Depression, mental (treatment)—Amitriptyline, amoxapine, [clomipramine] , desipramine, doxepin, imipramine, nortriptyline, protriptyline, and trimipramine are indicated for the relief of symptoms of major depressive episodes {200}9; bipolar disorder, depressed type {200}8; dysthymia {200}7; and atypical depressions. Some conditions associated with or accompanied by depression that are treated with tricyclic antidepressants include alcoholism, organic disease such as stroke or Parkinson's disease, and agitation or anxiety.

Enuresis (treatment adjunct)—Imipramine hydrochloride {200}6, but not pamoate, and [amitriptyline{200}5] are indicated as aids in the temporary treatment of nocturnal enuresis in children 6 years of age or older, after possible organic causes have been excluded by appropriate tests.

Obsessive-compulsive disorder (treatment)—Clomipramine is used to relieve symptoms of obsessive-compulsive disorders, independent of concomitant depression {200}4 {200}3 {200}2 {200}1 {200}0.

[Panic disorder (treatment)]1{122}9{122}8{122}7—Tricyclic antidepressants, especially clomipramine, desipramine, doxepin, {122}6 imipramine, and nortriptyline {122}5 {122}4 {122}3 are used in conjunction with psychotherapy and behavior therapy to block the recurrence of panic attacks, with or without phobias. Imipramine's antipanic effect does not appear to be correlated with presence of depressive symptoms. {122}2

[Pain, neurogenic (treatment)]1—Tricyclic antidepressants, especially amitriptyline, clomipramine {122}1 {122}0, desipramine, doxepin, imipramine, nortriptyline, and trimipramine {01}9 are used in patients with normal or depressed mood {01}8 {01}7 for the management of chronic, severe pain as in cancer; migraine and chronic, daily muscle-contraction headaches; rheumatic disorders; atypical facial pain; post-herpetic neuralgia; post-traumatic neuropathy {01}6; and diabetic or other {01}5 peripheral neuropathy.

[Attention deficit hyperactivity disorder (treatment)]1{01}4—Desipramine, imipramine, and protriptyline {01}3 are used to relieve the symptoms of attention deficit hyperactivity disorder in some children over 6 years of age and in young adults {01}2. Tricyclic antidepressants may be more useful than stimulants when the patient has become withdrawn and depressed {01}1.

[Headache (prophylaxis)]1—Tricyclic antidepressants are used in the prophylaxis of vascular headache (including migraine) and mixed headache syndrome {01}0 {113}9 {113}8 {113}7 {113}6 {113}5 {113}4.

[Ulcer, peptic (treatment)]1—Although amitriptyline, doxepin, and trimipramine are effective in the treatment of peptic ulcer disease and in relieving nocturnal ulcer pain {113}3 {113}2, their use has been largely supplanted by histamine H 2-receptor antagonists, omeprazole, and sucralfate {113}1.

[Narcolepsy/cataplexy syndrome (treatment)]1or
[Narcolepsy/cataplexy syndrome (treatment adjunct)]1—Tricyclic antidepressants, especially clomipramine, desipramine, imipramine, and protriptyline, are used to treat cataplexy associated with narcolepsy, with little or no effect on narcoleptic sleep attacks. Imipramine may be used in combination with amphetamines or methylphenidate when a patient requires treatment for both cataplexy and sleep attacks. {113}0 Patients with sleep disorders such as hypersomnia or impaired morning arousal may benefit by the use of protriptyline {122}9.

[Bulimia nervosa{122}8 (treatment)]1{122}7—Amitriptyline, clomipramine {122}6, desipramine, and imipramine have been shown to be effective in controlling the binge eating and subsequent purging of bulimia nervosa {122}5 {122}4.

[Cocaine withdrawal (treatment)]1{122}3—Desipramine and imipramine are used to reduce craving and/or prevent depression upon withdrawal of cocaine {122}2 {122}1.

[Urinary incontinence (treatment)]1—Imipramine is used for the treatment of stress and urge incontinence {122}0 {113}9 {113}8 {113}7 {113}6 {113}5 {113}4 {113}3.

[Pruritus (treatment)]1—Doxepin is used in treatment of pruritus in idiopathic cold urticaria.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Table 1. Pharmacology/Pharmacokinetics



Drug
Anticholinergic Effects *
Sedation *
Orthostatic Hypotension *
Active Metabolites
Protein Binding (%)
Volume of Distribution (L/Kg)
Half-life (hours)
Therapeutic Plasma Concentration (ng/mL)
Amitriptyline
High {113}2 {113}1 {113}0
High {122}9 {122}8 {122}7
Moderate to high {122}6 {122}5 {122}4
Nortriptyline
10-Hydroxyamitriptyline {122}3 {122}2
95 {122}1 {122}0
12–18 {109}9 {109}8
10–26 {109}7 {109}6
 
Amoxapine
Moderate {109}5
Low to moderate {109}4
Low {109}3
7- and 8-Hydroxyamoxapine {109}2
92 {109}1
N.A.
8–30 {109}0
 
Clomipramine
High {122}9 {122}8 {122}7
Moderate {122}6 {122}5
Moderate
Desmethylclomipramine {122}4 {122}3 {122}2
96–97 {122}1 {122}0 {122}9
12 {122}8 {122}7
21–31 {122}6 {122}5
 
Desipramine
Low {122}4 {122}3
Low {122}2 {122}1 {122}0 {80}9
Moderate {80}8 {80}7
2-Hydroxydesipramine {80}6
90–92 {80}5 {80}4
17–42 {80}3 {80}2
12–27 {80}1 {80}0 {202}9
125–300 {202}8 {202}7 {202}6 {202}5 {202}4 {202}3
Doxepin
High {202}2 {202}1
High {202}0 {202}9 {202}8
High {202}7
Desmethyldoxepin {202}6
N.A.
12–28 {202}5 {202}4
11–23 {202}3 {202}2
 
Imipramine
Moderate {202}1 {202}0
Moderate {202}9 {202}8 {202}7 {202}6
High {202}5 {202}4
Desipramine
2-Hydroxydesipramine {202}3 {202}2
89–95 {202}1 {202}0
15–31 {202}9 {202}8
11–25 {202}7 {202}6
150–300 {202}5 {202}4 {202}3 {202}2 §
Nortriptyline
Low {202}1
Moderate {202}0 {202}9 {202}8
Low {202}7 {202}6 {202}5 {202}4
10-Hydroxynortriptyline {202}3 {202}2
92 {202}1 {202}0
14–22 {202}9 {202}8
18–44 {202}7 {202}6 {202}5
50–150 {202}4 {202}3 {202}2 {202}1 {202}0 {122}9 **
Protriptyline
Moderate {122}8 {122}7
Very low {122}6 {122}5
Low {122}4 {122}3
N.A.
92 {122}2 {122}1
22 {122}0
67–89 {17}9 {17}8
 
Trimipramine
High {17}7 {17}6
High {17}5 {17}4 {17}3
Moderate {17}2 {17}1
N.A.
N.A.
N.A.
9–11 {17}0
 
* Relative effects among tricyclic antidepressants only.
 Although various values have been reported, there is little consensus about therapeutic plasma concentrations, except for desipramine, imipramine, and nortriptyline {57}9 {57}8 {57}7 {57}6. Steady-state plasma levels exhibit marked interindividual variations due to genetic factors (e.g., hepatic metabolism) and physiochemical properties of the medication (e.g., lipid solubility) {57}5.
 Not available.
§ Includes metabolites.
** Denotes therapeutic window, outside of which effects are lessened {57}4 {57}3 {57}2.

Physicochemical characteristics:
Molecular weight—
    Amitriptyline hydrochloride: 313.87
    Amoxapine: 313.79
    Clomipramine hydrochloride: 351.32
    Desipramine hydrochloride: 302.85
    Doxepin hydrochloride: 315.84
    Imipramine hydrochloride: 316.87
    Imipramine pamoate: 949.2 {57}1
    Nortriptyline hydrochloride: 299.84
    Protriptyline hydrochloride: 299.84
    Trimipramine maleate: 410.51

pKa—
    Amitriptyline: 9.4
    Amoxapine: 7.6
    Clomipramine: 9.5 {57}0
    Desipramine: 1.5 and 10.2
    Doxepin: 9.0
    Imipramine: 9.5
    Nortriptyline: 9.7
    Trimipramine: 8.0

Mechanism of action/Effect:


Antidepressant:

Although the exact mechanism of action in the treatment of depression is unclear, tricyclic antidepressants have been thought to increase the synaptic concentration of norepinephrine (levarterenol; NE) and/or serotonin (5-hydroxytryptamine; 5-HT) in the central nervous system (CNS) {17}9. One theory suggests that these neurotransmitters are increased through inhibition of their reuptake by the presynaptic neuronal membrane {17}8.

Amoxapine {17}7, desipramine {17}6, trimipramine, nortriptyline, {17}5 and probably protriptyline mainly inhibit the reuptake of norepinephrine. Amitriptyline and clomipramine appear to be more potent than other tricyclics in blocking serotonin, although, through their metabolites, they become powerful inhibitors of norepinephrine reuptake also {17}4 {17}3. Clomipramine's effectiveness in the treatment of obsessive-compulsive disorder may be related to the inhibition of serotonin reuptake {17}2 {17}1. Imipramine inhibits reuptake of norepinephrine and serotonin equally {17}0. Doxepin is a moderate inhibitor of norepinephrine and a weak inhibitor of serotonin {39}9.

Recent research has shown that after long-term treatment with antidepressants, changes in postsynaptic {39}8 beta-adrenergic receptor sensitivity and increased responsiveness of the adrenergic and serotonergic systems to physiologic and environmental stimuli {39}7 contribute to the mechanism of action. Antidepressants may produce a downregulation (desensitization) of alpha 2- or beta-adrenergic and serotonin receptors, equilibrating the noradrenergic system, and thus correcting the dysregulated monoamine output of depressed patients {39}6. Receptor changes resulting from chronic administration of tricyclic antidepressants appear to correlate better with antidepressant action than does the synaptic reuptake blockade of neurotransmitters, and may also account for the delay of 2 to 4 weeks in therapeutic response {39}5 {39}4 {39}3.

Amoxapine, as a metabolite of the neuroleptic, loxapine, also has a potent postsynaptic dopamine-blocking effect. This may account for the extrapyramidal side effects and increases in serum prolactin concentrations seen with amoxapine. Amoxapine is metabolized to 7-hydroxyamoxapine, also a potent dopamine-blocking agent {39}2.



Antienuretic:

The exact antienuretic action of imipramine hydrochloride has not been established. It is thought to be associated with the anticholinergic effects of imipramine {39}1.



Antiobsessional agent:

The exact antiobsessional action of clomipramine has not been established. It is thought to be associated with clomipramine's inhibition of serotonin reuptake {39}0 and compensatory down regulation of serotonin receptor subtypes {172}9.



Antianxiety agent:

In panic disorders, studies suggest an impaired function of the autonomic nervous system that causes an excessive release of norepinephrine from the locus ceruleus. Tricyclic antidepressants are thought to decrease the firing rate of the locus ceruleus by regulating the alpha 2- and beta-adrenergic receptor functions and norepinephrine turnover. {172}8



Antineuralgic:

The exact mechanism by which tricyclic antidepressants relieve chronic pain is also unknown. Some studies support the theory that pain relief results when depression is relieved. However, other studies have found that pain may be ameliorated without a significant change in depression. Analgesic activity may be effected by the changing concentrations of central monoamines, especially serotonin, and by the direct or indirect effect of tricyclic antidepressants on the endogenous opioid systems. {172}7



Antiulcer agent:

In peptic ulcer disease, tricyclic antidepressants are effective in relieving pain and aid in complete healing because of their histamine 2-receptor blocking property on the parietal cells, and their sedative and anticholinergic effects {172}6 {172}5.



Antibulimic:

In bulimia nervosa, the mechanism of action is unclear, although it may be similar to that in depression. Evidence shows there is a distinct antibulimic effect in patients without depression and in depressed patients whose bulimia was relieved without a concomitant relief of depression. {172}4



Urinary incontinence:

The exact mechanism by which imipramine enhances urinary continence has not been established but may include anticholinergic activity, resulting in increased bladder capacity; direct beta-adrenergic stimulation; alpha-adrenergic agonist activity, resulting in increased sphincter tone {172}3 {172}2; and central blockade of serotonin uptake {172}1.



Other actions/effects:

Tricyclic antidepressants also produce prominent peripheral and central anticholinergic effects {172}0 {173}9 {173}8 due to their potent and high binding affinity for muscarinic receptors; sedative effects due to strong binding affinity for histamine H 1-receptors (although the central actions of histamine are poorly understood, increased cholinoceptive activity in the brain has been associated with clinical depression); and orthostatic hypotension due to alpha blockade {173}7. In addition, tricyclic antidepressants are Class 1A antiarrhythmic agents {173}6 which, like quinidine, moderately slow ventricular conduction in therapeutic doses {173}5 {173}4, and in overdose may cause severe conduction block and occasional ventricular arrhythmia {173}3.

Absorption:

Rapidly and well absorbed after oral administration {173}2 {173}1 {173}0 {174}9 {174}8 {174}7.

Protein binding:

Very highly protein bound (90% or more) in plasma and tissues {174}6 {174}5.

Biotransformation:

Exclusively hepatic {174}4 {174}3, with first-pass effect {174}2 {174}1.

Onset of action:

Antidepressant—2 to 3 weeks {174}0 {185}9 {185}8 {185}7 {185}6 {185}5 {185}4.

Elimination:
    As metabolites, primarily renal {185}3 {185}2 {185}1 {185}0 {187}9 {187}8, over several days; poorly dialyzable because of high protein binding.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one tricyclic antidepressant may be sensitive to other tricyclic antidepressants {187}7 {187}6 {187}5 {187}4 {187}3 {187}2 {187}1, and possibly to carbamazepine {187}0, maprotiline, and trazodone, also.

Carcinogenicity/Mutagenicity

Amitriptyline—In one study with rats, no evidence of increase in incidence of any tumor was found. However, amitriptyline has not been adequately studied in animals to permit an evaluation of its carcinogenic potential. {172}9 No evidence of mutagenicity was found in rats tested with the Ames salmonella test.

Amoxapine—Pancreatic islet cell hyperplasia occurred in rats, with slightly increased incidence at doses 5 to 10 times the human dose {172}8.

Pregnancy/Reproduction

Pregnancy—

For amitriptyline

Adequate and well-controlled studies in pregnant women have not been done.

Animal studies have shown amitriptyline to cause teratogenic effects when used in doses many times the human dose.

FDA Pregnancy Category C {172}7.



For amoxapine

Adequate and well-controlled studies in pregnant women have not been done.

Animal studies have shown amoxapine to cause embryotoxic effects in doses approximating the human dose and fetotoxic effects such as intrauterine death, stillbirth, decreased birth weight, and decreased postnatal (0 to 4 days) survival {172}6 at doses many times the human dose.

FDA Pregnancy Category C {172}5.



For clomipramine {172}4, desipramine {172}3, and nortriptyline {172}2

Adequate and well-controlled studies in pregnant women have not been done.

Animal reproduction studies have been inconclusive.

FDA Pregnancy Category C {172}1.



For doxepin

Adequate and well-controlled studies in pregnant women have not been done.

Animal studies have shown no evidence of teratogenic effects at doses up to 25 mg per kg of body weight (mg/kg) per day for 8 to 9 months and no changes in litter size, number of live births, or lactation. However, a decreased rate of conception was observed when male rats were given 25 mg/kg per day for prolonged periods. {172}0



For imipramine

Adequate and well-controlled studies in pregnant women have not been done {173}9 {173}8. However, there have been clinical reports of congenital malformations associated with the use of imipramine {173}7 {173}6.

Animal reproduction studies have been inconclusive {173}5 {173}4.



For protriptyline

Adequate and well-controlled studies in pregnant women have not been done.

Animal reproduction studies have shown that protriptyline causes no apparent adverse effects at doses 10 times greater than recommended human doses {173}3 {173}2.



For trimipramine

Adequate and well-controlled studies in pregnant women have not been done.

Animal studies have shown trimipramine to cause embryotoxicity and major anomalies at 20 times the human dose.

FDA Pregnancy Category C {173}1.


Delivery—

For all tricyclic antidepressants: There have been reports of cardiac problems {173}0, irritability {187}9, respiratory distress {187}8 {187}7, muscle spasms {187}6, seizures {187}5 {187}4, and urinary retention {187}3 in infants whose mothers received tricyclic antidepressants immediately prior to delivery.

Breast-feeding

Tricyclic antidepressants have been found in small amounts in breast milk {187}2 {187}1 {187}0 {39}9 {39}8 {39}7 in an approximate milk to plasma ratio of 0.4:1.5 {39}6. Doxepin has been reported to cause sedation and respiratory depression in the nursing infant {39}5 {39}4.

Pediatrics

Although tricyclic antidepressants are generally not recommended for depression in children under 12 years of age, some, especially amitriptyline, desipramine, imipramine, and nortriptyline {39}3, are used in children over the age of 6 years for recognized major depressive illness {39}2. However, the effectiveness of tricyclic antidepressants in the treatment of depression in children and adolescents has not been definitively established {39}1 {39}0 {39}9. Amitriptyline {39}8 and imipramine {39}7 are also used for treatment of enuresis in children 6 years of age or older. Clomipramine is used for the treatment of obsessive-compulsive disorder in children 10 years of age or older {39}6. Imipramine, desipramine, and protriptyline are being used in the treatment of attention deficit hyperactivity disorder in children over 6 years of age and adolescents {39}5. However, deaths have been reported in children treated with desipramine for hyperactivity {39}4 {39}3 {39}2.

Children are more sensitive than adults to acute overdosage, which should be considered serious and potentially fatal {39}1 {39}0 {17}9. Increasing the dose in children increases the risk of adverse effects, such as alterations in electrocardiogram (ECG) patterns, nervousness, sleep disorders, tiredness, hypertension in some children {17}8, or mild gastrointestinal problems, without necessarily enhancing the therapeutic effect. Adolescent patients may require reduced dosage because they are also prone to exhibit increased dose sensitivity {17}7 {17}6.


Geriatrics


Elderly patients often require lower dosage and more gradual dose increases {17}5 {17}4 {17}3 {17}2 {17}1 {17}0 {39}9 to avoid toxicity, because of slower metabolic rates {39}8 and/or excretion and an increased ratio of fat to lean tissue. The elderly also exhibit increased sensitivity to anticholinergic effects, such as urinary retention (especially in older men with prostatic hypertrophy) {39}7, anticholinergic delirium, and increased sedative and hypotensive effects. Increased anxiety may result from these adverse effects, possibly leading to unnecessary dose increases. If cardiovascular disease is present, the risk of conduction defects, arrhythmias, tachycardia, stroke, congestive heart failure, or myocardial infarction is increased. {39}6


Dental

The peripheral anticholinergic effects of tricyclic antidepressants may decrease or inhibit salivary flow, especially in middle-aged or elderly patients, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.

The blood dyscrasia–causing effects of tricyclic antidepressants, although rare, may be life-threatening {39}5. The result may be an increased incidence of microbial infection, delayed healing, and gingival bleeding. If agranulocytosis, leukopenia, or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patient instruction in proper oral hygiene should include caution in use of regular toothbrushes, dental floss, and toothpicks. {39}4

Extrapyramidal reactions that may be induced by amoxapine will result in increased motor activity of the head, face, and neck. Occlusal adjustments, bite registrations, and treatment for bruxism may be made less reliable. {39}3

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Although not all of the following interactions have been reported for every tricyclic antidepressant, the potential for their occurrence exists and should be considered.

» Alcohol{39}2{39}1{39}0{39}9{39}8{39}7{39}6{39}5{39}4{39}3{39}2{39}1{39}0 or
» CNS depression–producing medications, other{80}9{80}8{80}7{80}6{80}5{80}4{80}3{80}2{80}1{80}0{39}9 (See Appendix II)    (concurrent use with tricyclic antidepressants may result in serious potentiation of CNS depression, respiratory depression, and hypotensive effects; caution is recommended, and dosage of one or both agents should be reduced {39}8)

    (in addition, tricyclics may increase the effects of alcohol, especially during first few days of tricyclic antidepressant treatment; in patients who use alcohol excessively, tricyclics may increase the danger inherent in any suicide attempt {39}7 {39}6)


Amantadine or
Anticholinergics or other medications with anticholinergic activity{39}5{39}4{39}3{39}2{39}1{39}0{39}9{39}8{39}7{39}6{39}5{39}4{39}3 (See Appendix II ) or
Antidyskinetics or
Antihistamines    (concurrent use with tricyclic antidepressants may intensify anticholinergic effects, especially mental confusion, hallucinations, and nightmares, because of secondary anticholinergic activities of tricyclic antidepressants)

    (concurrent use may potentiate the CNS depressant effects of either antihistamines or tricyclic antidepressants)

    (concurrent use with tricyclic antidepressants may block detoxification of atropine and related compounds; patients should be advised to report occurrence of gastrointestinal problems promptly since paralytic ileus may occur with concurrent therapy)


Anticoagulants{39}2{39}1 , coumarin- or indandione-derivative    (concurrent use with tricyclic antidepressants, especially amitriptyline or nortriptyline, may increase anticoagulant activity, possibly by inhibiting enzymatic metabolism of the anticoagulant)


Anticonvulsants{39}0    (tricyclic antidepressants may enhance CNS depression, lower the seizure threshold when taken in high doses, and decrease the effects of the anticonvulsant medication; dosage adjustment of the anticonvulsant may be necessary to control seizures; monitoring of serum concentrations of both medications may be necessary to detect possible interaction {02}9; concurrent use of phenytoin with desipramine may lower serum concentrations of desipramine; dosage increases of desipramine above maximum recommended doses may be required to produce clinical improvement in depression {02}8)


» Antithyroid agents    (concurrent use with tricyclic antidepressants may increase the risk of agranulocytosis)


Barbiturates{02}7{02}6{02}5 or
Carbamazepine{02}4    (plasma concentrations and therapeutic effects of tricyclic antidepressants may be decreased during concurrent use with barbiturates, especially phenobarbital, or carbamazepine because of increased metabolism resulting from induction of hepatic microsomal enzymes)


Bupropion{02}3 or
Clozapine{02}2{02}1 or
Cyclobenzaprine or
Haloperidol{02}0{17}9 or
Loxapine{17}8 or
Maprotiline{17}7 or
Molindone{17}6 or
» Phenothiazines{17}5{17}4 or
Thioxanthenes{17}3    (the sedative and anticholinergic effects of either these medications or tricyclic antidepressants may be prolonged and intensified; these medications may increase the risk of seizures by lowering the seizure threshold and should be added or withdrawn with caution; psychotic depressions respond well to a combination of tricyclic antidepressant and antipsychotic agent, but both medications must be initially administered at lower {17}2 doses and are increased only as clinically indicated {17}1)

    (concurrent use of phenothiazines may increase serum concentrations of tricyclic antidepressants, especially desipramine and imipramine, due to inhibition of metabolism; conversely, tricyclics may inhibit phenothiazine metabolism {17}0; also, the risk of neuroleptic malignant syndrome [NMS] may be increased {39}9)


» Cimetidine{39}8{39}7{39}6{39}5{39}4{39}3{39}2{39}1{39}0{39}9{39}8{39}7{39}6{39}5    (cimetidine may inhibit tricyclic metabolism and increase plasma concentrations, leading to toxicity; lowering the dose of the tricyclic antidepressant by 20 to 30% may be necessary when cimetidine is given concurrently; patient should be closely observed for sedation, anticholinergic effects, and orthostatic hypotension {39}4)


» Clonidine{39}3{39}2{39}1{39}0 or
» Guanadrel{39}9 or
» Guanethidine{39}8{39}7{39}6{39}5{39}4{39}3{39}2{39}1{39}0{204}9{204}8    (concurrent use may decrease the hypotensive effects of these medications)

    (concurrent use of clonidine with tricyclic antidepressants may result in potentiation of CNS depressant effects)


Cocaine    (concurrent use with tricyclic antidepressants may increase the risk of cardiac arrhythmias; if use of cocaine is necessary in patients receiving tricyclics, it is recommended that the cocaine be administered with caution, in reduced dosage, and in conjunction with electrocardiographic monitoring {204}7)


Contraceptives, oral, estrogen-containing{204}6 or
Estramustine or
Estrogens{204}5    (concurrent use of imipramine and possibly other tricyclic antidepressants by chronic long-term users of oral contraceptives or estrogens may increase the bioavailability of imipramine because of inhibition of hepatic enzyme metabolism; this may result in toxicity, obscuring therapeutic effects and worsening depression; may be dose-related, with lower doses of estrogens having less effect on enzyme inhibition than larger doses; dosage adjustments of the tricyclic may be necessary {204}4 {204}3 {204}2 {204}1)


Corticosteroids, glucocorticoid    (tricyclic antidepressants do not relieve, and may exacerbate, corticosteroid-induced mental depression {204}0)


Disulfiram{196}9 or
Ethchlorvynol{196}8    (concurrent use with tricyclics, especially amitriptyline, may result in transient delirium)

    (also, CNS depressant effects may be increased when ethchlorvynol is used concurrently with tricyclic antidepressants)


Electroconvulsive therapy{196}7{196}6{196}5{196}4{196}3{196}2{196}1{196}0{123}9{123}8{123}7{123}6    (although electroconvulsive therapy may be used in conjunction with tricyclic antidepressants, caution should be used as hazards may be increased)


» Extrapyramidal reaction–causing medications, other (See Appendix II )    (concurrent use with amoxapine and possibly other tricyclic antidepressants may increase the severity and frequency of extrapyramidal effects)


Fluoxetine    (concurrent use with tricyclic antidepressants has produced increased plasma concentrations of the tricyclic antidepressant {123}5 {123}4, possibly due to inhibition of tricyclic antidepressant metabolism {123}3; some clinicians recommend dosage reductions for tricyclic antidepressants of about 50% if used concurrently with fluoxetine {123}2 {123}1 {123}0 {123}9)


Methylphenidate{123}8{123}7{123}6{123}5    (serum concentrations of tricyclic antidepressants, especially desipramine and imipramine, may be increased due to inhibition of metabolism when methylphenidate is used concurrently; also, concurrent use may antagonize the effects of methylphenidate)


» Metrizamide    (administration of intrathecal metrizamide may lower the seizure threshold and increase the risk of seizures in patients taking tricyclic antidepressants; it is recommended that tricyclic antidepressants be discontinued for at least 48 hours before and at least 24 hours after myelography)


» Monoamine oxidase (MAO) inhibitors{123}4{123}3{123}2{123}1{123}0{123}9{123}8{123}7{123}6{123}5{123}4{123}3{123}2{123}1{123}0 , including furazolidone, procarbazine, and selegiline    (concurrent use with tricyclic antidepressants has resulted in an increased incidence of hyperpyretic episodes, severe convulsions, hypertensive crises, and death; however, recent studies have shown that concurrent use of some tricyclic antidepressants with MAO inhibitors can be used for refractory depression with no adverse effects if both medications are initiated simultaneously at lower than usual doses, with doses being raised gradually thereafter, or if the MAO inhibitor is gradually added to the tricyclic, also at low doses; a tricyclic should not be added to an existing MAO inhibitor regimen; the tricyclic antidepressants most commonly used in this combined therapy are amitriptyline, doxepin, and trimipramine {123}9; imipramine, desipramine, nortriptyline, protriptyline, and clomipramine are not recommended for use in such a regimen because of potential excessive stimulation {123}8)


Naphazoline, ophthalmic or
Oxymetazoline, nasal or ophthalmic or
Phenylephrine, nasal or ophthalmic or
Xylometazoline, nasal    (if significant systemic absorption occurs, concurrent use with tricyclic antidepressants may potentiate pressor effects of these medications {123}7)


Pimozide    (concurrent use with tricyclic antidepressants may potentiate cardiac arrhythmias, which are seen on ECG as prolongation of the QT interval)


Probucol{123}6    (additive QT interval prolongation may increase risk of ventricular tachycardia)


» Sympathomimetics{123}5{123}4{123}3{123}2{123}1{123}0{123}9{123}8{123}7{123}6{123}5{123}4{123}3{123}2    (concurrent use with tricyclic antidepressants may potentiate cardiovascular effects possibly resulting in arrhythmias, tachycardia, or severe hypertension or hyperpyrexia; phentolamine can control the adverse reaction)

    (significant systemic absorption of ophthalmic epinephrine may also potentiate cardiovascular effects; also, local anesthetics with vasoconstrictors should be avoided or a minimal amount of the vasoconstrictor should be used with the local anesthetic)

    (concurrent use with tricyclic antidepressants may decrease the pressor effect of ephedrine and mephentermine)


Thyroid hormones{123}1{123}0{123}9{123}8{123}7{123}6    (concurrent use with tricyclic antidepressants may increase the therapeutic and toxic effects of both medications, possibly due to increased receptor sensitivity to catecholamines; toxic effects include cardiac arrhythmias and CNS stimulation {123}5)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
ECG    (changes include prolonged PR intervals, widened QRS complexes, and inverted or flattened T-waves {123}4 {123}3 {123}2 {123}1 {123}0 {123}9 {123}8 {123}7)


Metyrapone test    (amitriptyline may decrease the response to metyrapone {123}6)

With physiology/laboratory test values
Blood sugar concentrations    (may be increased or decreased {123}5 {123}4 {123}3 {123}2 {123}1 {123}0 {123}9 {123}8 {123}7 {123}6 {123}5)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Note: This medication should not be used during the acute recovery period following a myocardial infarction.


Risk-benefit should be considered when the following medical problems exist
» Alcoholism, active{123}4{123}3{123}2{123}1    (CNS depression may be potentiated)


» Asthma    (may be aggravated)


» Bipolar disorder    (swing to hypomanic or manic phase may be accelerated {123}0 {127}9 {127}8 {127}7 {127}6 {127}5 {127}4 {127}3 {127}2 {127}1 {127}0 {115}9 and reversible rapid cycling between mania and depression may be induced by antidepressants in some patients; tricyclic antidepressant may have to be discontinued and lithium considered for a sustained remission {115}8 {115}7)


» Blood disorders{115}6{115}5    (may be potentiated)


» Cardiovascular disorders{115}4{115}3{115}2{115}1{115}0{117}9{117}8{117}7{117}6{117}5{117}4{117}3 , especially in children and the elderly    (increased risk of arrhythmias, heart block, congestive heart failure, myocardial infarction, or stroke)


» Gastrointestinal disorders    (risk of paralytic ileus {117}2 {117}1)


Genitourinary disease    (may be masked by the use of imipramine for enuresis in children {117}0)


» Glaucoma, narrow-angle{117}9{117}8{117}7{117}6{117}5{117}4{117}3{117}2{117}1{117}0{80}9{80}8{80}7 , predisposition to or
» Increased intraocular pressure{80}6{80}5{80}4{80}3{80}2{80}1{80}0{115}9    (may be aggravated)


» Hepatic function impairment{115}8{115}7{115}6{115}5{115}4{115}3    (metabolism of tricyclic may be altered)


» Hyperthyroidism{115}2{115}1{115}0{117}9{117}8{117}7{117}6{117}5{117}4{117}3{117}2{117}1    (risk of cardiovascular toxicity)


» Prostatic hypertrophy    (risk of urinary retention)


» Renal function impairment{117}0{115}9{115}8{115}7    (excretion of tricyclic may be altered)


» Schizophrenia{115}6{115}5{115}4{115}3{115}2{115}1{115}0{117}9{117}8{117}7{117}6{117}5{117}4    (psychosis may be activated)


» Seizure disorders{117}3{117}2{117}1{117}0{115}9{115}8{115}7{115}6{115}5{115}4{115}3{115}2{115}1    (seizure threshold may be lowered)


» Sensitivity to tricyclic antidepressants, carbamazepine, maprotiline, or trazodone{115}0{117}9{117}8{117}7{117}6{117}5{117}4{117}3{117}2{117}1{117}0{117}9{117}8
» Urinary retention{117}7{117}6{117}5{117}4{117}3{117}2{117}1{117}0{117}9{117}8{117}7{117}6{117}5{117}4    (may be aggravated)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood cell counts (usually during extended therapy and in patients with sore throat or fever){117}3{117}2{117}1{117}0{84}9{84}8{84}7{84}6 and
Blood pressure{84}5 and pulse measurements and
Glaucoma tests and
Hepatic function determinations{84}4{84}3{84}2 and
Renal function determinations    (may be required at periodic intervals during therapy to detect development of adverse effects that may not be evident to the patient {84}1)


Cardiac function monitoring{84}0{124}9    (ECG may be required in the elderly, in children, and in patients with existing cardiac disease, or in patients receiving antiarrhythmics such as quinidine, procainamide, or disopyramide, before initiation of therapy as a baseline and at periodic intervals thereafter)

    (for children taking imipramine for enuresis who are not responding to standard doses, ECG may be required before dosage is increased)


Careful supervision of depressed patients with suicidal tendencies{124}8{124}7    (recommended especially during early weeks of treatment; hospitalization may be required as a protective measure)


Dental examination    (recommended at least twice yearly {124}6)


Plasma tricyclic determinations    (recommended for patients who fail to respond to treatment, when there are increased side effects, when patient is at high risk, when there is doubt about patient compliance, or as a means of maximizing the response; optimum sampling time is immediately before the first morning dose or a minimum of 8 hours after a dose {124}5; See Table 1 for therapeutic plasma concentration ranges {124}4)


For amoxapine (in addition to the above)
Careful observation for early signs of tardive dyskinesia{124}3    (recommended at periodic intervals, especially in the elderly; if early symptoms of tardive dyskinesia appear, amoxapine should be discontinued)




Side/Adverse Effects

Note: Although not all of these side effects have been attributed specifically to each tricyclic antidepressant, a potential exists for their occurrence during the use of any tricyclic antidepressant.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
For all tricyclic antidepressants
    
Anticholinergic effects (blurred vision{124}2{124}1{124}0{124}9{124}8{124}7{124}6{124}5{124}4{124}3{124}2{124}1{124}0; confusion{124}9{124}8{124}7{124}6{124}5{124}4{124}3{124}2{124}1{124}0{124}9{124}8{124}7{124}6; delirium or hallucinations{124}5{124}4{124}3{124}2{124}1{124}0{124}9{124}8{124}7{124}6{124}5{124}4{124}3{124}2; constipation{124}1{124}0{124}9{124}8{124}7{124}6{124}5{124}4{124}3{124}2{124}1{124}0{205}9 , especially in the elderly{205}8 , possibly resulting in paralytic ileus{205}7{205}6{205}5{205}4{205}3{205}2{205}1{205}0{205}9{205}8{205}7; difficult urination{205}6{205}5{205}4{205}3{205}2{205}1{205}0{116}9{116}8{116}7{116}6{116}5{116}4{116}3; eye pain due to aggravation of glaucoma{116}2)
    
fast, slow, or irregular heartbeat{116}1{116}0{116}9{116}8{116}7{116}6{116}5{116}4{116}3{116}2{116}1{116}0{116}9{116}8
    
fine-muscle tremors, especially in arms, hands, head, and tongue{116}7{116}6{116}5{116}4{116}3{116}2{116}1{116}0{02}9{02}8{02}7 (shakiness)
    
hypotension{02}6{02}5{02}4{02}3{02}2{02}1{02}0{31}9{31}8{31}7{31}6{31}5 (fainting)
    
nervousness or restlessness{31}4{31}3{31}2{31}1{31}0{116}9{116}8{116}7{116}6{116}5{116}4{116}3
    
Parkinsonian syndrome{116}2{116}1{116}0{116}9{116}8{116}7 (difficulty in speaking or swallowing; loss of balance control; mask-like face; shuffling walk; slowed movements; stiffness of arms and legs; trembling and shaking of fingers and hands)
    
sexual function impairment{116}6{116}5{116}4{116}3{116}2{116}1{116}0{116}9{116}8{116}7{116}6{116}5{116}4{116}3 —more common with amoxapine and clomipramine{116}2{116}1

For amoxapine only (in addition to the above)
    
Tardive dyskinesia{116}0 (lip smacking or puckering; puffing of cheeks; rapid or worm-like movements of tongue; uncontrolled chewing movements; uncontrolled movements of the arms or legs)


Incidence rare
For all tricyclic antidepressants
    
Agranulocytosis or other blood dyscrasias{116}9{116}8{116}7{116}6{116}5{116}4{116}3{116}2{116}1{116}0{128}9{128}8{128}7{128}6 (red or brownish spots on skin; sore throat and fever; unusual bleeding or bruising)
    
allergic reaction (increased sensitivity to sunlight; skin rash and itching; swelling of face and tongue){128}5{128}4{128}3{128}2{128}1{128}0{117}{118}{119}{120}{121}{122}{123}{124}
    
alopecia{39}{113}{115}{116}{117}{118}{119}{120}{122}{123}{124} (hair loss)
    
anxiety{69}{112}{115}{116}{118}{119}{120}{124}
    
breast enlargement in both males and females{39}{69}{112}{113}{115}{116}{117}{118}{119}{120}{121}{122}{123}{124} —more common with amoxapine
    
cholestatic jaundice{39}{69}{112}{113}{115}{116}{117}{119}{120}{121}{122}{123}{124} (yellow eyes or skin)
    
galactorrhea (inappropriate secretion of milk)—in females{39}{69}{81}{112}{113}{115}{116}{117}{118}{119}{120}{121}{122}{123}{124}
    
seizures{39}{69}{112}{113}{115}{116}{117}{118}{119}{122}{123}{124} —more common with clomipramine{150}{176}{177}
    
syndrome of inappropriate secretion of antidiuretic hormone [SIADH]{113}{115}{116}{117}{119}{120}{121}{123}{124} (irritability; muscle twitching; weakness)
    
testicular swelling{39}{69}{115}{116}{117}{118}{119}{120}{122}{123}{124} —more common with amoxapine
    
tinnitus{39}{112}{113}{115}{116}{117}{118}{119}{120}{121}{122}{123}{124} (ringing, buzzing, or other unexplained noises in the ears)
    
trouble with teeth or gums{112} —more common with clomipramine

For amoxapine only (in addition to the above)
    
Neuroleptic malignant syndrome (NMS){119} (convulsions; difficult or fast breathing; fast heartbeat or irregular pulse; fever; high or low [irregular] blood pressure; increased sweating; loss of bladder control; severe muscle stiffness; unusually pale skin; unusual tiredness or weakness)
Note: May occur after prolonged treatment or after combined treatment with tricyclic antidepressants and neuroleptics {02}.






Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Drowsiness{39}{69}{112}{113}{115}{116}{117}{118}{119}{120}{121}{122}{123}{124}
    
dryness of mouth{39}{69}{112}{113}{115}{116}{117}{118}{119}{120}{121}{122}{123}{124}
    
headache{69}{112}{113}{115}{116}{117}{118}{119}{120}{121}{122}{123}{124}
    
increased appetite{112}{118}{119} —may include craving for sweets{140}{141}
    
nausea{39}{69}{112}{113}{115}{116}{117}{118}{119}{120}{121}{122}{123}{124}
    
orthostatic hypotension{39}{69}{112}{113}{115}{116}{117}{118}{119}{120}{121}{122}{123}{124} (dizziness)
    
tiredness or weakness, mild{39}{69}{112}{113}{115}{116}{117}{118}{119}{120}{122}{123}{124}
    
unpleasant taste{39}{112}{113}{115}{117}{118}{119}{120}{122}{123}{124}
    
weight gain{39}{69}{112}{113}{115}{116}{117}{118}{119}{120}{122}{123}{124}

Incidence less frequent
    
Diarrhea{39}{69}{112}{113}{115}{116}{117}{120}{121}{122}{123}{124}
    
excessive sweating{39}{69}{112}{113}{115}{116}{117}{118}{119}{120}{121}{122}{124}
    
heartburn{39}{112}{113}{115}{116}{117}{118}{119}{120}{121}{122}{123}{124}
    
trouble in sleeping{112}{113}{115}{116}{118}{119}{121} —more common with protriptyline, especially when taken late in the day
    
vomiting{39}{69}{112}{113}{115}{116}{117}{118}{119}{120}{122}{123}{124}



Those indicating possible withdrawal and the need for medical attention if they occur after medication is discontinued
Occurring upon abrupt withdrawal, due to cholinergic rebound
For all tricyclic antidepressants
    
Headache{39}{69}{112}{113}{115}{116}{117}{118}{120}{121}{123}{124}
    
nausea{39}{69}{112}{113}{115}{116}{117}{118}{120}{121}{123}{124} , vomiting{112} , or diarrhea
    
trouble in sleeping{112} , with vivid dreams
    
unusual excitement


Occurring with gradual withdrawal after long-term treatment
For all tricyclic antidepressants
    
Irritability{112}
    
restlessness
    
trouble in sleeping, with vivid dreams

For amoxapine only (in addition to the above)
    
Tardive dyskinesia{119} , withdrawal-emergent (lip smacking or puckering; puffing of cheeks; rapid or worm-like movements of tongue; uncontrolled chewing movements; uncontrolled movements of the arms and legs)






Overdose
For specific information on the agents used in the management of tricyclic antidepressant overdose, see:
   • Anesthetics, Inhalation (Systemic) monograph;
   • Charcoal, Activated (Oral-Local) monograph;
   • Diazepam in Benzodiazepines (Systemic) monograph;
   • Digitalis Glycosides (Systemic) monograph;
   • Lidocaine (Systemic) monograph;
   • Paraldehyde (Systemic) monograph;
   • Phenytoin in Anticonvulsants, Hydantoin (Systemic) monograph;
   • Physostigmine (Systemic) monograph;
   • Propranolol in Beta-adrenergic Blocking Agents (Systemic) monograph; and/or
   • Sodium Bicarbonate (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Confusion{112}{115}{116}{117}{124}
    
convulsions{39}{69}{112}{113}{115}{116}{117}{120}{121}{122}{123}{124} —more severe and refractory with amoxapine
    
disturbed concentration{96}{119}{124}
    
drowsiness, severe{39}{69}{112}{113}{116}{121}{122}{123}
    
enlarged pupils{39}{96}{115}{116}{121}{122}{123}{124}
    
fast, slow, or irregular heartbeat{39}{69}{112}{115}{116}{120}{121}{122}{123}{124}
    
fever{69}{115}{117}{120}{123}
    
hallucinations{124}
    
restlessness and agitation{39}{69}{112}{113}{115}{116}{117}{120}{121}{122}{123}{124}
    
shortness of breath or troubled breathing{39}{69}{112}{115}{116}{117}{120}{121}{122}{123}
    
unusual tiredness or weakness, severe{39}{69}{116}{117}{123}
    
vomiting{39}{69}{112}{115}{116}{117}{120}{121}{122}{123}{124}


Treatment of overdose
Treatment is essentially symptomatic and supportive {119} {122}, possibly including:


To decrease absorption:
Emptying stomach with {32} gastric lavage {39} {69} {112} {113} {116} {117} {119} {121} {122} {123} {124}.



To enhance elimination:
Administering activated charcoal slurry {39} {112} {113} {115} {116} {119} {121} {122} {123} {124} repeatedly {32}, followed by a stimulant cathartic.



Specific treatment:
Digitalizing cautiously for congestive heart failure {39} {69} {112} {113} {116} {117} {120} {121} {123}.

Controlling cardiac arrhythmias with lidocaine or {32} {115} by alkalinizing {115} blood to pH 7.4 to 7.5 with intravenous sodium bicarbonate {32} {35}. Arrhythmias refractory to lidocaine and sodium bicarbonate may be managed with slow intravenous infusion of phenytoin while monitoring ECG. Propranolol is also effective but should be used with caution because of its negative inotropic and hypotensive effects. Quinidine and procainamide should be avoided. {115}

For all tricyclics except amoxapine: Although routine use is not recommended, administering physostigmine salicylate {39} {112} {113} {115} {116} {117} {120} {121} {122} {123} {124}, 1 to 3 mg (adults) {39} {116} {120} {121} {122} {123} {124} by slow intravenous infusion {39} {113} {116} {120} {121} {123} over 2 to 3 minutes, may help reverse severe anticholinergic effects (myoclonic seizures, severe hallucinations, hypertension, and ventricular arrhythmias) {73}. For children, start with 0.5 mg {113} {116} and repeat dosage at 5 minute intervals to determine the minimum effective dose, not exceeding 2 mg per dose {39} {116} {120} {121} {123}. Because of the short duration of action of physostigmine, dosage may need to be repeated at 30- to 60-minute intervals {113} {116} {120} {121} {123}, especially if life-threatening symptoms occur {81}. Routine administration of physostigmine is not recommended because of its toxicity {112} {115} {124}. When used in tricyclic antidepressant overdose, it may cause bronchospasm, increased respiratory secretions, muscle weakness, bradycardia, hypotension, and may itself cause seizures {112}. Physostigmine should be reserved for patients in coma with respiratory depression, uncontrollable seizures, severe hypertension, or serious cardiac arrhythmias {83}. Physostigmine is contraindicated in amoxapine overdose because it may increase seizure activity {74}.

Administering anticonvulsants {39} {69} {112} {113} {116} {117} {119} {121} {122} {123} {124} such as diazepam {39} {69} {113} {115} {116} {117} {119} {121} {123}, paraldehyde {39} {69} {113} {116} {117} {121} {123}, phenytoin {119} {120}, or an inhalation anesthetic to control convulsions. Seizures may be especially severe and refractory {80} with amoxapine overdose and may lead to acute tubular necrosis and rhabdomyolysis {02}.



Monitoring:
Monitoring cardiovascular function (ECG) {39} {69} {113} {115} {116} {120} {121} {122} {123} {124} for not less than 5 days {124}.



Supportive care:
Maintaining respiratory {39} {69} {112} {113} {115} {116} {117} {119} {120} {121} {122} {123} {124} and cardiac {124} function.

Maintaining body temperature {39} {69} {112} {113} {116} {121} {123} {124}.

Using standard measures to manage circulatory shock {39} {69} {112} {113} {116} {120} {121} {123} {124} and metabolic acidosis {69} {115} {120} {124}.

Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.


Note: Hemodialysis {39} {69} {112} {116} {121} {123}, peritoneal dialysis {39} {69} {112} {116} {121} {123}, exchange transfusions {39} {112} {116} {121} {123}, and forced diuresis {39} {69} {112} {115} {116} {121} {122} {123} of tricyclic antidepressants have not been successful because of their high protein binding {69} {122} and rapid fixation in tissues {39} {122} {123}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Antidepressants, Tricyclic (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to tricyclic antidepressants, maprotiline, or trazodone

Pregnancy—Clinical reports of fetal malformations with imipramine; animal studies have shown some tricyclics to cause embryotoxic or fetotoxic effects, and decreased rate of conception; when tricyclics taken by mother immediately before delivery, clinical reports of newborns suffering from muscle spasms, and heart, breathing, and urinary problems





Breast-feeding—Pass into breast milk and may cause drowsiness in nursing baby





Use in children—Children and adolescents more sensitive to effects, requiring lower doses; may cause nervousness, sleeping problems, tiredness, mild stomach upset; generally not recommended for depression in children






Use in the elderly—Elderly more sensitive to effects; lower doses and more gradual increases required





Dental—Decreased salivary flow contributes to caries, periodontal disease, candidiasis, and discomfort; blood dyscrasias may cause increased infections, delayed healing, and gingival bleeding; increased extrapyramidal motor activity of head, face, and neck with amoxapine may cause difficulty with occlusal and other procedures
Other medications, especially CNS depressants, antithyroid agents, cimetidine, clonidine, guanadrel, guanethidine, phenothiazines, extrapyramidal reaction–causing medications, MAO inhibitors, metrizamide, or sympathomimetics
Other medical problems, especially alcoholism (active), asthma, bipolar disorder, blood disorders, cardiovascular disorders, gastrointestinal disorders, glaucoma or increased intraocular pressure, hepatic function impairment, hyperthyroidism, prostatic hypertrophy, renal function impairment, schizophrenia, seizure disorders, or urinary retention

Proper use of this medication
Taking with food to reduce gastrointestinal irritation

» Compliance with therapy; not taking more or less medicine than prescribed

» May require from 1 to 6 weeks of therapy to obtain antidepressant effects

Proper administration of doxepin oral solution
Using dropper provided by manufacturer for accurate measurement

Diluting medication in one-half glass of recommended beverage (water, milk, or fruit juice, but not grape juice or carbonated beverages) immediately before use

Not preparing or storing bulk solutions {21}

» Proper dosing
Missed dose: If dosing schedule is—


More than one dose a day: Taking as soon as possible unless almost time for next dose; not doubling doses


One dose at bedtime: Not taking in morning because of side effects; checking with physician

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress of therapy

» Avoiding the use of alcoholic beverages {69} {113} {115} {116} {117} {120} {121}; not taking other medication unless prescribed by physician

» Possible drowsiness; caution when driving or doing things requiring alertness {39} {69} {113} {115} {116} {117} {118} {119} {120} {121} {122} {123} {124}

» Possible dizziness or lightheadedness; caution when getting up suddenly from a lying or sitting position

» Possible dryness of mouth; using sugarless gum or candy, ice, or saliva substitute for relief; checking with physician or dentist if dry mouth continues for more than 2 weeks

» Possible skin photosensitivity; avoiding unprotected exposure to sun; using protective clothing; using a sun block product that includes protection against both UVA-caused photosensitivity reactions and UVB-caused sunburn reactions; avoiding use of sunlamp, tanning bed, or tanning booth

Caution if any laboratory tests required; possible interference with results of metyrapone test.

» Caution if any kind of surgery, dental treatment, or emergency treatment is required

» Checking with physician before discontinuing medicine; gradual dosage reduction may be needed to avoid worsening of condition or withdrawal symptoms

» Observing precautions for 3 to 7 days after stopping medication

For protriptyline
Possibility of sleep interference if taken late in the day


Side/adverse effects
Signs of potential side effects, especially anticholinergic effects; hypotension; fast, slow, or irregular heartbeat; Parkinsonian syndrome; nervousness or restlessness; sexual function impairment; shakiness or tremors; neuroleptic malignant syndrome (NMS) or tardive dyskinesia (with amoxapine only); anxiety; breast enlargement in males and females; galactorrhea; testicular swelling; alopecia; allergic reactions; blood dyscrasias; cholestatic jaundice; seizures; SIADH; tinnitus; or trouble with teeth or gums


General Dosing Information
Dosage of tricyclic antidepressants must be individualized for each patient by titration {39} {69} {115} {116} {117} {120}.

Plasma concentrations of tricyclic antidepressants, in general, vary greatly among patients {57}. However, nortriptyline appears to have a well-defined “therapeutic window” at 50 to 150 nanograms per mL of plasma {45} {115} {117} {139} {150}. Other therapeutic plasma concentration ranges that are generally accepted include desipramine, 150 to 250 nanograms per mL {150} {153} {164}, and imipramine, 200 to 250 nanograms per mL {149}. See Table 1.

Although a sedative action may occur following the initial dose (with the possible exception of protriptyline), 1 to 6 weeks of therapy may be required before the desired antidepressant response is obtained.

Maintenance therapy of the sedating tricyclic antidepressants is usually given as a single dose at bedtime {112} {113} {116} {119} {123} {176}. A divided dose may be preferred, however, for protriptyline, and for all tricyclic antidepressants in geriatric or cardiovascular patients, or in adolescents or children {176} {177} {186}. Maintenance is often continued for 6 months to 1 year {139}. Recent data suggest that some patients with recurrent depression may benefit from prolonged maintenance treatment at the full (acute treatment) daily dose {159} {165} {176}.

A trial of four to six weeks at the upper therapeutic dose range may be considered an adequate antidepressant trial, after which alternate therapy should be considered {52} {159} {166} {176}.

The single daily dose at bedtime is useful when side effects such as excessive drowsiness or dizziness might be bothersome or dangerous during working hours. An exception to bedtime dosage is protriptyline, which if taken late in the day may cause insomnia or nightmares in some patients. Therefore, protriptyline is often given in divided doses with the last daily dose in the afternoon.

Withdrawal symptoms, such as headache {39} {69} {112} {113} {115} {116} {117} {118} {120} {121} {123} {124}, malaise {04} {39} {69} {112} {113} {115} {116} {117} {118} {120} {121} {123} {124}, nausea {39} {69} {112} {113} {115} {116} {117} {118} {120} {121} {123} {124} or vomiting {112}, and vivid dreams, may occur if high or prolonged dosage is abruptly discontinued. Also, patients with a history of only unipolar depression may experience a fast-cycling bipolar disorder (manic-depressive illness) with mania or hypomania {112} {113} {115} {116}. Although this has not been reported with all of the tricyclics, a gradual reduction in dosage {112} over a 1- to 2-month period is recommended when any of these medications is to be discontinued.

Potentially suicidal patients should not have access to large quantities of these medications since depressed patients, particularly those who may use alcohol excessively, may continue to exhibit suicidal tendencies until significant improvement occurs {39} {69} {112} {113} {115} {116} {117} {118} {119} {120} {121} {122} {123} {124}. Some clinicians recommend that not more than the equivalent of 1 gram of amitriptyline be dispensed to such patients at any one time. However, most clinicians agree that the judgment must be made according to each patient's individual condition. {02}

The condition of depressed patients with bipolar disorder may sometimes change to the manic phase during tricyclic antidepressant therapy, although such change has not been reported with every tricyclic antidepressant {112} {113} {115} {116} {117}.

Diet/Nutrition
Oral doses may be taken with or immediately after food to lessen gastric irritation.

The requirements for riboflavin may be increased in patients receiving amitriptyline or imipramine {130} {131}.

For treatment of adverse effects


Neuroleptic malignant syndrome (NMS) (for amoxapine only):
Treatment is essentially symptomatic and supportive {119} and includes

   • Discontinuing amoxapine immediately {119}.
   • Hyperthermia: Administering antipyretics (aspirin or acetaminophen); using cooling blanket.
   • Dehydration: Restoring fluids and electrolytes.
   • Cardiovascular instability: Monitoring blood pressure and cardiac rhythm closely.
   • Hypoxia: Administering oxygen; considering airway insertion and assisted ventilation.
   • Muscle rigidity: Dantrolene sodium may be administered (100 to 300 mg a day in divided doses; 0.75 to 1 mg per kg, intravenously, every 6 hours, increased up to 3 mg per kg every 6 hours as needed {72}).



Parkinsonism:
In most cases, mild effects may be reversed by dosage reduction. Administration of antiparkinsonism drugs such as benztropine, diphenhydramine, or trihexyphenidyl may reverse severe reactions.



Secretion of inappropriate antidiuretic hormone syndrome (SIADH):
Recommended treatment includes

   • Discontinuing tricyclic antidepressant.
   • If urgent treatment is required, administering several hundred milliliters of 5% sodium chloride intravenously over several hours while monitoring serum sodium concentration and the symptoms, and watching for fluid overload.
   • After initial phase, or for less urgent treatment, restricting water intake to 1000 mL a day.
   • Monitoring serum electrolytes for several days {34}.



Tardive dyskinesia (for amoxapine only):
No known effective treatment. Dosage of the tricyclic should be lowered or medication gradually discontinued at earliest signs of tardive dyskinesia, to prevent irreversible effects {107} {119}.


AMITRIPTYLINE

Summary of Differences


Indications:
Also used to manage some types of chronic, severe, neurogenic pain, and to treat bulimia and peptic ulcer disease.



Pharmacology/pharmacokinetics:


Effects—
Anticholinergic: High.

Sedative: High.

Orthostatic hypotension: Moderate to high.




Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

AMITRIPTYLINE HYDROCHLORIDE TABLETS USP

Usual adult dose
Antidepressant
Oral, initially 25 mg two to four times a day, the dosage being adjusted gradually as needed and tolerated {16} {67} {118}.


Usual adult prescribing limits
Outpatients—Up to 150 mg a day {16} {67} {118}.

Hospitalized patients—Up to 300 mg a day {16} {67} {118}.

Geriatric patients—Up to 100 mg a day {16}.

Usual pediatric dose
Antidepressant
Children 6 to 12 years of age: Oral, 10 to 30 mg, or 1 to 5 mg per kg of body weight, a day in two divided doses {80}.

Adolescents: Oral, initially 10 mg three times a day and 20 mg at bedtime, the dosage being adjusted as needed and tolerated {16} {67} {118}, up to a maximum of 100 mg a day in divided doses or as a single dose at bedtime.

[Enuresis]
Children up to 6 years of age: Oral, 10 mg a day as a single dose at bedtime {118}.

Children over 6 years of age: Oral, initially 10 mg a day as a single dose at bedtime, the dose being increased as needed and tolerated up to a maximum of 25 mg {118}.


Usual geriatric dose
Antidepressant
Oral, initially 25 mg at bedtime {02}, the dosage being adjusted as needed and tolerated, up to 10 mg three times a day and 20 mg at bedtime {16} {67} {118}.


Strength(s) usually available
U.S.—


10 mg (Rx) [Elavil{190}] [Endep (scored){191}][Generic]


25 mg (Rx) [Elavil{190}] [Endep (scored){191}][Generic]


50 mg (Rx) [Elavil{190}] [Endep (scored){191}][Generic]


75 mg (Rx) [Elavil{190}] [Endep (scored){191}][Generic]


100 mg (Rx) [Elavil{190}] [Endep (scored){191}][Generic]


150 mg (Rx) [Elavil{190}] [Endep (scored){191}][Generic]

Canada—


10 mg (Rx) [Apo-Amitriptyline] [Elavil] [Novotriptyn]


25 mg (Rx) [Apo-Amitriptyline] [Elavil] [Novotriptyn][Generic]{194}


50 mg (Rx) [Apo-Amitriptyline] [Elavil] [Novotriptyn]


75 mg (Rx) [Apo-Amitriptyline] [Elavil] [Levate{195}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.


AMITRIPTYLINE PAMOATE SYRUP

Usual adult dose
Antidepressant
Oral, initially 25 mg (base) two to four times a day, the dosage being adjusted gradually as needed and tolerated {118}.


Usual pediatric dose
Antidepressant
Children 6 to 12 years of age: Oral, 10 to 30 mg (base), or 1 to 5 mg per kg of body weight, a day in two divided doses {80}.

Adolescents: Oral, initially 10 mg (base) three times a day and 20 mg at bedtime {118}, the dosage being adjusted as needed and tolerated, up to a maximum of 100 mg a day, in divided doses or as a single dose at bedtime.

[Enuresis]
Children up to 6 years of age: Oral, 10 mg (base) a day as a single dose at bedtime {118}.

Children over 6 years of age: Oral, initially 10 mg (base) a day as a single dose at bedtime, the dose being increased as needed and tolerated up to a maximum of 25 mg {118}.


Usual geriatric dose
Antidepressant
Oral, initially 10 mg (base) three times a day and 20 mg at bedtime, the dosage being adjusted as needed and tolerated {118}, up to a maximum of 100 mg a day, in divided doses or as a single dose at bedtime.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


10 mg (base) per 5 mL (Rx) [Elavil (methyl- and propylparaben)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.



Parenteral Dosage Forms

AMITRIPTYLINE HYDROCHLORIDE INJECTION USP

Usual adult dose
Antidepressant
Intramuscular, 20 to 30 mg four times a day {16} {67}.


Usual pediatric dose
Antidepressant
Children up to 12 years of age: Dosage has not been established {16} {67}.


Strength(s) usually available
U.S.—


10 mg per mL (Rx) [Elavil (dextrose) (methylparaben) (propylparaben){190}][Generic]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.


AMOXAPINE

Summary of Differences


Pharmacology/pharmacokinetics:


Effects—
Anticholinergic: Moderate.

Sedative: Low to moderate.

Orthostatic hypotension: Low.



Onset of action—
Antidepressant: Within 1 to 2 weeks.




Side/adverse effects:
Neuroleptic malignant syndrome, parkinsonian reactions and tardive dyskinesia may occur. Sexual function impairment, breast enlargement in both males and females, testicular swelling, and severe, refractory seizures on acute overdose {30} are all more frequent with amoxapine than with other tricyclic antidepressants.



Oral Dosage Forms

AMOXAPINE TABLETS USP

Usual adult dose
Antidepressant
Oral, initially 50 mg two or three times a day, the dosage being increased to 100 mg two or three times a day within the first week of treatment as needed and tolerated {119}.


Note: Increases above 300 mg a day should be made with caution and only if 300 mg a day has been ineffective during a trial period of at least two weeks {119}.


Usual adult prescribing limits
Hospitalized patients—Up to 600 mg a day in divided doses {119}.

Usual pediatric dose
Children up to 16 years of age—Dosage has not been established {119}.

Usual geriatric dose
Antidepressant
Oral, initially 25 mg two or three times a day, the dosage being increased, if tolerated, to 50 mg two or three times a day within the first week {119}.


Strength(s) usually available
U.S.—


25 mg (Rx) [Asendin (scored)][Generic]


50 mg (Rx) [Asendin (scored)][Generic]


100 mg (Rx) [Asendin (scored)][Generic]


150 mg (Rx) [Asendin (scored)][Generic]

Canada—


25 mg (Rx) [Asendin (scored)]


50 mg (Rx) [Asendin (scored)]


100 mg (Rx) [Asendin (scored)]


150 mg (Rx) [Asendin (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.


CLOMIPRAMINE

Summary of Differences


Indications:
Also used to treat obsessive-compulsive disorder, panic disorder, bulimia nervosa, cataplexy associated with narcolepsy, and to manage some types of chronic, severe, neurogenic pain.



Pharmacology/pharmacokinetics:


Effects—
Anticholinergic: High.

Sedative: Moderate.

Orthostatic hypotension: Moderate.




Precautions:


Drug interactions and/or related problems—
Not recommended for concurrent use with monoamine oxidase inhibitors.




Side/adverse effects:
Sexual function impairment, seizures, and nausea and vomiting may occur more frequently with clomipramine than with other tricyclic antidepressants.



Additional Dosing Information
See also General Dosing Information.

Clomipramine should be given in divided doses with meals during initial titration to minimize gastrointestinal side effects; after titration, the total daily dose may be given at bedtime to minimize daytime sedation {112} {126}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CLOMIPRAMINE HYDROCHLORIDE CAPSULES

Usual adult dose
[Antidepressant]
Oral, initially 25 mg three times a day, the dosage being adjusted as needed and tolerated {69} {126}.

Antiobsessional agent
Oral, initially 25 mg once a day, the dosage being gradually increased to 100 mg during the first two weeks. The dosage may be further increased over the next several weeks, up to a maximum of 250 mg a day. {112} {126}


Usual adult prescribing limits
Outpatients: Up to 250 mg a day {112} {126}.

Hospitalized patients: Up to 300 mg a day {69}.

Usual pediatric dose
[Antidepressant]
Children up to 12 years of age: Dosage has not been established {69}.

Adolescents: Oral, 20 to 30 mg a day, the dosage being increased by 10 mg at 4 or 5 day intervals as needed and tolerated {150} {160} {169} {171}.

Antiobsessional agent
Children up to 10 years of age: Dosage has not been established {112}.

Children 10 years of age and over, and adolescents: Oral, initially 25 mg once a day, the dose being increased as needed and tolerated up to 100 mg a day or 3 mg per kg of body weight, whichever is less. The dosage may be further increased up to a maximum of 200 mg a day or 3 mg per kg of body weight, whichever is less. {112} {126}


Note: The strengths of the specific products may not conform to the recommended pediatric doses.


Usual geriatric dose
Oral, 20 to 30 mg a day, the dosage being increased as needed and tolerated {69}.

Note: The strengths of the specific products may not conform to the recommended geriatric doses.


Strength(s) usually available
U.S.—


25 mg (Rx) [Anafranil (methylparaben) (propylparaben){198}][Generic]


50 mg (Rx) [Anafranil (methylparaben) (propylparaben){198}][Generic]


75 mg (Rx) [Anafranil (methylparaben) (propylparaben){198}][Generic]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a tight, light-resistant container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.


CLOMIPRAMINE HYDROCHLORIDE TABLETS

Usual adult dose
See Clomipramine Hydrochloride Capsules.

Usual adult prescribing limits
See Clomipramine Hydrochloride Capsules.

Usual pediatric dose
See Clomipramine Hydrochloride Capsules.

Usual geriatric dose
See Clomipramine Hydrochloride Capsules.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


10 mg (Rx) [Anafranil (lactose)]


25 mg (Rx) [Anafranil (lactose)]


50 mg (Rx) [Anafranil (lactose)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a tight, light-resistant container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.


DESIPRAMINE

Summary of Differences


Indications:
Also used to manage some types of chronic, severe, neurogenic pain; to reduce craving and/or prevent depression upon withdrawal of cocaine; to control binge eating and purging in bulimia; and to treat cataplexy associated with narcolepsy; and is being used to relieve the symptoms of attention deficit hyperactivity disorder in children over 6 years of age and in adolescents.



Pharmacology/pharmacokinetics:


Effects—
Anticholinergic: Low.

Sedative: Low.

Orthostatic hypotension: Moderate.




Precautions:


Drug interactions and/or related problems—
Not recommended for concurrent use with monoamine oxidase inhibitors.

Concurrent use of phenytoin with desipramine may lower serum concentrations of desipramine; dosage increases above maximum recommended doses of desipramine may be necessary for clinical improvement of depression.




Oral Dosage Forms

DESIPRAMINE HYDROCHLORIDE TABLETS USP

Usual adult dose
Antidepressant
Oral, 100 to 200 mg a day in divided doses or as a single dose, the dosage being adjusted as needed and tolerated {82} {120}.


Usual adult prescribing limits
Up to 300 mg a day {82} {120}.

Note: Geriatric patients—Up to 150 mg a day {120}.


Usual pediatric dose
Antidepressant
Children 6 to 12 years of age: Oral, 10 to 30 mg, or 1 to 5 mg per kg of body weight, a day in divided doses {80}.

Adolescents: Oral, 25 to 50 mg a day in divided doses, the dosage being adjusted as needed and tolerated, up to a maximum of 100 mg a day {120}.


Usual geriatric dose
Antidepressant
Oral, 25 to 50 mg a day in divided doses, the dosage being adjusted as needed and tolerated, up to a maximum of 150 mg a day {120}.


Strength(s) usually available
U.S.—


10 mg (Rx) [Norpramin{199}][Generic]


25 mg (Rx) [Norpramin{199}][Generic]


50 mg (Rx) [Norpramin{199}][Generic]


75 mg (Rx) [Norpramin{199}][Generic]


100 mg (Rx) [Norpramin{199}][Generic]


150 mg (Rx) [Norpramin{199}][Generic]

Canada—


10 mg (Rx) [Norpramin (sucrose) (mannitol) (corn starch){111}{200}]


25 mg (Rx) [Norpramin{200}] [Pertofrane][Generic]


50 mg (Rx) [Norpramin{200}] [Pertofrane{201}][Generic]


75 mg (Rx) [Norpramin{200}][Generic]


100 mg (Rx) [Norpramin{200}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.


DOXEPIN

Summary of Differences


Indications:
Also used in treatment of some types of chronic, severe neurogenic pain; peptic ulcer disease; and pruritus in idiopathic cold urticaria.



Pharmacology/pharmacokinetics:


Effects—
Anticholinergic: High.

Sedative: High.

Orthostatic hypotension: High.




Additional Dosing Information
See also General Dosing Information.

Patients with mild symptomology or emotional symptoms accompanying organic disease may be controlled on doses as low as 25 to 50 mg a day {122}.

The once-a-day dosage maximum is 150 mg, which may be given at bedtime {01} {113} {122}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

DOXEPIN HYDROCHLORIDE CAPSULES USP

Usual adult dose
Antidepressant
Oral, initially 25 mg (base) three times a day, the dosage being adjusted gradually as needed and tolerated {113} {122}.

[Antipruritic]1
Oral, initially 10 mg (base) at bedtime, the dosage being increased gradually up to 25 mg, as needed and tolerated {109}.


Usual adult prescribing limits
Outpatients: Up to 150 mg (base) a day {122}.

Hospitalized patients: Up to 300 mg (base) a day.

Usual pediatric dose
Antidepressant
Children up to 12 years of age: Dosage has not been established {122}.


Usual geriatric dose
Antidepressant
Oral, initially 25 to 50 mg (base) a day, the dosage being adjusted gradually as needed and tolerated {80}.


Strength(s) usually available
U.S.—


10 mg (base) (Rx) [Sinequan][Generic]


25 mg (base) (Rx) [Sinequan][Generic]


50 mg (base) (Rx) [Sinequan][Generic]


75 mg (base) (Rx) [Sinequan][Generic]


100 mg (base) (Rx) [Sinequan][Generic]


150 mg (base) (Rx) [Sinequan][Generic]

Canada—


10 mg (base) (Rx) [Sinequan{202}] [Triadapin]


25 mg (base) (Rx) [Novo-Doxepin] [Sinequan{202}] [Triadapin]


50 mg (base) (Rx) [Novo-Doxepin] [Sinequan{202}] [Triadapin]


75 mg (base) (Rx) [Novo-Doxepin] [Sinequan{202}] [Triadapin]


100 mg (base) (Rx) [Novo-Doxepin] [Sinequan{202}] [Triadapin]


150 mg (base) (Rx) [Novo-Doxepin] [Sinequan{202}]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.

Note: The 150-mg capsule is intended for maintenance therapy only, and not for initiation of therapy.



DOXEPIN HYDROCHLORIDE ORAL SOLUTION USP

Usual adult dose
See Doxepin Hydrochloride Capsules USP.

Usual adult prescribing limits
See Doxepin Hydrochloride Capsules USP.

Usual pediatric dose
See Doxepin Hydrochloride Capsules USP.

Strength(s) usually available
U.S.—


10 mg (base) per mL (Rx) [Sinequan][Generic]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.

Incompatibilities:
Oral solution may be incompatible with many carbonated beverages and with grape juice {122}.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.
   • Must be diluted before taking.

Note: When dispensing, include the manufacturer-provided graduated dropper.



IMIPRAMINE

Summary of Differences


Indications:
Imipramine hydrochloride (but not pamoate) is indicated in treatment of childhood enuresis.

Imipramine is also used to manage some types of chronic, severe, neurogenic pain; to reduce craving and/or prevent depression upon cocaine withdrawal; to relieve symptoms of attention deficit hyperactivity disorder in children over 6 years of age and in adolescents; as a treatment adjunct with amphetamines or methylphenidate in cataplexy associated with narcolepsy; to block the recurrence of panic attacks, with or without phobias; in the treatment of stress and urge incontinence; and to control binge eating and purging in bulimia.



Pharmacology/pharmacokinetics:


Effects—
Anticholinergic: Moderate.

Sedative: Moderate.

Orthostatic hypotension: High.




Precautions:


Drug interactions and/or related problems—
Not recommended for concurrent use with monoamine oxidase inhibitors.




Additional Dosing Information
See also General Dosing Information.

For oral dosage forms only
In enuretic children, a daily dose exceeding 75 mg does not normally increase results. The usual pediatric prescribing limits are 2.5 mg per kg of body weight (mg/kg) a day. {17}

For early-night bedwetters, the dosage may be more effective when one-half of the dose is given at mid-afternoon and one-half at bedtime.

A gradual decrease in dosage is less likely to cause relapse than an abrupt discontinuation.

Younger children should not be allowed to self-administer imipramine because of their increased sensitivity to side effects, especially cardiovascular effects and acute overdosage (plasma concentrations over 225 nanograms per mL) {57}, which are potentially fatal.

A medication-free interval after adequate therapeutic trial should be considered for children. However, dosage should be decreased gradually to prevent relapse. Children who have relapsed may not respond when treatment is reinitiated.

For parenteral dosage forms only
Used only for initiating therapy in patients who are not able or are unwilling to take oral medication. Oral dosage forms should replace the parenteral as soon as possible. {17}


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

IMIPRAMINE HYDROCHLORIDE TABLETS USP

Usual adult dose
Antidepressant
Oral, 25 to 50 mg three or four times a day, the dosage being adjusted as needed and tolerated {39}.

[Urinary incontinence]1
Oral, 10 to 50 mg a day {172} {173} {174} {185} {187}, the dosage being adjusted as needed and tolerated, to a maximum of 150 mg a day {172} {173} {187}.


Usual adult prescribing limits
Outpatients: Up to 200 mg a day {39}.

Hospitalized patients: Up to 300 mg a day {39}.

Geriatric patients: Up to 100 mg a day {17} {39}.

Usual pediatric dose
Antidepressant
Children up to 6 years of age: Use is not recommended {39}.

Children 6 to 12 years of age: Oral, 10 to 30 mg a day in two divided doses {80}.

Adolescents: Oral, 25 to 50 mg a day in divided doses, the dosage being adjusted as needed and tolerated, up to 100 mg a day {39}.

Antienuretic
Oral, 25 mg once a day, one hour before bedtime. If a satisfactory response is not obtained within one week, the dosage may be increased to 50 mg nightly in children under 12 years of age and to 75 mg nightly in children 12 or over. {39}


Usual geriatric dose
Antidepressant
Oral, initially 25 mg at bedtime, the dosage being adjusted as needed and tolerated, up to 100 mg a day in divided doses {02} {17}.


Strength(s) usually available
U.S.—


10 mg (Rx) [Tipramine] [Tofranil{39}][Generic]


25 mg (Rx) [Norfranil] [Tipramine] [Tofranil{39}][Generic]


50 mg (Rx) [Norfranil] [Tipramine] [Tofranil{39}][Generic]

Canada—


10 mg (Rx) [Apo-Imipramine] [Novopramine] [Tofranil]


25 mg (Rx) [Apo-Imipramine] [Novopramine] [Tofranil]


50 mg (Rx) [Apo-Imipramine] [Novopramine] [Tofranil]


75 mg (Rx) [Apo-Imipramine (scored){204}] [Impril] [Tofranil{196}]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.


IMIPRAMINE PAMOATE CAPSULES

Usual adult dose
Antidepressant
Oral, initially 75 mg a day, usually given at bedtime, the dosage being adjusted as needed and tolerated {123}.


Note: The dose level at which optimum response is usually obtained is 150 mg a day, usually given at bedtime {123}.


Usual adult prescribing limits
Outpatients: Up to 200 mg a day {123}.

Hospitalized patients: Up to 300 mg a day {123}.

Usual pediatric dose
Antidepressant
Children up to 12 years of age: Use is not recommended.


Strength(s) usually available
U.S.—


75 mg (Rx) [Tofranil-PM{123}]


100 mg (Rx) [Tofranil-PM{123}]


125 mg (Rx) [Tofranil-PM{123}]


150 mg (Rx) [Tofranil-PM{123}]

Note: The above strengths of imipramine pamoate are equivalent to the same strengths of imipramine hydrochloride.


Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.



Parenteral Dosage Forms

IMIPRAMINE HYDROCHLORIDE INJECTION USP

Usual adult dose
Antidepressant
Intramuscular, up to 100 mg a day in divided doses {127}.


Usual adult prescribing limits
Up to 300 mg a day.

Usual pediatric dose
Antidepressant
Children up to 12 years of age: Use is not recommended.


Strength(s) usually available
U.S.—


12.5 mg per mL (Rx) [Tofranil (ascorbic acid 1 mg) (sodium bisulfite 0.5 mg) (anhydrous sodium sulfite 0.5 mg)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Auxiliary labeling:
   • For intramuscular use only.


NORTRIPTYLINE

Summary of Differences


Indications:
Also used to manage some types of chronic, severe, neurogenic pain and in the treatment of panic disorder.



Pharmacology/pharmacokinetics:


Effects—
Anticholinergic: Low.

Sedative: Moderate.

Orthostatic hypotension: Low.




Oral Dosage Forms

NORTRIPTYLINE HYDROCHLORIDE CAPSULES USP

Usual adult dose
Antidepressant
Oral, 25 mg (base) three or four times a day, the dosage being adjusted as needed and tolerated {115} {117}.


Usual adult prescribing limits
Up to 150 mg (base) a day {117}.

Usual pediatric dose
Antidepressant
Children 6 to 12 years of age: Oral, 10 to 20 mg (base), or 1 to 3 mg per kg of body weight, a day in divided doses {80}.

Adolescents: Oral, 25 to 50 mg, or 1 to 3 mg per kg of body weight, a day in divided doses, the dosage being adjusted as needed and tolerated.


Usual geriatric dose
Oral, 30 to 50 mg a day in divided doses, the dosage being adjusted as needed and tolerated {115} {117}.

Strength(s) usually available
U.S.—


10 mg (base) (Rx) [Aventyl{115}] [Pamelor{117}][Generic]


25 mg (base) (Rx) [Aventyl{115}] [Pamelor{117}][Generic]


50 mg (base) (Rx) [Pamelor{117}][Generic]


75 mg (base) (Rx) [Pamelor{117}][Generic]

Canada—


10 mg (base) (Rx) [Aventyl]


25 mg (base) (Rx) [Aventyl]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.


NORTRIPTYLINE HYDROCHLORIDE ORAL SOLUTION USP

Usual adult dose
See Nortriptyline Hydrochloride Capsules USP.

Usual pediatric dose
See Nortriptyline Hydrochloride Capsules USP.

Strength(s) usually available
U.S.—


10 mg (base) per 5 mL (Rx) [Aventyl (alcohol 4%)] [Pamelor (alcohol 4%)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Protect from freezing.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.


PROTRIPTYLINE

Summary of Differences


Indications:
Also used in the treatment of narcolepsy, as an adjunct with amphetamines or methylphenidate in the treatment of cataplexy associated with narcolepsy, in sleep disorders such as hypersomnia or impaired morning arousal, and may be used to relieve symptoms of attention deficit hyperactivity disorder in some children over 6 years of age and in adolescents.



Pharmacology/pharmacokinetics:


Effects—
Anticholinergic: Moderate.

Sedative: Very low.

Orthostatic hypotension: Low.




Additional Dosing Information
See also General Dosing Information.

When dosage increases of protriptyline are indicated, the increase should be made in the morning. This drug often has a psychic-energizing action and usually not the sedative action exhibited by other tricyclics, although it may intensify the sedative effect of other medications.

Protriptyline is often given in divided doses with the last daily dose in the afternoon to avoid insomnia or nightmares when given to some patients before bedtime.

When protriptyline is used in narcolepsy, 15 to 20 mg given in a single daily dose at bedtime may relieve symptoms of arousal difficulty and daytime sleepiness {84}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

PROTRIPTYLINE HYDROCHLORIDE TABLETS USP

Usual adult dose
Antidepressant
Oral, initially 5 to 10 mg three or four times a day, the dosage being adjusted as needed and tolerated {124}.

[Anticataplectic]1
Oral, 15 to 20 mg a day at bedtime.


Usual adult prescribing limits
Up to 60 mg a day {124}.

Usual pediatric dose
Antidepressant
Children up to 12 years of age: Dosage has not been established {124}.

Adolescents: Oral, initially 5 mg three times a day, the dosage being adjusted as needed and tolerated {124}.


Usual geriatric dose
Antidepressant
Oral, initially 5 mg three times a day, the dosage being adjusted as needed and tolerated {124}.


Note: When the daily dose for geriatric patients exceeds 20 mg, the cardiovascular response should be closely monitored {124}.


Strength(s) usually available
U.S.—


5 mg (Rx) [Vivactil (lactose){205}][Generic]


10 mg (Rx) [Vivactil (lactose){205}][Generic]

Canada—


10 mg (Rx) [Triptil]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.


TRIMIPRAMINE

Summary of Differences


Indications:
Also used in treatment of peptic ulcer disease and in the management of some types of chronic, severe, neurogenic pain.



Pharmacology/pharmacokinetics:


Effects—
Anticholinergic: High.

Sedative: High.

Orthostatic hypotension: Moderate.




Additional Dosing Information
See also General Dosing Information.

For patient compliance and convenience of therapy for outpatients, the total daily dosage may be given at bedtime.

Following remission, maintenance therapy should continue for about 3 months at the lowest dose necessary to maintain remission {116}.

In resistant cases of depression in adults in which dosage exceeds 2.5 mg per kg of body weight (mg/kg) a day, the ECG should be monitored during initiation of therapy and at appropriate intervals during stabilization of dose {116}.


Oral Dosage Forms

Note: The dosing and strengths of the dosage forms available are expressed in terms of trimipramine base (not the maleate).


TRIMIPRAMINE MALEATE CAPSULES

Usual adult dose
Antidepressant


Outpatients:
Initial—Oral, 75 mg (base) a day in divided doses, the dosage being adjusted gradually to 150 mg a day as needed and tolerated, up to a maximum of 200 mg a day {116}.

Maintenance—Oral, 50 to 150 mg (base) a day {02} {31} {116}.



Hospitalized patients:
Oral, initially 100 mg (base) a day in divided doses, the dosage being increased gradually in a few days to 200 mg a day, up to 250 to 300 mg a day in two to three weeks {116}.



Usual pediatric dose
Antidepressant
Children up to 12 years of age: Dosage has not been established.

Adolescents: Oral, initially 50 mg (base) a day in divided doses, the dosage being adjusted as needed and tolerated, up to a maximum of 100 mg a day {116}.


Usual geriatric dose
Oral, initially 50 mg (base) a day in divided doses, the dosage being adjusted as needed and tolerated, up to a maximum of 100 mg a day {116}.

Strength(s) usually available
U.S.—


25 mg (base) (Rx) [Surmontil][Generic]


50 mg (base) (Rx) [Surmontil][Generic]


100 mg (base) (Rx) [Surmontil][Generic]

Canada—


75 mg (base) (Rx) [Apo-Trimip] [Rhotrimine] [Surmontil]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.


TRIMIPRAMINE MALEATE TABLETS

Usual adult dose
See Trimipramine Maleate Capsules.

Usual pediatric dose
See Trimipramine Maleate Capsules.

Usual geriatric dose
Antidepressant
Oral, initially 25 to 50 mg (base) a day in divided doses, the dosage being increased by 25 mg a week, up to a maximum of 150 mg a day {128}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


12.5 mg (base) (Rx) [Apo-Trimip] [Rhotrimine] [Surmontil]


25 mg (base) (Rx) [Apo-Trimip] [Novo-Tripramine] [Rhotrimine] [Surmontil]


50 mg (base) (Rx) [Apo-Trimip] [Novo-Tripramine] [Rhotrimine] [Surmontil]


100 mg (base) (Rx) [Apo-Trimip] [Novo-Tripramine] [Rhotrimine] [Surmontil]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a tight container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.



Revised: 08/08/1997



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  1. Desipramine (Norpramin—Marion Merril Dow). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993: 826.
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  1. Protriptyline (Vivactil—Merck). In: Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data, 1994: 1559-60.
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