VA Class:CN601
Clomipramine, a dibenzazepine-derivative tricyclic antidepressant, is the 3-chloro analog of imipramine.1,2,3,235
Clomipramine is used in the treatment of obsessive-compulsive disorder when obsessions or compulsions cause marked distress, are time-consuming (take longer than 1 hour daily), or interfere substantially with the patient's normal routine, occupational or academic functioning, or usual social activities or relationships.1,310,341 Obsessions are recurrent and persistent thoughts, impulses, or images that, at some time during the disturbance, are experienced as intrusive and inappropriate (i.e., ego dystonic) and that cause marked anxiety or distress but that are not simply excessive worries about real-life problems.1,310,341 Compulsions are repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) performed in response to an obsession or according to rules that must be applied rigidly (e.g., in a stereotyped fashion).1,310,341 Although the behaviors or acts are aimed at preventing or reducing distress or preventing some dreaded event or situation, they either are not connected in a realistic manner with what they are designed to neutralize or prevent or are clearly excessive.310,341 At some time during the course of the disturbance, the patient, if an adult, recognizes that the obsessions or compulsions are excessive or unreasonable;1,310,341 children may not make such recognition.310,341
The efficacy of clomipramine for the management of obsessive-compulsive disorder has been established in several multicenter, placebo-controlled, parallel-group studies, including 2 studies of 10 weeks' duration in adults1,3,65,66,67,79 and one study of 8 weeks' duration in children and adolescents 10-17 years of age.1,242 In these clinical studies, clomipramine was more effective than placebo in reducing the severity of obsessive-compulsive manifestations in patients with moderate to severe obsessive-compulsive disorder.1,65,67,89,90,91,92,242 The drug produced substantial improvement in scores on both the Yale-Brown Obsessive-Compulsive Scale (YBOCS) and the National Institute of Mental Health (NIMH) Clinical Global Obsessive-Compulsive Scale (NIMH-OC), while the response with placebo was clinically insignificant.1,65,242 Scores on the YBOCS decreased by an average of approximately 10 from baseline values of 26-28, representing an average improvement of 35-42% in adults and 37% in children and adolescents treated with clomipramine.1,65,242 Scores on the NIMH-OC were reduced by an average of 3.5 units from a mean baseline of 10 in adults, children, and adolescents treated with clomipramine, which represents an improvement in obsessive-compulsive disorder from severe at baseline to subclinical after treatment with the drug.1,65 The maximum dosage of clomipramine hydrochloride was 250 mg daily for most adults and 3 mg/kg (up to 200 mg) daily for children and adolescents.1,65,67,242
Although obsessive-compulsive manifestations often persist to some extent in patients who respond to clomipramine, responders generally find it easier to resist the manifestations and spend less time engaged in the associated behavior.33,66,271 Data from a retrospective analysis suggest that clomipramine may be more effective in patients who developed obsessive-compulsive disorder during middle age (35-62 years of age) than in those in whom onset occurred during early adulthood (16-23 years old), independent of the length of illness.77
Therapeutic response to clomipramine in patients with obsessive-compulsive disorder generally is evident within 2-6 weeks but may not be maximal until 3-4 months after beginning therapy with the drug.33,66,99,103 Thus, it is essential that patients receive an adequate trial of clomipramine at a therapeutic dosage in order to determine efficacy.293
Many clinicians consider clomipramine or a serotonin-reuptake inhibitor (e.g., fluoxetine, fluvoxamine) to be the drugs of choice in obsessive-compulsive disorder.69,289,293,296,297 In addition, behavior therapy often is recommended in patients with obsessive-compulsive disorder even when pharmacologic therapy alone has been partially effective.293
Results from comparative studies to date suggest that clomipramine is more effective than other tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline)81,271,276 and as or more effective than selective serotonin-reuptake inhibitors (e.g., fluoxetine, fluvoxamine)68,69,83,96,100,101,290,292,296,297,300 in the management of obsessive-compulsive disorder. In a pooled analysis of separate short-term (10-13 weeks) studies comparing clomipramine, fluoxetine, fluvoxamine, or sertraline with placebo, clomipramine was calculated as being more effective (as determined by measures on the YBOC scale) than selective serotonin-reuptake inhibitors, although all drugs were superior to placebo.69 Like clomipramine, selective serotonin-reuptake inhibitors reduce but do not completely eliminate obsessions and compulsions.96,271,292,300 The decision whether to initiate therapy with clomipramine or a selective serotonin-reuptake inhibitor often is made based on the adverse effect profile of these drugs.69,96,101,271,289,296,297,300 For example, some clinicians prefer clomipramine in patients who may not tolerate the adverse effect profile of selective serotonin-reuptake inhibitors (nausea, headache, overstimulation, sleep disturbances) while selective serotonin-reuptake inhibitors may be useful alternatives in patients unable to tolerate the adverse effects (anticholinergic effects, cardiovascular effects, sedation) associated with clomipramine therapy.96,101,271,289,296,297 Consideration of individual patient characteristics (age, concurrent medical conditions), the pharmacokinetics of the drug, potential drug interactions, and cost of therapy may also influence clinicians when selecting between clomipramine and selective serotonin-reuptake inhibitors as first-line therapy in patients with obsessive-compulsive disorder.289,290,291 Although not clearly established, it has been suggested that the mechanism of action of clomipramine and other drugs (fluoxetine, fluvoxamine) used in the management of obsessive-compulsive disorder may be related to their serotonergic activity.1,2,107,213,271,290 Clomipramine also has been effective when used in combination with clonidine in several patients with obsessive-compulsive disorder; however, additional experience is needed to confirm the safety and efficacy of this combination.280,341
The manufacturers state that the efficacy of clomipramine for long-term use (i.e., longer than 10 weeks) in the treatment of obsessive-compulsive disorder has not been established in placebo-controlled studies.1,356 After 36 weeks of treatment with clomipramine, improvement compared with placebo was observed on measures of rituals, mood, and social adjustment, although such effects were more substantial after 18 weeks of treatment.2,80 At follow-up 22 weeks after treatment ended, clomipramine differed from placebo on one measure of rituals.80 Clomipramine was not distinguishable from placebo in efficacy at follow-up 6 years after the conclusion of treatment.87 The combination of clomipramine or placebo with the same behavioral therapy resulted in greater improvement with clomipramine on measures of rituals, mood, and social adjustment at 8 weeks of treatment, but thereafter through the last 15 weeks of treatment and at follow-up through 52 weeks, clomipramine was indistinguishable from placebo.4,84 However, clomipramine has been used in some patients for prolonged periods (e.g., up to 1 year) without apparent loss of clinical effect.1,3,4,70,242 If clomipramine is used for extended periods, dosage should be adjusted so that patients are maintained on the lowest effective dosage,1,299 and the need for continued therapy with the drug should be reassessed periodically.1
Discontinuance of clomipramine frequently results in a progressive recurrence of symptoms in patients with obsessive-compulsive disorder, and therefore long-term continued therapy with the drug may be advisable on an individual basis.2,4,33,78,80,81,82,148,341 In a study conducted under double-blind conditions, most patients with obsessive-compulsive disorder who had improved clinically following 5-27 months of clomipramine therapy experienced profound worsening of manifestations after discontinuance of the drug.78 This worsening started at 4 weeks and continued for the rest of the 7-week placebo period and appeared to be unrelated to the duration of clomipramine therapy or to the type of obsessive-compulsive manifestations originally present.78 However, readministration of clomipramine resulted in clinical improvement similar to that obtained prior to discontinuance of the drug.78
Disorders with an Obsessive-Compulsive Component
Depressive episodes may be associated with obsessive-compulsive disorder.288,310 Clomipramine and selective serotonin-reuptake inhibitors are effective antidepressants when obsessive manifestations accompany an episode of major depression.288 However, the antiobsessional effectiveness of clomipramine does not appear to depend on the presence of depression.33,65,78,79
Clomipramine also may reduce obsessive-compulsive manifestations in some patients with schizophrenia and such accompanying manifestations.85,86,88,103 However, exacerbation of psychosis has been reported in some patients treated with clomipramine.2,88,102,103 Therefore, the possibility of exacerbating psychosis should be considered in patients with obsessive-compulsive manifestations and schizophrenia, and such patients receiving clomipramine should be observed closely for early signs of worsening psychosis.102,103
There is a high incidence of obsessive-compulsive disorder in patients with Tourette's disorder (Gilles de la Tourette's syndrome),310 and clomipramine can reduce obsessive-compulsive manifestations associated with Tourette's and suppress associated motor and vocal tics.93,94 However, in at least one controlled study, clomipramine did not differ from placebo in the number of tics observed during 4 weeks of treatment.95
Obsessive thoughts were decreased with the combination of clomipramine and lithium carbonate in a limited number of patients who had obsessive manifestations that previously failed to respond to clomipramine therapy alone.2,3,97,98,281 However, in a study of patients with obsessive-compulsive disorder treated with clomipramine for at least 6 months and who were partial responders to the drug, the addition of lithium carbonate for 4 weeks did not result in improvement in scores on the YBOCS.99
Clomipramine has been used effectively for the treatment of panic disorder with or without agoraphobia.2,3,4,104,105,106,107,108,109,110,116,347 In an uncontrolled study, clomipramine reduced both the weekly frequency and severity of panic attacks when given in an average dosage of 45 mg daily (range: 6.25-75 mg daily).2,4,104 In many patients, complete or nearly complete relief from panic attacks was reported during therapy.104,105,107,108 The number of days that panic attacks occurred was less with clomipramine (mean dosage of 83 mg daily) than with placebo after 8 weeks of treatment in one study.4,110 Therapeutic response generally is seen within about 1-3 weeks but may take up to 6 weeks.4,104,105,110 Although clomipramine therapy generally is well tolerated,116 a transient increase in the number and intensity of panic attacks may occur during initial therapy with the drug.4,104,105,106,288 (See Dosage and Administration: Dosage.) Clomipramine (mean dosage of 109 mg daily; range: 25-200 mg daily) was at least as effective as imipramine (mean dosage of 109 mg daily; range: 25-200 mg daily) in patients with panic disorder and had a faster onset of action in reducing panic attacks and improving phobic avoidance and associated anxiety.2,4,109,116
Clomipramine generally is equally effective in patients with panic disorder with or without agoraphobia.4,105,106 In a limited number of patients whose panic disorder with agoraphobia did not respond to exposure-based behavioral treatment, measures of fear (i.e., fear of bodily incapacitation, fear of losing control), state and trait anxiety, depression, severity of condition, and avoidance of separation situations indicated improvement compared with placebo after receiving clomipramine for about 5 weeks (3 weeks at the maximum dosage of 150 mg daily).117 Despite such improvement, the efficacy of clomipramine in the treatment of such patients was uncertain.117 A clinical response, as indicated by improvement by at least 50% on assessment of avoidance of separation situations with the Phobic Avoidance Rating Scale, was produced by clomipramine in 29% of the patients, while such response was observed with behavioral treatment in 47% of the patients.117
Preliminary results from an uncontrolled study suggest that clomipramine is effective in patients with panic disorder or agoraphobia with panic attacks who have concurrent mitral valve prolapse.106
Although it has been suggested that the mechanism of action of clomipramine in patients with panic disorder may be related to the drug's serotonergic activity,107,108 the absence of clear superiority compared with less selective antidepressants (e.g., desipramine) suggests that this may not be the case.341
For further information on treatment of panic disorder, see Uses: Panic Disorder, in the Tricyclic Antidepressants General Statement 28:16.04.28.
Clomipramine has been used effectively in the treatment of major depressive disorder.2,3,254,255,256,257,258,259,260,267,277,278,282,288 Clinical studies have shown that the antidepressant effect of clomipramine exceeds that of placebo and is comparable to that of usual dosages of other tricyclic antidepressants (e.g., amitriptyline, doxepin, imipramine) or selective serotonin-reuptake inhibitors (e.g., fluoxetine, paroxetine).2,3,255,256,257,258,260,277,282,283 Several (e.g., 4-6) weeks may be required for optimal antidepressant effect at a given clomipramine dosage.2,3,256,257,258,259,260,277,282,283 Despite comparable efficacy,2,3,255,256,257,258,260,277,282,283 the adverse effect profile (e.g., anticholinergic effects) of clomipramine may limit its usefulness relative to other antidepressants,2,257,258,277,282,283,288,289 and antidepressant therapy should be individualized based on patient response and tolerance.288 Clomipramine appears to offer no substantial advantage over other tricyclic antidepressants for the management of typical depression in the absence of obsessive-compulsive manifestations and may be more poorly tolerated, particularly compared with tricyclics exhibiting only mild to moderate anticholinergic effects.2,289,341 Although some clinicians have preferred clomipramine to other tricyclic antidepressants for atypical depression (e.g., because of clomipramine's dopaminergic activity), other agents (e.g., selective serotonin-reuptake inhibitors such as fluoxetine) generally have replaced this preference for clomipramine in such depression.341
For further information on treatment of major depressive disorder and considerations in choosing the most appropriate antidepressant for a particular patient, including considerations related to patient tolerance, patient age, and cardiovascular, sedative, and suicidal risks, see Considerations in Choosing Antidepressants under Uses: Major Depressive Disorder, in the Tricyclic Antidepressants General Statement 28:16.04.28.
Like other tricyclic antidepressants, clomipramine has been used for the treatment of chronic pain, including central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, and pain of other neuropathic origin (e.g., cancer pain).2,3,52,111,112,113,114,115,118,119,120,121,122,123,124,125,343,344 Antidepressants have been used alone or as adjuncts to conventional analgesics in the management of such pain.2,3,52,111,112,113,114,115,118,119,120,121,122,123,124,125,343,344 In patients with central pain (e.g., phantom or stump pain, post-herpetic neuralgia, deafferentation pain secondary to posttraumatic nerve lesions), reduction in pain intensity, as indicated by scores on a visual analog scale for pain, was greater during treatment with clomipramine for 3 weeks than with placebo.124 Treatment of idiopathic pain disorder with clomipramine (mean dosage of 97 mg daily) for 6 weeks resulted in improvement, as indicated by the physicians' global assessment, in 63% of patients.2,115 The patients' scores on visual analog scales that included assessment of pain also were improved.2,115 In patients with tension headache, a greater decrease in headache pain, as indicated by scores on a visual analog scale, occurred with clomipramine administered for 6 weeks than with placebo.121,122 Treatment of diabetic peripheral neuropathy with clomipramine for 2 weeks resulted in a greater decrease compared with placebo in the severity of symptoms overall, as evaluated by a physician through use of a scale that quantified pain, paresthesia, dyesthesia, numbness, nightly deterioration, and sleep disturbances.118,125,126,127
Cataplexy and Associated Narcolepsy
Clomipramine has been used for the symptomatic management of cataplexy in a limited number of patients with cataplexy and associated narcolepsy.3,132,133,279 Cataplexy attacks and sleep paralysis resolved or were reduced in frequency during clomipramine therapy (25-200 mg daily); however, the drug did not consistently improve sleep attacks.132,133,279 Although the precise mechanism of clomipramine's anticataplectic action is not known, it has been suggested that its serotonergic and REM-suppressing activity may be involved.132,133,279
Clomipramine has been effective in a limited number of patients with autistic disorder.134,135,141,285,286 In a double-blind study, clomipramine therapy (mean dosage: 152 mg daily) was superior to both desipramine and placebo in improving standardized ratings of autistic manifestations, including repetitive and obsessive-compulsive behaviors and hyperactivity in a limited number of pediatric outpatients aged 6-18 years with autistic disorder.135,141 However, in an open study involving younger inpatients aged 3-9 years with autistic disorder but with relatively low intellectual functioning and without prominent obsessive-compulsive manifestations, clomipramine was not found to be effective and was commonly associated with adverse effects, including acute urinary retention.226
Clomipramine has been used in a limited number of patients with trichotillomania (an urge to pull out one's hair).3,136,137,138,139 In one double-blind, crossover study, clomipramine (mean dosage of 181 mg daily; range: 100-250 mg daily) was shown to be more effective than desipramine (mean dosage of 173 mg daily; range: 150-200 mg daily) in the short-term management of trichotillomania.136 However, relapse has been reported in some patients receiving long-term treatment with clomipramine.140
Clomipramine has been used in a limited number of patients with severe onychophagia (nail biting) and no history of obsessive-compulsive disorder.142 In one study, the severity of nail biting decreased in patients treated with clomipramine hydrochloride 25-200 mg daily for 5 weeks.142 However, the relatively high dropout rate secondary to adverse effects and drug intolerance suggests that clomipramine should not be considered as first-line therapy in most patients with onychophagia.142,341
Clomipramine has been used in a limited number of patients with stuttering.143 Following 5 weeks of therapy (mean dosage: 147 mg daily), clomipramine improved the severity of stuttering, preoccupation with thoughts about stuttering, amount of energy spent resisting stuttering, and expectancy of stuttering.143 Additional study of the efficacy of clomipramine in the management of stuttering is necessary.143,341
Clomipramine has been used in a limited number of patients with anorexia nervosa.229,230,231 In a placebo-controlled study, clomipramine therapy was associated with increased appetite, hunger, and calorie consumption during initial therapy; however, the drug was not associated with improved eating behavior after 8 weeks of therapy or greater weight gain.229,230,231,234 In addition, body weight did not differ between the clomipramine and placebo groups at 1-year follow-up and a measure of outcome based on nutritional status, sexual adjustment, socioeconomic adjustment, and mental state did not differ between the 2 groups at 4-year follow-up.229 Few controlled studies on the pharmacotherapy for anorexia nervosa have been published, and results with most drugs have been unimpressive.288 Because malnourished depressed patients may be particularly susceptible to the adverse cardiovascular effects or other severe toxicities (including death) of tricyclic antidepressants, the American Psychiatric Association (APA) states that tricyclic antidepressants should be avoided in underweight individuals and in those exhibiting suicidal ideation. For further information on use of antidepressants in the treatment of eating disorders see Uses: Eating Disorders, in Fluoxetine Hydrochloride 28:16.04.20.288,341
Clomipramine has been used with some success in the treatment of premature ejaculation.3,128,129,130,131 In a controlled study, mean ejaculatory latency was prolonged in patients receiving 25 or 50 mg of the drug daily.131 Sexual and relationship satisfaction also was improved.131 A trial with drug therapy may be particularly useful in patients who fail or refuse behavioral or psychotherapeutic treatment or when partners are unwilling to cooperate with such therapy.274,341
Clomipramine has been used in the management of premenstrual syndrome.261,262,263,264 In a limited number of women with severe premenstrual irritability and/or depressed mood, clomipramine given either continuously or intermittently (i.e., premenstrual administration) during 3 menstrual cycles at a dosage of 25-75 mg daily was more effective than placebo in reducing premenstrual irritability and depressed mood.261,262 However, preliminary data suggest that patients with premenstrual syndrome may be particularly sensitive to the adverse effects associated with the drug.261,262,341
Clomipramine hydrochloride is administered orally.1,3,356 The drug also has been administered IM or IV, but a parenteral dosage form is not commercially available in the US.4,272
During initial therapy when the dosage is being titrated, the manufacturers recommend that clomipramine be given in divided doses with meals to lessen adverse GI effects.1,356 After dosage titration, the total daily dose may be given once daily at bedtime1,2,4,271,356 to minimize adverse effects such as sedation during waking hours1,2,356 and enhance patient compliance.2
Dosage of clomipramine hydrochloride is expressed in terms of the hydrochloride.1
Because there is wide interindividual variation in dosage and dosage may differ in various disease states, the dosage of clomipramine hydrochloride must be individualized carefully.2
Patients receiving clomipramine should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.348,349,350,355,356 (See Cautions: Precautions and Contraindications.)
For the management of obsessive-compulsive disorder in adults, children, or adolescents, the recommended initial dosage of clomipramine hydrochloride is 25 mg daily.1 During the first 2 weeks of therapy, dosage should be increased gradually as tolerated to approximately 100 mg daily in adults.1 In children and adolescents, dosage should be increased gradually, as tolerated, during the first 2 weeks of therapy up to a maximum of 3 mg/kg or 100 mg daily, whichever is lower.1,2,242 This initial period of titration is intended to minimize adverse effects by permitting tolerance to develop or allowing the patient time to adapt if tolerance does not develop.1
During the next several weeks, the dosage of clomipramine hydrochloride may be increased gradually up to a maximum of 250 mg daily in adults and 3 mg/kg or 200 mg daily (whichever is lower) in children and adolescents.1,2,3,4,66,67 Daily clomipramine hydrochloride dosages exceeding 250 mg in adults or 3 mg/kg (up to 200 mg) in children and adolescents should be avoided because of the increased risk of seizures (see Cautions: Nervous System Effects).3,66,67
Because of the long elimination half-lives of both clomipramine and its active metabolite, desmethylclomipramine, clinicians should take into consideration that steady-state plasma concentrations may not be achieved for 2-3 weeks or even longer.1,2,4,6,7,9,13,14,23,27,55,356 Therefore, the manufacturers state that it may be appropriate to wait 2-3 weeks between any further dosage adjustments after the initial dosage titration period.1,356
Although the optimum duration of clomipramine therapy has not been established, obsessive-compulsive disorder is a chronic condition and it seems reasonable to consider continuation of therapy in responding patients.1,78,271 Although the manufacturers state that the efficacy of clomipramine when given for periods exceeding 10 weeks has not been established systematically in controlled studies, the drug has been given under double-blind conditions for up to 1 year without loss of clinical efficacy.1,3,4,70,242,356 Pending further accumulation of data, some clinicians recommend that clomipramine therapy be continued for at least 18 months in patients with obsessive-compulsive disorder before attempting to discontinue therapy.271 However, the dosage should be adjusted during maintenance therapy so that patients are maintained on the minimum effective dosage and patients should be reassessed periodically to determine the need for continued therapy.1,299
Clomipramine should not be used concomitantly with MAO inhibitors and it is recommended that at least 2 weeks elapse between discontinuance of therapy with a MAO inhibitor and initiation of clomipramine therapy and vice versa.1 A similar interval is recommended between discontinuance of therapy with a selective serotonin-reuptake inhibitor (e.g., citalopram, escitalopram, fluvoxamine, paroxetine, sertraline) and initiation of therapy with a tricyclic antidepressant agent such as clomipramine and vice versa.1 However, because fluoxetine and its active metabolite have a long half-life, at least 5 weeks should elapse between discontinuance of fluoxetine therapy and initiation of clomipramine therapy.1
Abrupt discontinuance of clomipramine therapy should be avoided since a variety of withdrawal symptoms have been reported.1,78,148,301 (See Cautions: Nervous System Effects and also see Chronic Toxicity.) In addition, patients may experience a worsening of psychiatric status when the drug is discontinued abruptly.1,2,78,148 Therefore, it is recommended that dosage be tapered gradually (e.g., over a period of approximately 2 weeks) and the patient monitored carefully when clomipramine therapy is discontinued.1,2,78,148,301
For the management of panic disorder with or without agoraphobia, clomipramine hydrochloride usually has been effective in dosages ranging from 12.5-150 mg (maximum: 200 mg) daily.2,4,104,105,106,107,108,110,116,272 Most patients with panic attacks respond to a clomipramine hydrochloride dosage of less than 50 mg daily; however, patients with agoraphobia may require a higher dosage.4,104,105,106 Because clomipramine may worsen anxiety symptoms during initial therapy, some clinicians recommend that patients be started on a low dosage initially, and then the dosage can be increased gradually until therapeutic response or bothersome adverse effects occur.4,104,105,106,288
For the management of major depressive disorder or chronic pain, clomipramine hydrochloride is generally given in dosages ranging from 100-250 mg daily.2,115,272,277,278,288
For the management of cataplexy and associated narcolepsy, clomipramine hydrochloride has been given in dosages ranging from 25-200 mg daily.132,133,272,279
The manufacturers and some clinicians recommend selecting an initial clomipramine dosage at the lower end of the recommended range since decreased hepatic, renal, or cardiac function and concomitant illness and medications are more frequent in geriatric patients.2,4,272,282,355,356
Clomipramine shares the toxic potentials of the tricyclic antidepressants, and the usual precautions of tricyclic antidepressant administration should be observed.2,3,4,235,288,289 (See Cautions in the Tricyclic Antidepressants General Statement 28:16.04.28.)
Common adverse effects of clomipramine are extensions of its pharmacologic activity, principally anticholinergic effects; adverse effects secondary to antihistaminic and α-adrenergic activity also may occur.1,2,3,4,35,65,235,242,288,289 Like other tricyclics, adverse effects of clomipramine could affect compliance and result in dosage reduction; however, the possibility that such reductions could affect response should be considered.289
In controlled studies, the most common adverse effects occurring more frequently in patients receiving clomipramine than in those receiving placebo included GI effects such as dry mouth, constipation, nausea, dyspepsia, anorexia, and increased appetite; nervous system effects such as somnolence, tremor, dizziness, nervousness, fatigue, and myoclonus; genitourinary effects such as changed libido, ejaculatory failure, impotence, and micturition disorder; sweating; weight gain; and visual changes.1,2,35,65,242 Approximately 20% of the 3616 patients who participated in US premarketing clinical trials for obsessive-compulsive or other disorders discontinued clomipramine therapy because of an adverse effect.1,342 About one-half of those who discontinued therapy (9% of the total) experienced multiple adverse effects, none of which could be classified as the principal reason.1 However, in the cases in which a principal reason for discontinuing therapy could be identified, most of the patients did so because of nervous system effects (5.4%), mainly somnolence, and GI effects (1.3%), mainly nausea and vomiting.1
The incidences of adverse effects reported by the manufacturers to have occurred in at least 1% of clomipramine-treated patients were obtained from pooled data from placebo-controlled clinical trials involving 322 adults and 46 children or adolescents who received clomipramine for the treatment of obsessive-compulsive disorder.1,356 However, clinicians prescribing clomipramine should be aware that these figures cannot be used to predict the incidence of adverse effects during usual medical practice, in which patient characteristics and other factors differ from those that prevailed during these trials.1 Similarly, the cited incidences cannot be compared with the incidences obtained from other trials involving different treatments, uses, and investigators.1 However, the incidences from these trials provide the clinician with a basis for estimating the relative contribution of both drug and nondrug factors to the incidence of adverse effects in the populations studied.1 Various other adverse effects have been reported in 3525 out of approximately 3600 individuals who received multiple doses of clomipramine for obsessive-compulsive or other disorders during premarketing trials in the US; however, these adverse effects have not been definitely attributed to the drug.1,342
Some evidence suggests that patients with depression may tolerate clomipramine relative to placebo more poorly than those with obsessive-compulsive disorder.2,289,341
Seizure is the most clinically important risk associated with clomipramine therapy.1 However, seizure remains a relatively uncommon adverse effect of clomipramine therapy.1,4 The cumulative incidence of seizures in patients treated with clomipramine hydrochloride dosages of up to 300 mg daily was 0.64, 1.12, and 1.45% at 90, 180, and 365 days, respectively.1,210 The cumulative rates correct the crude incidence of 0.7% (25 of 3519 patients) for the variable duration of exposure to clomipramine in clinical trials.1 Seizures also have been associated with abrupt withdrawal of the drug.3,203
Dose appears to be a predictor of the development of seizures.1,65,66,67,210 However, the influence of dose is confounded by the duration of exposure to the drug, making independent assessment of the effect of either factor alone difficult.1,210 Seizures occurred in about 0.5 or 2% of patients who received a maximum daily dose of 250 mg or higher than 250 mg, respectively, of the drug.2,65,66,67,210 The ability to predict seizures with daily doses exceeding 250 mg is limited because plasma concentrations achieved during clomipramine therapy may be dose dependent and vary considerably among individuals administered the same dosage.1
Rare reports of fatalities in association with clomipramine-associated seizures have been reported in foreign postmarketing surveillance, but not in US clinical trials.1 In some of these cases, clomipramine had been administered with other epileptogenic agents, while in other cases the patients had possible predisposing medical conditions.1 Thus, a causal relationship between clomipramine therapy and these fatalities has not been established.1 (See Cautions: Precautions and Contraindications.)
Withdrawal syndrome has been reported rarely in patients receiving clomipramine.1,148,301 In a limited number of patients, abrupt discontinuance of clomipramine resulted in a variety of withdrawal manifestations, including dizziness, nausea, vomiting, headache, malaise, sleep disturbance, hyperthermia, sweating, and irritability.1,148,301 Abrupt discontinuance of the drug also reportedly has resulted in seizures.3,203 In addition, some patients have experienced a worsening of psychiatric status when the drug was discontinued abruptly.1,148 Therefore, abrupt discontinuance of clomipramine therapy should be avoided.1,148,301 (See Cautions: Precautions and Contraindications.)
The manifestation of a group of adverse effects (e.g., tremor, myoclonus, diaphoresis, shivering, restlessness, fever, mental status changes, diarrhea) that resembles the serotonin syndrome observed in animals has been reported with clomipramine monotherapy.211,241 In an open study in which patients received clomipramine 150 mg daily for about 4 weeks for the treatment of depression, tremor of the tongue and myoclonus occurred most commonly (42 and 36% of patients, respectively).241 Tremor of the tongue or fingers and myoclonus were accompanied by diaphoresis and shivering in over a quarter of the patients.241 In most cases, these manifestations were transient and resolved despite continued therapy.241 More severe and sometimes fatal reactions resembling the serotonin syndrome have been reported when clomipramine has been given concurrently with other serotonergic agents such as MAO inhibitors, fluoxetine, lithium, or alprazolam.1,2,3,33,75,159,160,161,170,174,176,178 (See Drug Interactions.)
In controlled trials, somnolence,1,65,238,242 dizziness,1,35,65,242,245,252 or tremor1,33,35,65,66,67,241,242,248,250,252 was each reported in about 54% of adults and in about 46, 41, or 33%, respectively, of children and adolescents receiving clomipramine.1,242 Headache1,65,242,245,248,250 occurred in about 52% of adults and 28% of children and adolescents receiving clomipramine.1,242 Fatigue1,65,242,252 occurred in about 39% of adults and 35% of children and adolescents receiving the drug.1,242 Insomnia1,65,238,250 occurred in about 25% of adults and 11% of children and adolescents1 and nervousness1,65 occurred in about 18% of adults and 4% of children and adolescents treated with clomipramine.1
Myoclonus1,65,191,196,197,241 occurred in about 13% of adults and 2% of children and adolescents receiving clomipramine.1 Motor hyperactivity that included jerking of the arms and legs during nocturnal sleep also has been reported.201 Memory impairment occurred in about 9 or 7% of adults or children and adolescents, respectively, receiving clomipramine.1 Paresthesia1,206 and anxiety1,250,251 each occurred in about 9 or 2% of adults or children and adolescents, respectively, receiving the drug.1 Twitching occurred in about 7 or 4% of adults or children and adolescents, respectively, receiving clomipramine.1 Impaired concentration1 and depression1 each occurred in about 5% of adults receiving clomipramine.1 Sleep disorder occurred in about 4 or 9% of adults or children and adolescents, respectively, treated with the drug.1 Disturbance of sleep by fright that was accompanied by myoclonus also has been reported in association with clomipramine therapy.4,191 Hypertonia occurred in about 4 or 2% of adults or children and adolescents, respectively, receiving the drug.1
Confusion1,241 occurred in about 3 or 2% of adults or children and adolescents, respectively, receiving clomipramine.1 Psychosomatic disorder,1 speech disorder,1 dream abnormalities,1 agitation,1 or migraine1 occurred in about 3% of adults treated with the drug.1 Depersonalization1 or irritability1 occurred in about 2% of both adults and children or adolescents receiving clomipramine.1 Emotional lability occurred in about 2% of adults1 and aggressive reaction1,238 occurred in about 2% of children and adolescents treated with the drug.1 Paresis1 and asthenia1 each occurred in about 2% of children and adolescents1 and panic reaction occurred in about 1 or 2% of adults or children and adolescents, respectively, receiving clomipramine.1
During premarketing clinical trials in patients with affective disorder, hypomania or mania was precipitated infrequently in patients receiving clomipramine therapy.1,3,155,156,295 Activation of mania or hypomania also has been reported in patients treated with other tricyclic antidepressants.1,155
More than 30 cases of hyperthermia with clomipramine have been reported by foreign postmarketing surveillance systems.1 Most of these cases occurred in patients receiving clomipramine in combination with other drugs (e.g., antipsychotic agents).1,157,199 When clomipramine and an antipsychotic agent were used concomitantly, the cases sometimes were considered to be examples of neuroleptic malignant syndrome (NMS).1,157,199
Abnormal thinking1 and vertigo1,248 each occurred in 1% or more of patients receiving clomipramine; however, a causal relationship to the drug has not been established.1
Dyskinesia occurred in less than 1% of patients receiving clomipramine, although a causal relationship to the drug has not been established.1,35,240 Persistent tardive dyskinesia has been reported after initiation of clomipramine in a patient who was already receiving dextroamphetamine.240 A severe tardive dyskinesia-like syndrome consisting of orobuccal movements, choreoathetosis of the arms and other abnormal movements of the extremities, motor restlessness, and incoordination has been reported in another patient who was receiving clomipramine concurrently with thiothixene, buspirone, and trihexyphenidyl.198
Other adverse nervous system effects occurring in less than 1% of clomipramine-treated patients include apathy,1 ataxia,1,245,248 coma,1 abnormal coordination,1 delirium,1 delusions,1 dysphonia,1 EEG abnormalities,1 encephalopathy,1 euphoria,1 extrapyramidal disorder,1,249,250 abnormal gait,1 hallucinations,1 hostility,1 hyperkinesia,1 hypnagogic hallucinations,1 hypokinesia,1 neuralgia,1 paranoia,1,238 phobic disorder,1 psychosis,1 sensory disturbance,1 somnambulism,1 stimulation,1 and teeth grinding;1 however, a causal relationship to the drug has not been established.1
Rarely reported adverse nervous system effects for which a causal relationship to clomipramine has not been established include anticholinergic syndrome,1 aphasia,1 apraxia,1 catalepsy,1 cholinergic syndrome,1 choreoathetosis,1 hemiparesis,1 hyperesthesia,1 hyperreflexia,1 hypoesthesia,1 illusion,1 impaired impulse control,1 indecisiveness,1 mutism,1 neuropathy,1 nystagmus,1 oculogyric crisis,1 oculomotor nerve paralysis,1 schizophrenic reaction,1 generalized spasm,1 stupor,1 and torticollis.1 Dystonia1,200 has been reported rarely in clomipramine-treated patients, although a causal relationship to the drug has not been established.1 Acute dystonia that included oculogyric crisis, torticollis, and lead-pipe rigidity has occurred in a patient receiving clomipramine.200 Exacerbation of motor tics and development of vocal tics also have been reported in a patient receiving the drug.202
Suicidal ideation1,237 and suicide attempt1 have been reported in less than 1% of patients receiving clomipramine and suicide has been reported rarely.1 (See Cautions: Precautions and Contraindications.)
During clinical trials, modest orthostatic decreases in blood pressure1,193 and modest tachycardia1 each occurred in about 20% of patients receiving clomipramine, although patients frequently were asymptomatic.1,65 Postural hypotension occurred in about 6 or 4% of adults or children and adolescents, respectively,1 and tachycardia occurred in about 4 or 2% of adults or children and adolescents, respectively, receiving clomipramine in controlled clinical trials.1 Flushing occurred in about 8 or 7% of adults or children and adolescents, respectively, treated with the drug in controlled clinical trials.1
Palpitations1,35 occurred in about 4% of both adults and children or adolescents receiving clomipramine in controlled clinical trials.1 Chest pain occurred in about 4 or 7% of adults or children and adolescents, respectively,1 and syncope1 occurred in about 2% of children and adolescents receiving clomipramine in controlled clinical trials.1
Among approximately 1400 patients who received clomipramine during the premarketing evaluation,1,148 ECG abnormalities were observed in about 1.5% of the patients compared with 3.1% of those who received an active control and 0.7% of those receiving placebo.1 The most commonly observed ECG changes were ventricular premature contractions, ST-T wave changes, and intraventricular conduction abnormalities.1 These changes rarely were associated with clinically important symptoms; nevertheless, caution is necessary when treating patients with known cardiovascular disease with clomipramine, and gradual dosage titration is recommended in such patients.1
Arrhythmia,1 bradycardia,1 cardiac arrest,1 extrasystoles,1 and pallor1 occurred in less than 1% of patients receiving clomipramine, although a causal relationship to the drug has not been established.1 Aneurysm,1 atrial flutter,1 bundle-branch block,1 cardiac failure,1 cerebral hemorrhage,1 heart block,1 myocardial infarction,1 myocardial ischemia,1 peripheral ischemia,1 thrombophlebitis,1 vasospasm,1 and ventricular tachycardia1 have occurred rarely, but these adverse effects also have not been attributed definitely to the drug.1 Hypertension also has been reported.204
General edema,1 greater susceptibility to infection,1 malaise,1 and parosmia1 have been reported in less than 1% of clomipramine-treated patients and dependent edema1 has been reported rarely, although these adverse effects have not been attributed definitely to the drug.1
There have been reports of fatigue and dizziness during physical exertion in children and adolescents receiving clomipramine.341 Because the cardiovascular effects of the drug have not been studied during such stress in this age group, some clinicians state that clomipramine should be used with caution in children and adolescents who participate in active sports.341
Adverse GI effects are encountered commonly during initial clomipramine therapy and in some cases can lead to early withdrawal of the drug.3 Dry mouth1,35,65,66,67,88,242,245,246,248,250,251,252 occurs in about 84 or 63% of adults or children and adolescents, respectively,1,242 and constipation1,35,65,88,242,245,248,250 occurs in about 47 or 22% of adults or children and adolescents, respectively, receiving clomipramine.1,242
Nausea1,65,88,194,245,248,250 has been reported in about 33 or 9% of adults or children and adolescents, respectively, receiving clomipramine.1 Dyspepsia1,65,242 occurred in about 22 or 13% of adults or children and adolescents, respectively,1,242 and diarrhea occurred in about 13 or 7% of adults or children and adolescents, respectively, receiving the drug.1 Anorexia1,65,242,245,246,248,250 occurred in about 12 or 22% of adults or children and adolescents, respectively, receiving the drug.1,242 Abdominal pain occurred in about 11 or 13% of adults or children and adolescents, respectively, receiving clomipramine.1,242 Increase in appetite1,249,250 occurred in 11% of adults treated with the drug.1 Taste perversion1,35,250 occurred in about 8 or 4% of adults or children and adolescents, respectively, receiving clomipramine.1 Vomiting1,194,250 occurred in about 7% of clomipramine-treated adults, children, and adolescents.1 Flatulence has been reported in about 6% of adults receiving the drug.1 GI disorder1 or dysphagia1 occurred in about 2% of clomipramine-treated adults,1 and eructation,1 ulcerative stomatitis,1 or halitosis1 occurred in about 2% of children and adolescents receiving the drug.1 Esophagitis occurred in about 1% of adults receiving clomipramine.1
Blood in stool,1 colitis,1 duodenitis,1 gastric ulcer,1 gastritis,1 gastroesophageal reflux,1 gingivitis,1 glossitis,1 hemorrhoids,1 increased salivation,1,35 irritable bowel syndrome,1 peptic ulcer,1 rectal hemorrhage,1 taste loss,1 and tongue ulceration1 were reported in less than 1% of patients receiving clomipramine, but a causal relationship to the drug has not been established.1 Cheilitis,1 chronic enteritis,1 discolored feces,1 gastric dilatation,1 gingival bleeding,1 intestinal obstruction,1 oral/pharyngeal edema,1 paralytic ileus,1 and salivary gland enlargement1 have occurred rarely but have not been attributed definitely to clomipramine.1
Dermatologic and Sensitivity Reactions
In controlled trials, increased sweating1,35,65,88,245,248,250,251,252 occurred in about 29 or 9% of adults or children and adolescents, respectively, receiving clomipramine.1 Rash1,252 occurred in about 8% of adults and 4% of children and adolescents treated with the drug.1 Pruritus occurred in about 6% of adults and 2% of children and adolescents receiving clomipramine.1 Dermatitis,1 acne,1 or dry skin1 occurred in about 2% of clomipramine-treated adults.1 Abnormal skin odor occurred in about 2% of children and adolescents receiving clomipramine therapy.1 Urticaria occurred in about 1% of adults1 and allergy occurred in about 3% of adults and 7% of children and adolescents treated with the drug.1
Alopecia,1 cellulitis,1 cyst,1 eczema,1 genital pruritus,1 psoriasis,1 and rash that was erythematous, maculopapular, or pustular1 have been reported in less than 1% of patients receiving clomipramine, but these effects have not been attributed definitely to the drug.1 Lupus erythematosus rash has occurred rarely.1 Photosensitivity reaction1,35,239,265 or skin discoloration1 has occurred in less than 1% of patients receiving clomipramine, although a causal relationship to the drug has not been established.1 Pseudocyanotic (e.g., slate-gray, blue-black, purplish) pigmentation that affected areas of the body exposed to sunlight and therefore may have been a photosensitivity reaction also has occurred with clomipramine.205,265 Chloasma has been reported rarely.1 Folliculitis,1 hypertrichosis,1 piloerection,1 polyarteritis nodosa,1 seborrhea,1 skin hypertrophy,1 or skin ulceration1 has been reported rarely in patients receiving clomipramine, although a causal relationship has not been established.1
Metabolic and Electrolyte Effects
In controlled studies, weight gain1,245,247,249 occurred in about 18% of adults who received clomipramine therapy for the treatment of obsessive-compulsive disorder compared with 1% of those receiving placebo.1 In these studies, a weight gain of at least 7% of initial body weight occurred in about 28% of clomipramine-treated patients compared with 4% of those receiving placebo.1 In several patients, weight gain exceeded 25% of the initial body weight.1 Conversely, weight losses of at least 7% of initial body weight occurred in about 5% of clomipramine-treated patients compared with 1% of those who received placebo.1 In controlled studies, weight gain1,242 or weight loss1 occurred in about 2 or 7% of children and adolescents, respectively, receiving clomipramine.1
Thirst1,250 occurred in about 2% of adults receiving clomipramine.1 Dehydration,1 gout,1 hypercholesterolemia,1 hyperglycemia,1 hyperuricemia,1 and hypokalemia1 have been reported in less than 1% of patients receiving clomipramine, although a causal relationship to the drug has not been established.1 Fat intolerance1 and glycosuria1 have been reported rarely in patients receiving clomipramine, although these adverse effects have not been attributed definitely to the drug.1
Abnormal vision1,65,209 occurred in about 18 or 7% of adults or children and adolescents, respectively, receiving clomipramine.1 Abnormal lacrimation,1 mydriasis,1 and conjunctivitis1 occurred in about 3, 2, and 1% of adults, respectively, receiving the drug.1 Anisocoria,1 blepharospasm,1 and ocular allergy1 occurred in about 2% of children and adolescents receiving clomipramine.1 Adverse ocular effects reported in less than 1% of clomipramine-treated patients include abnormal accommodation,1,248 diplopia,1 ocular pain,1 foreign body sensation,1 photophobia,1 and scleritis;1 however, a causal relationship to the drug has not been established.1
Glaucoma has been reported rarely in patients receiving clomipramine, although a causal relationship to the drug has not been established.1,209 Angle-closure glaucoma that presented clinically as amaurosis fugax (transient monocular blindness) attacks that were precipitated by rising from a sitting or supine position has been reported in at least one female patient treated with the drug.209 Although the precise mechanism is unclear, it was suggested that an abnormally large fall in blood pressure upon standing up combined with an increase in intraocular pressure may have been responsible.209 Blepharitis,1 chromatopsia,1 conjunctival hemorrhage,1 exophthalmos,1 keratitis,1 night blindness,1 retinal disorder,1 strabismus,1 and visual field defect1 occurred rarely in patients receiving clomipramine, but have not been attributed definitely to the drug.1
Tinnitus occurred in about 6 or 4% of adults or children and adolescents, respectively, receiving clomipramine.1 Otitis media1 or vestibular disorder1 occurred in about 4 or 2% of children and adolescents, respectively, receiving clomipramine.1 Adverse otic effects reported in less than 1% of clomipramine-treated patients include hyperacusis, 1 deafness,1 earache,1 and labyrinth disorder;1 however, these effects have not been attributed definitely to the drug.1
Myalgia occurred in about 13% of adults receiving clomipramine. 1 Back pain1 and arthralgia1 occurred in about 6 and 3% of adults, respectively, receiving clomipramine.1 Muscle weakness occurred in about 1 or 2% of adults or children and adolescents, respectively, receiving clomipramine.1 Arthrosis1 and leg cramps1 have been reported in less than 1% of patients receiving clomipramine, although a causal relationship to the drug has not been established.1 Exostosis,1 bruising,1 myopathy,1 and myositis1 have been reported rarely in clomipramine-treated patients, although these effects have not been attributed definitely to the drug.1
Purpura1 has been reported in about 3% of adults receiving clomipramine.1 Although no cases of severe hematologic toxicity were reported during the premarketing evaluation of clomipramine, there subsequently have been rare reports of bone marrow depression1,227 in patients receiving the drug, including leukopenia,1 agranulocytosis,1,3,162,164,165,166 thrombocytopenia,1 anemia,1 and pancytopenia.1,3,163 In controlled trials, anemia occurred in about 2% of children and adolescents receiving the drug.1
Pharyngitis occurred in about 14% of adults receiving clomipramine.1 Rhinitis occurred in about 12 or 7% of adults or children and adolescents, respectively, receiving clomipramine.1 Cough occurred in about 6 or 4% of adults or children and adolescents, respectively, receiving clomipramine.1 Sinusitis occurred in about 6 or 2% of adults or children and adolescents, respectively, treated with the drug.1 Yawning occurred in about 3% of adults receiving clomipramine.1 Bronchospasm occurred in about 2 or 7% of adults or children and adolescents, respectively, receiving clomipramine.1
Epistaxis occurred in about 2% of adults receiving clomipramine.1 Dyspnea1 or laryngitis1 occurred in about 2% of clomipramine-treated children and adolescents.1 The development of adverse respiratory effects (e.g., dry sore throat, cough) severe enough to result in aphonia also has been reported.194
Although a causal relationship has not been established, bronchitis,1 hyperventilation,1 increased sputum,1 and pneumonia1 have been reported in less than 1% of patients receiving clomipramine, and cyanosis,1 hemoptysis,1 hiccup,1 hypoventilation,1 and laryngismus1 have been reported rarely.1
One characteristic of clomipramine therapy that may be troublesome to some patients is its relatively high incidence of sexual dysfunction.1,3,180 The incidence of sexual dysfunction in male patients receiving clomipramine therapy for obsessive-compulsive disorder during premarketing clinical trials was substantially higher than in those receiving placebo.1 Normal sexual functioning usually returns within a few days after discontinuing clomipramine therapy.2,3,180
Libido change1,65,189,251 occurred in about 21% of adults receiving clomipramine.1 Ejaculatory failure1,65,180,188,251 occurred in about 42% of adult males treated with clomipramine compared with 2% of those receiving placebo,1 and impotence1,65,189,245,270 occurred in 20% of clomipramine-treated adult males compared with about 3% of those receiving placebo.1 Approximately 85% of adult males who experienced sexual dysfunction during clomipramine therapy chose to continue therapy with the drug.1 About 6% of adolescent males experienced ejaculation failure while receiving clomipramine.1 Premature ejaculation has been reported rarely but has not been attributed definitely to the drug.1 On the other hand, clomipramine has been used in the treatment of premature ejaculation in a limited number of patients.3,128,129,130,131 Painful ejaculation or orgasm has been reported in a limited number of male patients receiving the drug.180,190
Anorgasmy has been reported in both male and female patients receiving clomipramine.1,180,182,183,184,185,269 In a controlled trial, difficulty or inability to reach orgasm was the most common adverse sexual effect in clomipramine-treated patients;180 sexual function generally returned to normal within 3 days after discontinuance of the drug.2,3,180 Anorgasmy associated with clomipramine has responded to anticipatory administration of yohimbine in several patients.185,232,233 Orgasm during yawning also has been reported in a limited number of patients receiving clomipramine.3,181,268
Micturition disorder1,35,65,248,250 occurred in about 14 or 4% of adults or children and adolescents, respectively, receiving clomipramine.1 Urinary tract infection1 and frequent micturition1 occurred in about 6 and 5%, respectively, of adults receiving the drug.1 Urinary retention1,195,226 occurred in about 2 or 7% of adults or children and adolescents, respectively, receiving clomipramine1 while dysuria,1 including painful urination in men,180 and cystitis1 have been reported in about 2% of adults receiving clomipramine.1
Dysmenorrhea has been reported in about 12 and 10% of adult and adolescent females, respectively, receiving clomipramine,1 and menstrual disorder (including irregular menstruation) has been reported in about 4% of adult females receiving the drug.1,3 Vaginitis1 and leukorrhea1 each occurred in about 2% of adult females receiving clomipramine therapy.1 Amenorrhea1,3,4,186 occurred in about 1% of adult females receiving clomipramine.1
Although not attributed definitely to the drug, endometriosis,1 epididymitis,1 hematuria,1 nocturia,1 oliguria,1 ovarian cyst,1 perineal pain,1 polyuria,1 prostatic disorder,1 urethral disorder,1 urinary incontinence,1 uterine hemorrhage,1 or vaginal hemorrhage1 has been reported in less than 1% of clomipramine-treated patients.1 Albuminuria,1 cervical dysplasia,1 endometrial hyperplasia,1 pyuria,1 uterine inflammation,1 and vulvar disorder1 have occurred rarely; however, a causal relationship to the drug has not been established.1
During premarketing evaluation, potentially clinically important elevations in serum ALT (SGOT)1,65 and AST (SGPT)1 concentrations exceeding 3 times the upper limit of normal were reported in approximately 1 and 3%, respectively, of patients receiving clomipramine.1 In most cases, these elevations in hepatic enzyme concentrations were not associated with other clinical findings suggestive of hepatic injury, and jaundice was not observed.1 Severe hepatic injury that was fatal in some cases has been reported rarely in foreign postmarketing experience.1 (See Cautions: Precautions and Contraindications.) Abnormal hepatic function1 and hepatitis1 have been reported in less than 1% of patients receiving clomipramine, although a causal relationship to the drug has not been established.1 Cross hepatotoxicity (e.g., elevated values on hepatic function tests, abdominal pain) involving different tricyclic antidepressants including clomipramine also has been reported.207
Hot flushes1,252 occurred in about 5% of adults and 2% of children and adolescents receiving clomipramine.1 Fever occurred in about 4% of adults and 2% of children and adolescents treated with the drug.1 Pain has been reported in about 3% of adults and 4% of children and adolescents receiving clomipramine therapy.1 Chills1 and local edema1 each occurred in about 2% of adults receiving the drug.1
Tooth disorder occurred in about 5% of clomipramine-treated adults,1,208 and dental caries1,208 has been reported in less than 1% of patients receiving the drug.1,208 Although the exact mechanism for these effects is unclear, it has been suggested that long-term therapy with clomipramine or other antidepressants with prominent anticholinergic activity can lead to dental caries through inhibition of saliva secretion.1,208
Elevations in serum prolactin concentrations have been reported following single and multiple doses of clomipramine.3 Nonpuerperal lactation1,3,4,186,187 has been reported in about 4% of adult females receiving clomipramine therapy.1 Breast enlargement1 and breast pain1 have been reported in about 2 and 1% of adult females, respectively, receiving the drug.1 Breast engorgement,1 breast fibroadenosis,1 and gynecomastia1 have been reported rarely in patients receiving clomipramine; however; these effects have not been attributed definitely to the drug.1
Lymphadenopathy1 has been reported in less than 1% of clomipramine-treated patients,1 and leukemoid reaction1 and lymphoma-like disorder1 have been reported rarely, although a causal relationship to the drug has not been established.1
Diabetes mellitus1 and hypothyroidism1 each have been reported in less than 1% of patients receiving clomipramine,1 and goiter1 and hyperthyroidism1 have been reported rarely; however, these effects have not been attributed definitely to the drug.1
Oliguria,1 renal calculus,1 and renal pain1 have been reported in less than 1% of patients receiving clomipramine, and pyelonephritis1 and renal cyst1 have been reported rarely; however, a causal relationship to the drug has not been established.1 Hyponatremia also has occurred with clomipramine.4,192
Precautions and Contraindications
Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Cautions: Pediatric Precautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants.348,349,350,354,355,356 This risk may persist until clinically important remission occurs.348,349,355,356 Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.348,349,350,355,356 However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.349,355,356 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.348,349,355 An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older.348,349,355 It currently is unknown whether the suicidality risk extends to longer-term use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression.348,349,355,356
The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.348,349,350,355,356 Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.349,350,355,356
Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.349,350,355,356 Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.349,355,356 If a decision is made to discontinue therapy, clomipramine dosage should be tapered as rapidly as is feasible but with recognition of the risks of abrupt discontinuance.349,355,356 (See Dosage and Administration.) FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.349,355,356
It is generally believed (though not established in controlled trials) that treating a major depressive episode with an antidepressant alone may increase the likelihood of precipitating a mixed or manic episode in patients at risk for bipolar disorder.349,355,356 Therefore, patients should be adequately screened for bipolar disorder prior to initiating treatment with an antidepressant; such screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, and depression).349,355,356 Clomipramine is not approved for use in treating bipolar depression.355,356
As with closely related tricyclic antidepressants, clomipramine should be used with caution in patients with concurrent cardiovascular disease; hyperthyroidism; increased intraocular pressure, a history of angle-closure glaucoma, or urinary retention; tumors of the adrenal medulla; clinically important renal impairment; or hepatic disease.1
In patients with cardiovascular disease, gradual dosage titration of clomipramine is recommended.1 In hyperthyroid patients or patients receiving thyroid agents, the possibility of cardiac toxicity also should be considered.1 The manufacturers state that clomipramine should be used with caution in patients with increased intraocular pressure, a history of angle-closure glaucoma, or urinary retention, since its anticholinergic effects may exacerbate these conditions.1,356 Caution also should be exercised in patients with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma), since hypertensive crises may be provoked by clomipramine.1
Clomipramine should be used with caution in patients with known hepatic disease, and the manufacturers recommend periodic monitoring of hepatic enzyme concentrations in such patients.1,356
A variety of neuropsychiatric manifestations, including delusions, hallucinations, psychotic episodes, confusion, and paranoia, have been reported in patients receiving clomipramine.1,3,155,156,238 (See Cautions: Nervous System Effects.) However, because of the uncontrolled design of many of these studies, it is not possible to provide a precise estimate of the extent of the risk of such effects in clomipramine-treated patients.1 In patients whose schizophrenia has been unrecognized, an acute psychotic episode may be precipitated by clomipramine or other antidepressants.1 Another possibility is that clomipramine, like other antidepressants, may precipitate mania or hypomania in patients with affective disorder.1,3,155,156,295
As with other tricyclic antidepressants, the development of fever and sore throat in any patient receiving clomipramine therapy should prompt the clinician to obtain leukocyte and differential blood cell counts.1 (See Cautions: Hematologic Effects.)
Male patients for whom clomipramine therapy is considered should be informed about the relatively high incidence of sexual dysfunction associated with the drug.1,3,180 Sexual dysfunction occurred in more males with obsessive-compulsive disorder treated with clomipramine than with placebo in premarketing experience.1,180 (See Cautions: Genitourinary Effects.)
As with closely related tricyclic antidepressants, the risks associated with electroconvulsive therapy (ECT) may be increased during concurrent clomipramine therapy.1,356 Because of the limited clinical experience to date, the manufacturers recommend that the combination of clomipramine and ECT be limited to those patients for whom it is essential.1,356
Prior to elective surgery with general anesthetics, the manufacturers state that clomipramine therapy should be discontinued for as long as is clinically feasible, and the anesthetist should be so advised.1,356
The withdrawal effects of clomipramine have not been systematically evaluated in controlled studies, although such effects have been reported following abrupt withdrawal of closely related tricyclic antidepressants.1 (See Cautions: Nervous System Effects and also see Chronic Toxicity in the Tricyclic Antidepressants General Statement 28:16.04.28.) Therefore, gradual tapering of clomipramine dosage and careful monitoring of the patient is recommended during discontinuance of clomipramine therapy.1
Clomipramine can produce somnolence and impaired concentration, and patients should be cautioned that the drug may impair the mental and/or physical abilities required for the performance of these complex tasks.1,244 Patients also should be cautioned about the use of alcohol, barbiturates, or other CNS depressants because the effects of these agents may be exaggerated during concurrent clomipramine therapy.1,243
The possibility of seizure is the most clinically important risk associated with clomipramine therapy (see Cautions: Nervous System Effects), and the drug should be used with caution in patients with a history of seizures or other predisposing factors (e.g., brain damage of various etiology, alcoholism, concurrent use of other drugs that lower the seizure threshold).1 The ability to predict the occurrence of seizures with daily doses exceeding 250 mg is limited because plasma concentrations may be dose dependent and may vary considerably among individuals administered the same dosage.1 Nevertheless, the manufacturers recommend limiting the daily dose of clomipramine to a maximum of 250 mg in adults or 3 mg/kg (up to 200 mg) in children and adolescents.1,356 Patients receiving clomipramine should be informed about the risk of seizures associated with the drug.1 In addition, physicians should discuss with patients the risk and the possibility of serious injury to themselves or other people resulting from sudden loss of consciousness while engaged in certain complex and hazardous activities (e.g., operation of complex machinery, driving a motor vehicle, swimming, climbing).1
Clomipramine is contraindicated in patients with known hypersensitivity to the drug or other tricyclic antidepressants.1 The drug also is contraindicated in patients currently receiving, or having recently received (i.e., within 2 weeks), monoamine oxidase (MAO) inhibitor therapy.1 (See Drugs Associated with Serotonin Syndrome: Monoamine Oxidase Inhibitors, under Drug Interactions.) Clomipramine also is contraindicated during the acute recovery phase following myocardial infarction.1
Safety and efficacy of clomipramine in children younger than 10 years of age have not been established.1,356 Therefore, the manufacturers state that no specific recommendations can be made for the use of the drug in this age group.1,356
Safe use of clomipramine in pediatric patients 10 years of age or older for the treatment of obsessive-compulsive disorder (OCD) is based on relatively short-term studies in this patient population and from extrapolation of experience gained with adult patients.1,356 The potential risks associated with long-term clomipramine therapy have not been systematically evaluated in children and adolescents.1,356 Although there is no evidence that the drug adversely affects growth, development, or maturation in these patients, the absence of such findings does not rule out a potential for such effects with long-term use.1,356
In a controlled study, clomipramine has been administered for up to 8 weeks to 46 children and adolescents 10-17 years of age.1,356 In addition, 150 adolescent patients have received clomipramine therapy for periods ranging from several months to several years in uncontrolled studies.1,356 Out of a total of 196 children and adolescents studied, 50 patients were 13 years of age or younger and 146 patients were 14-17 years of age.1,356 The adverse effect profile in this age group is similar to that observed in adults.1,356
FDA warns that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.348,349,350,355,356 The risk of suicidality for these drugs was identified in a pooled analysis of data from a total of 24 short-term (4-16 weeks), placebo-controlled studies of 9 antidepressants (i.e., bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine) in over 4400 children and adolescents with major depressive disorder, OCD, or other psychiatric disorders.348,349,355,356 The analysis revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in pediatric patients receiving antidepressants than in those receiving placebo.348,349,355,356 The average risk of such events was 4% among children and adolescents receiving these drugs, twice the risk (2%) that was observed among those receiving placebo.348,349,355,356 However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.354 No suicides occurred in these pediatric trials.348,349,354,355,356
The risk of suicidality in FDA's pooled analysis differed across the different psychiatric indications, with the highest incidence observed in the major depressive disorder studies.348,349,355,356 In addition, although there was considerable variation in risk among the antidepressants, a tendency toward an increase in suicidality risk in younger patients was found for almost all drugs studied.348,349,355,356 It is currently unknown whether the suicidality risk in pediatric patients extends to longer-term use (i.e., beyond several months).348,349,355,356
As a result of this analysis and public discussion of the issue, FDA has directed manufacturers of all antidepressants to add a boxed warning to the labeling of their products to alert clinicians of this suicidality risk in children and adolescents and to recommend appropriate monitoring and close observation of patients receiving these agents.348,349,355,356 (See Cautions: Precautions and Contraindications.) The drugs that are the focus of the revised labeling are all drugs included in the general class of antidepressants, including those that have not been studied in controlled clinical trials in pediatric patients, since the available data are not adequate to exclude any single antidepressant from an increased risk.348,349,352 In addition to the boxed warning and other information in professional labeling on antidepressants, FDA currently recommends that a patient medication guide explaining the risks associated with the drugs be provided to the patient each time the drugs are dispensed.348,349,350
Anyone considering the use of clomipramine in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.349,350,354,355,356
The manufacturers state that clinical studies with clomipramine did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger patients.355,356 No unusual age-related adverse effects were identified in 152 patients at least 60 years of age participating in US clinical studies who received the drug for periods of several months to several years.355,356 In addition, other clinical experience revealed no evidence of age-related differences in response to clomipramine.355,356
In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.348,349,355,356 (See Cautions: Precautions and Contraindications.)
Clomipramine is eliminated more slowly in geriatric patients.1,41,240,355,356 In addition, older patients may not tolerate the drug's adverse effects as well as younger patients.1,41,42,240 The manufacturers and some clinicians recommend cautiously selecting a clomipramine dosage regimen in geriatric patients, usually starting at the lower end of the recommended dosage range, since decreased hepatic, renal, or cardiac function and concomitant illnesses and medications are more frequent in this population.2,4,272,282,355,356
Mutagenicity and Carcinogenicity
No clear evidence of carcinogenicity was seen in rats receiving oral clomipramine hydrochloride dosages of 20 times the maximum recommended human daily dosage in a 2-year bioassay.1 Hemangioendothelioma was observed in 3 out of 235 rats administered clomipramine;1 the relationship between this rare tumor and the drug is not known.1
Pregnancy, Fertility, and Lactation
Teratogenic effects were not observed in rats and mice receiving clomipramine hydrochloride dosages up to 20 times the maximum human daily dosage.1 Slight, nonspecific fetotoxic effects were observed in the offspring of pregnant mice receiving 10 times the maximum human daily dosage.1 Slight, nonspecific embryotoxicity occurred in rats receiving 5-10 times the maximum human daily dosage.1
There are no adequate and controlled studies using clomipramine in pregnant women, and the drug should be used during pregnancy only if the possible benefits justify the potential risk to the fetus.1 Women should be advised to notify their physician if they are or plan to become pregnant during clomipramine therapy.1 Neonates whose mothers had received clomipramine throughout pregnancy in dosages of 75-250 mg daily have exhibited withdrawal manifestations or adverse effects, including jitteriness,1,71,152,158 tremor,1,71,153,154 seizures,1,3,152,153 twitching,153,154 hypertonia,152,153,154 hypotonia,71,153,154 tachypnea,71,153,154 respiratory acidosis,154 cyanosis,153,154 feeding difficulties,153,154 hypothermia,153,154,158 lethargy,153,154 and diaphoresis.153 Phenobarbital has been recommended by some clinicians for the management of neurologic withdrawal symptoms.153 Abrupt discontinuance of clomipramine at 32 weeks of pregnancy resulted in premature birth of a neonate who developed seizures soon after delivery.169 Because of the risk of neonatal withdrawal, some clinicians state that clomipramine therapy particularly should be avoided during late pregnancy.153
Reproduction studies in rats using clomipramine hydrochloride dosages approximately 5 times the maximum human daily dosage have not revealed evidence of impaired fertility.1
Clomipramine is distributed into milk.1,4,22,55,60,62,71,150 (See Pharmacokinetics: Distribution.) Adverse effects were absent in an infant who was breast-feeding from a woman who continued treatment with clomipramine at a dosage of 150 mg daily.71,150 However, because of the potential for adverse reactions, including concern about the potential for tricyclic antidepressants to affect development of the CNS of infants, a decision should be made whether to discontinue nursing or clomipramine, taking into account the importance of the drug to the woman.1,62,149,150,151 Women should be advised to notify their physician if they are breast-feeding.1
Because of the similarity of clomipramine to other tricyclic antidepressants, all drug interactions that may occur with this class of drugs should be considered when clomipramine is used.2,159 (See Drug Interactions in the Tricyclic Antidepressants General Statement 28:16.04.28.) In addition, the possibility that clomipramine may interact with any concomitantly administered drug has not been evaluated systematically but should be considered.1
Drugs Associated with Serotonin Syndrome
Use of clomipramine concurrently or in close succession with other serotonergic drugs may result in serotonin syndrome.175,302,303 Although the syndrome appears to be relatively uncommon and usually mild in severity, serious complications, including seizures, disseminated intravascular coagulation, respiratory failure, severe hyperthermia, and death occasionally have been reported.175,302,303,304,306
The syndrome most commonly occurs when 2 or more serotonergic agents with different mechanisms of action are administered either concurrently or in close succession.175,302,303,304,306 Serotonergic agents include those that increase serotonin synthesis (e.g., the serotonin precursor tryptophan),302,304,306 stimulate synaptic serotonin release (e.g., some amphetamines, dexflenfluramine, fenfluramine),303,304 inhibit the reuptake of serotonin after release (e.g., selective serotonin-reuptake inhibitors, tricyclic antidepressants, trazodone, dextromethorphan, meperidine, tramadol),303,304,306 decrease the metabolism of serotonin (e.g., monoamine oxidase [MAO] inhibitors),303,304,306 have direct serotonin postsynaptic receptor activity (e.g., buspirone),303,304 or nonspecifically induce increases in serotonergic neuronal activity (e.g., lithium salts).303,304,306
The combination of selective serotonin-reuptake inhibitors and MAO inhibitors appears to be responsible for most of the recent case reports of serotonin syndrome.175,302,303,306 The syndrome also has been reported when MAO inhibitors have been combined with tricyclic antidepressants such as clomipramine,303,306 tryptophan,175,306 meperidine,303,306 or dextromethorphan.302,303,306 In rare cases, the serotonin syndrome reportedly has occurred with the recommended dosage of a single serotonergic agent (e.g., clomipramine)303,306 or during accidental overdosage (e.g., sertraline intoxication in a child).303,306 Some other drugs that have been implicated in certain circumstances include buspirone, bromocriptine, dextropropoxyphene, methylenedioxymethamphetamine (MDMA; ecstasy), selegiline (a selective MAO-B inhibitor), and sumatriptan.306,308 Other drugs that have been associated with the syndrome but for which less convincing data are available include carbamazepine, fentanyl, and pentazocine.306
Clinicians should be aware of the potential for serious, possibly fatal reactions associated with the serotonin syndrome in patients receiving 2 or more drugs that increase the availability of serotonin in the CNS, even if no such interactions with the specific drugs have been reported to date in the medical literature.302 Pending further accumulation of data, all drugs with serotonergic activity should be used cautiously in combination and such combinations avoided whenever clinically possible.302 Some clinicians state that patients who have experienced serotonin syndrome may be at higher risk for recurrence of the syndrome upon reinitiation of serotonergic drugs.303 Pending further experience in such cases, some clinicians recommend that therapy with serotonergic agents be limited following recovery.303 In cases in which the potential benefit of the drug is thought to outweigh the risk of serotonin syndrome, lower potency agents and reduced dosages should be used, combination serotonergic therapy should be avoided, and patients should be monitored carefully for symptoms of serotonin syndrome.303
For further information on serotonin syndrome, including manifestations and treatment, see Serotonin Syndrome under Drug Interactions: Drugs associated with Serotonin Syndrome, in Fluoxetine Hydrochloride 28:16.04.20.
Concomitant administration of clomipramine and MAO inhibitors is contraindicated, and at least 2 weeks elapse between discontinuance of clomipramine therapy and initiation of MAO inhibitor therapy and vice versa.1 Concomitant administration of clomipramine and an MAO inhibitor is potentially hazardous and may result in severe adverse effects associated with serotonin syndrome such as hyperpyrexia,1,160,172,173 seizures,1,159,177 and coma.1,2,159,160,172 Other adverse effects that have occurred with this combination of drugs include confusion,2,160,177 agitation,2,160 myoclonus,172,177 tremor,173 diaphoresis,160 shivering,160 rigors,172 rigidity,2,160,172 hypotension,2,159,160 tachycardia,2,160 cardiac arrhythmia,159 and disseminated intravascular coagulation.2,160 Some reactions occurring in patients receiving clomipramine and an MAO inhibitor have been fatal.1,2,159,160
Clonus, hyperreflexia, tremor, rigidity, and diaphoresis were observed in some patients after administration of clomipramine about 1 month after discontinuance of a selective inhibitor of monoamine oxidase-A.3,33,175,176 Status epilepticus developed in a patient after treatment with clomipramine was started approximately 24 hours after discontinuance of phenelzine sulfate.2,3,161 Although the mechanism has not been clearly established, the reactions resemble serotonin syndrome and may be caused by excessive serotonergic activity in the CNS.175
Concurrent administration of clomipramine and other serotonergic drugs (e.g., lithium, alprazolam) has resulted in the development of adverse effects similar to those reported with the combination of clomipramine and an MAO inhibitor and which resemble the serotonin syndrome.174,178
Concurrent administration of clomipramine and fluoxetine has resulted in seizures.170 Concurrent administration of clomipramine and fluvoxamine has resulted in a severalfold elevation of the plasma clomipramine concentration.171
Like other tricyclic antidepressants, clomipramine may be additive with or may potentiate the action of other CNS depressants such as alcohol and barbiturates.1 In addition, concomitant administration of clomipramine with phenobarbital reportedly resulted in an increase in the plasma concentration of phenobarbital.1
Drugs Affecting the Seizure Threshold
Caution should be observed with concurrent administration of clomipramine and drugs (e.g., other antidepressants, antipsychotic agents) that lower the seizure threshold.1 (See Cautions: Nervous System Effects.)
Concomitant administration of clomipramine with haloperidol reportedly resulted in increases in the plasma concentrations of clomipramine, presumably because of haloperidol-induced inhibition of clomipramine metabolism.1,2
The initiation of clomipramine therapy in a patient with a seizure disorder that was well controlled by valproic acid resulted in status epilepticus.298 The serum clomipramine concentration at the time of the seizures was elevated despite the relatively small dosage of clomipramine received (75 mg daily for 12 days).298 Although the mechanism has not been established clearly, it was suggested that valproic acid may have inhibited the metabolism and/or elimination of clomipramine.298 Pending further experience, it should be kept in mind that elevated serum concentrations of clomipramine and possibly its metabolites may occur when clomipramine and valproic acid are used concomitantly and that these changes may precipitate seizures in predisposed individuals.298
The risks associated with concurrent administration of clomipramine and other CNS-active agents have not been fully evaluated to date; therefore, caution should be exercised when such agents are administered concomitantly.1
Limited data suggest that oral contraceptives do not interfere with the therapeutic effects of clomipramine.159 No difference in adverse effects or depression was observed in patients receiving clomipramine and oral contraceptives compared with those receiving clomipramine alone in one study.2,159 However, the clomipramine dosage given (25 mg daily) was lower than those commonly used in the treatment of obsessive-compulsive disorder or depression.2 Further study to confirm the safety and efficacy of combined clomipramine and oral contraceptive therapy is necessary.159
Substantially lower plasma clomipramine concentrations have been reported in cigarette smokers receiving clomipramine when compared with nonsmokers.1,2,41,55,60 The presumed mechanism appears to be induction of clomipramine metabolism by nicotine or other substances present in cigarette smoke.2,41,55,60
Clomipramine and its active metabolite, desmethylclomipramine, are highly protein bound;1,2,4,26,29,55,56 therefore, they theoretically could be displaced from binding sites by or could displace from binding sites other protein-bound drugs such as oral anticoagulants (e.g., warfarin) and digoxin.1,2 Pending further accumulation of data, patients receiving clomipramine with any highly protein-bound drug should be observed for potential adverse effects associated with combined therapy.1,2
Concomitant use of clomipramine with anticholinergic or sympathomimetic drugs requires close supervision and careful adjustment of the dosage of clomipramine because of potential additive effects.1,2
Consideration of the structural similarity of clomipramine with other tricyclic antidepressants would suggest that blockade of the pharmacologic effects (such as hypotension) and possibly the adverse effects of guanethidine, clonidine, or other similar hypotensive agents, as has been reported with several other tricyclic antidepressants, may be anticipated with clomipramine.1,2,159
The plasma concentrations of several tricyclic antidepressants closely related to clomipramine reportedly were increased with concomitant administration of methylphenidate or drugs that inhibit hepatic microsomal enzyme systems (e.g., cimetidine, fluoxetine) and were decreased with concomitant administration of drugs that induce hepatic microsomal enzymes (e.g., barbiturates, phenytoin).1,159 Such effects also may be anticipated with clomipramine.1,159
Limited information is available on the acute toxicity of clomipramine.1
Postmarketing reports from the UK suggest that clomipramine overdosage results in lethality similar to that reported for other closely related tricyclic antidepressants.1
In 10 out of 12 patients who overdosed on clomipramine taken alone or with other drugs during US clinical studies, complete recovery occurred with overdosages of up to 5 g that produced plasma concentrations of up to 1010 ng/mL.1 In the 2 remaining patients, who were suspected of ingesting overdosages of 7 g and 5.75 g, death occurred.1 Other fatalities have been reported after overdosages of clomipramine were ingested.4,145,146,147 The lowest dosage of clomipramine associated with fatality outside of the US is 750 mg.1
Overdosage with clomipramine produces signs and symptoms similar to that with other tricyclic antidepressants.1,2,144 (See Acute Toxicity: Manifestations, in the Tricyclic Antidepressants General Statement 28:16.04.28.) Acute pancreatitis accompanied by prolonged ileus has occurred following an overdose of clomipramine in one patient.167
The signs and symptoms of clomipramine overdosage vary in severity depending on a number of factors, including the amount of drug absorbed, the patient's age, and the amount of time elapsed since ingestion.1 Plasma concentrations of clomipramine should not guide management of the patient.1 However, they may be of qualitative value when the diagnosis is not clear.168,266 In addition, evidence from one patient who experienced biphasic absorption (delayed) and elimination of clomipramine in which, after an initial decline, the serum concentration of clomipramine and desmethylclomipramine increased to a peak and declined subsequently, suggests that monitoring such concentrations until the patient is stable may be of diagnostic benefit, since manifestations of severe toxicity and the need for aggressive management also were biphasic, recurring 3-4 days after the initial toxic episode.266 Although clomipramine and desmethylclomipramine have low cross-reactivity266,346 (e.g., 40-50% to antibody for clomipramine at concentrations of 189-472 ng/mL) with a fluorescent polarization immunoassay (FPIA) for tricyclic antidepressants,266 clomipramine concentrations of 100 ng/mL are detectable by the assay,346 and therefore this nonspecific assay may still be useful in diagnosing overdosage with the drug.266,346
For information on the management of tricyclic antidepressant overdosage, see Acute Toxicity: Treatment, in the Tricyclic Antidepressants General Statement 28:16.04.28. In addition, clinicians should consult a poison control center for current information about therapy for overdoses of tricyclic antidepressants because such treatment is complex and changeable.1
Clomipramine has not been evaluated systematically in animals or humans to determine its potential for abuse, tolerance, or physical dependence.1 Although discontinuance of therapy has been associated with a variety of withdrawal manifestations (see Cautions: Nervous System Effects), there is no evidence of drug-seeking behavior, except for one patient with a history of dependence on codeine, benzodiazepines, and multiple psychoactive drugs.1 This patient received clomipramine for depression and panic attacks and appeared to become dependent on the drug after hospital discharge.1
Although foreign clinical experience has not revealed substantial evidence for abuse potential with clomipramine, it is impossible to predict the extent to which the drug may be misused or abused.1 Because of such uncertainty, clinicians should carefully evaluate patients for a history of substance abuse and such patients who receive clomipramine should be monitored closely.1
The pharmacology of clomipramine is complex and in many ways resembles that of other antidepressants, particularly those agents (e.g., selective serotonin-reuptake inhibitors, trazodone) that predominantly potentiate the pharmacologic effects of serotonin (5-HT).2,3,4,212,213,214,220,221 Although clomipramine's principal pharmacologic effect in vitro is the selective inhibition of serotonin reuptake, in vivo the drug's pharmacologic activity is not so selective because of the action of its demethylated metabolite, desmethylclomipramine, as an inhibitor of norepinephrine reuptake.2,3,4,48,212,213,214,220,221,235 As a result of this and other effects, clomipramine also shares the pharmacologic profile of other tricyclic antidepressants.235,238
The precise mechanism of action that is responsible for the efficacy of clomipramine in the treatment of obsessive-compulsive disorder is unclear.1,2,3,213,214,220 However, because of its pronounced potency in blocking serotonin reuptake at the presynaptic neuronal membrane and its efficacy in the treatment of obsessive-compulsive disorder, a serotonin hypothesis has been developed to explain the pathogenesis of the condition.1,2,3,4,213,214,220 The hypothesis postulates that a dysregulation of serotonin is responsible for obsessive-compulsive disorder and that clomipramine is effective because it corrects this imbalance.1,2,3,213,214,220 The potency of clomipramine relative to other tricyclic antidepressants as a serotonin-reuptake inhibitor and its superiority in obsessive-compulsive disorder provide additional support to this hypothesis.65 Although the available evidence supports the serotonergic hypothesis of obsessive-compulsive disorder (see Pharmacology: Serotonergic Effects), additional studies are necessary to confirm this hypothesis.1,2,3,213,214,220
Like other tricyclic antidepressants, the exact mechanism of clomipramine's antidepressant action is unclear.2,3,221,235 Clomipramine and its principal metabolite, desmethylclomipramine, have been shown to block the reuptake of serotonin and norepinephrine, respectively, at the presynaptic neuronal membrane.2,3,4,48,220,221,235 The effects of serotonin and norepinephrine may thus be potentiated.2,3,4,48,220,221,235 However, it has been suggested that postsynaptic receptor modification is mainly responsible for the antidepressant action observed during long-term administration of antidepressant agents.3,235,311,312,313,314,315,316,317,318,319,320,321,322,323 During long-term therapy with most antidepressants (e.g., tricyclic antidepressants, monoamine oxidase [MAO] inhibitors), these adaptive changes generally consist of subsensitivity of the noradrenergic adenylate cyclase system in association with a decrease in the number of β-adrenergic receptors; such effects on noradrenergic receptor function commonly are referred to as down-regulation.3,312,314,315,316,317,318,319,320,323 In addition, some antidepressants reportedly decrease the number of 5-HT binding sites following chronic administration.235,316,320,322,323,324
Like other tricyclic antidepressants, clomipramine may produce sedation.1,65,238,242 The drug also may lower the seizure threshold, particularly at relatively high dosages.1,210 (See Cautions: Nervous System Effects.)
Clomipramine is a potent and somewhat selective inhibitor of serotonin reuptake at the presynaptic neuronal membrane.2,3,48,214,220,221,235 Clomipramine-induced inhibition of serotonin reuptake causes increased synaptic concentrations of the neurotransmitter, resulting in numerous functional changes associated with enhanced serotonergic neurotransmission.214,220
Clomipramine is the most potent inhibitor of serotonin reuptake among currently available tricyclic antidepressants.2,3,4,220,221 Data from in vitro studies suggest that clomipramine is approximately equivalent to325,326 or more potent than327 fluoxetine as a serotonin-reuptake inhibitor; however, in vivo studies indicate that the serotonin-reuptake inhibiting effect of fluoxetine may be more potent than that of clomipramine on a weight313,329,330 as well as an equimolar basis.328 This apparent discrepancy may be explained at least in part by the relatively long elimination half-lives of fluoxetine and its principal metabolite, norfluoxetine.311,325,326,329,330 In addition, metabolism by N -demethylation decreases the potency and specificity of serotonin-reuptake inhibition by clomipramine but not fluoxetine.214,313,325,326,329,330
Clomipramine appears to decrease the turnover of serotonin in the CNS, probably as a result of a decrease in the release and/or synthesis of serotonin.2,34,218,219,220 Several studies have investigated the effects of clomipramine on serotonin concentrations in patients with obsessive-compulsive disorder.2,4,29,34,214,217,218,219 The concentration of serotonin in platelets has been shown to be substantially lower in patients with obsessive-compulsive disorder treated with the drug,4,29,214,217 and this decrease has been shown to correlate with clinical improvement in obsessive-compulsive manifestations in these patients.4,214
Clomipramine reportedly decreases the concentration of 5-hydroxyindoleacetic acid (5-HIAA), the principal metabolite of serotonin, in the CSF of patients with obsessive-compulsive disorder2,4,34,218,219 or depression.4,221 Limited data suggest a possible relationship between improvement of obsessive-compulsive manifestations and decreased concentrations of 5-HIAA in the CSF.4,29,34,219
Manifestations of obsessive-compulsive disorder worsened after administration of a serotonin agonist, metachlorophenylpiperazine (mCPP), compared with placebo.2,29,212 Manifestations of obsessive-compulsive disorder also appeared to worsen after administration of a nonselective serotonin antagonist, metergoline, compared with placebo in patients receiving clomipramine.2,213 In contrast, such exacerbation was not observed with administration of mCPP in patients treated with clomipramine for several weeks or longer.212 If obsessive-compulsive disorder is related to increased serotonergic responsiveness, then these data suggest that clomipramine's efficacy following long-term administration may be related to induction of subsensitivity in the serotonergic system; such an effect has been referred to as down-regulation of serotonin receptors.2,4,212
Effects on Other Neurotransmitters
Clomipramine's principal metabolite, desmethylclomipramine, is an inhibitor of norepinephrine reuptake.2,4,220 Clomipramine decreases the concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG), a metabolite of norepinephrine, in CSF in patients with obsessive-compulsive disorder.2,34,218 Patients with depressive affective (mood) disorders (e.g., major depressive episode) also exhibit decreases in concentrations of 5-HIAA and MHPG in CSF during treatment with clomipramine.2,48,220,221 The decrease in the concentration of 5-HIAA in CSF was correlated with inhibition of the in vitro uptake of 3H-serotonin in plasma.2,220 The change in concentration of MHPG in CSF during clomipramine therapy was correlated with amelioration of depression.48
Preliminary evidence suggests that clomipramine may inhibit dopaminergic activity.2,331,336,337 Unlike many other antidepressants, clomipramine exhibited extensive binding to postsynaptic receptors of dopamine antagonists (3H-spiroperidol) in vitro.2,336 In animals, dopamine antagonism has been demonstrated by clomipramine's ability to reduce apomorphine-induced behavioral stereotypy.2,336,337 The drug also increases the CSF concentration of the dopamine metabolite homovanillic acid secondary to increased dopamine turnover.2,34,218,331 Because obsessive-compulsive disorder is common in patients with certain disorders of dopamine regulation (e.g., Sydenham's chorea, Tourette's disorder [Gilles de la Tourette's syndrome]), additional studies are needed to determine whether these initial findings are clinically important.2 (See Uses: Obsessive-Compulsive Disorder.)
Like other tricyclic antidepressants, clomipramine binds to cholinergic receptors and exhibits marked anticholinergic activity.3,4,288,289 As a result, clomipramine therapy may cause adverse effects commonly associated with blockade of muscarinic cholinergic receptors (e.g., dry mouth, blurred vision, urinary retention, constipation, confusion).3,4,288,289 In addition, clomipramine binds to α1-adrenergic and histaminergic receptors and consequently exhibits α1-adrenergic blocking and antihistaminic activity at usual therapeutic dosages.3,4 The drug also has been shown to bind to α2-adrenoceptors and opiate receptors.3
Brain imaging studies using positron emission tomography (PET) have demonstrated metabolic abnormalities (usually hypermetabolism) in certain regions of the brain (including the orbitofrontal cortex, caudate nucleus, and prefrontal gyri) in patients with obsessive-compulsive disorder.215,216,332,333,334,335 Clomipramine appears to produce a return of metabolism to a more normal level in the regions of the brain that may be involved in the pathology of obsessive-compulsive disorder (orbitofrontal cortex and the caudate nucleus).215,216 For example, the metabolic rate of glucose was decreased in regions of the orbitofrontal cortex and the left caudate nucleus and was increased in other areas of the basal ganglia, including the right anterior putamen, in patients with obsessive-compulsive disorder treated with clomipramine compared with pretreatment measurements.215
Other limited data suggest a relationship between decreases in the metabolic rate of glucose in the orbitofrontal cortex and the efficacy of clomipramine in obsessive-compulsive disorder.216 The decrease from baseline in the metabolic rate of glucose in the left orbitofrontal region was greater in patients whose obsessive-compulsive symptoms improved during clomipramine or fluoxetine therapy than in nonresponders to such therapy.216 In these patients, the decrease from baseline in the metabolic rate of glucose in the right orbitofrontal region was correlated with improvement in the manifestations of obsessive-compulsive disorder.216
Like tricyclic and most other antidepressants, clomipramine suppresses rapid eye movement (REM) sleep.2,279,338 The drug appears to be the most potent suppressor of REM sleep in the tricyclic antidepressant class.2,279 The REM-suppressing effect may be sustained following discontinuance of clomipramine therapy, and chronic therapy leads to substantial REM rebound upon withdrawal of the drug.2,338
Clomipramine shares the cardiovascular effects of other tricyclic antidepressants (see Pharmacology in the Tricyclic Antidepressants General Statement 28:16.04.24) and may produce ECG changes (e.g., increases from baseline in QRS duration, QT interval corrected for rate [QTc], and QRS axis; inversion or flattening of the T waves), cardiac arrhythmias, tachycardia, and postural hypotension.1,2,193,222,235,339
Clomipramine affects the endocrine system.2,4,213,218,223,224,340 IV administration of clomipramine produced a dose-related increase in plasma prolactin and corticotropin (ACTH) concentrations in healthy individuals; an increase in the plasma cortisol concentration also was observed.223 Patients with depressive affective (mood) disorders (e.g., major depressive episode) also exhibited increases in plasma prolactin, ACTH, and cortisol concentrations following IV administration of clomipramine; however, the increase in plasma prolactin noted in patients with a major depressive episode was less than in nondepressed individuals.224 Clomipramine-induced increases in prolactin secretion appear to be serotonergically mediated.2,212,213,224
Clomipramine appears to affect the CSF concentration of neuropeptides that are elevated in patients with obsessive-compulsive disorder.218 The concentrations of such neuropeptides (e.g., corticotropin-releasing hormone, vasopressin) are decreased during long-term (e.g., 20 months) therapy with the drug.218 In addition, an increase in the CSF concentration, corrected for age, of oxytocin has been observed.218
For further information on the pharmacology of clomipramine, see Pharmacology in the Tricyclic Antidepressants General Statement 28:16.04.24.
In all human studies described in the Pharmacokinetics section, clomipramine was administered as the hydrochloride salt.
Clomipramine hydrochloride appears to be well absorbed from the GI tract following oral administration.2,3,4,5,10,55 However, extensive first-pass metabolism decreases its oral bioavailability to about 50%.1,2,25,55 The oral capsules and solution of clomipramine hydrochloride reportedly are bioequivalent.1,24 Food does not appear to substantially affect the bioavailability of clomipramine from the capsules.1,29
Peak plasma clomipramine concentrations of approximately 56-154 ng/mL (mean: 92 ng/mL) usually occur within 2-6 hours (mean: 4.7 hours) following oral administration of a single 50-mg dose of clomipramine hydrochloride.1,10,11,12,25,29 Like other tricyclic antidepressants, clomipramine exhibits considerable interindividual variation in plasma concentrations achieved with a given dose due, at least in part, to genetic differences in the metabolism of the drug.18,23,38 (See Pharmacokinetics: Elimination.)
Following multiple-dose oral administration of clomipramine, steady-state plasma concentrations of the drug generally are achieved within about 1-2 weeks.1,2,6,7,9,13,23,55 Steady-state plasma desmethylclomipramine (the principal metabolite) concentrations may be achieved at about the same time as steady-state plasma clomipramine concentrations or later.1,2,4,6,7,14,23,27 In some cases, plasma desmethylclomipramine concentrations have been observed to continue to increase during 4-6 weeks of administration of a constant dosage of clomipramine hydrochloride.9,12,28,45,51,54,55 Plasma concentrations of desmethylclomipramine generally exceed those of the parent drug following multiple daily dosing of clomipramine hydrochloride.1,6,7,10,12,13,14,15,16,17,18,23,54,60
The manufacturers state that, after multiple daily dosing of clomipramine hydrochloride 150 mg, the accumulation factors for clomipramine and desmethylclomipramine are approximately 2.5 and 4.6, respectively.1,356 However, it may take 2 weeks or more to achieve this extent of accumulation at a constant dosage because of the relatively long elimination half-lives of clomipramine and desmethylclomipramine.1 At steady state, peak plasma concentrations of 94-339 (mean: 218) and 134-532 (mean: 274) ng/mL of clomipramine and desmethylclomipramine, respectively, were attained following multiple daily doses of 150 mg of clomipramine hydrochloride.1 Pharmacokinetic data in patients receiving clomipramine hydrochloride dosages ranging from 150-250 mg daily are lacking.1
In a dose-proportionality study involving multiple dosing, steady-state plasma concentrations and the areas under the plasma concentration-time curve (AUCs) of clomipramine and desmethylclomipramine were not proportional to dose at dosages ranging from 25-150 mg daily.1 However, at dosages ranging from 100-150 mg daily there was an approximately linear relationship between these variables and dose.1 The manufacturers state that the relationship between dose and plasma clomipramine or desmethylclomipramine concentrations has not been systematically evaluated at higher dosages.1,356 However, if there is a substantial dose dependency at dosages exceeding 150 mg daily, the potential exists for dramatically higher steady-state plasma concentrations and AUCs of clomipramine and desmethylclomipramine even in patients receiving dosages within the recommended range.1 Such an effect may pose a potential risk in some patients.1 (See Cautions: Precautions and Contraindications.)
The effect of age on plasma concentrations of clomipramine and desmethylclomipramine is not fully known.60 However, substantially lower plasma concentrations of clomipramine and desmethylclomipramine have been reported in younger adults (18-40 years of age) compared with those obtained in individuals older than 65 years of age.1,41,60 Children younger than 15 years of age also had substantially lower plasma concentration-dose ratios of clomipramine when compared with adults.1,43 In addition, clomipramine appears to be better tolerated in younger than in older patients.1,41,42
Substantially lower steady-state plasma clomipramine concentrations have been reported in smokers when compared with nonsmokers.1,41,55,60 However, smoking appears to have less effect on plasma concentrations of desmethylclomipramine.60
The relationship between plasma clomipramine and desmethylclomipramine concentrations and the therapeutic and/or toxic effects of the drug has not been clearly established.2,3,4,13,23,29,30,31,32,33,34,35,36,37,38,39,43,44,45,46,47,48,49,50,51,52,55,56,60 The results of studies involving plasma concentration monitoring in patients with obsessive-compulsive disorder and/or depression have been equivocal.2,3,4,13,23,29,30,31,32,33,34,35,36,37,38,39,43,44,45,46,47,48,49,50,51,52,55,56,60 In some studies, the sum of plasma clomipramine and desmethylclomipramine concentrations has been used as the drug concentration.56,60 In depressed patients, preliminary evidence suggests that lower plasma concentrations of clomipramine plus desmethylclomipramine (less than 150 ng/mL) are associated with nonresponse while higher concentrations (exceeding 450 ng/mL) may be associated with an increased risk of adverse effects and perhaps nonresponse.55,60 In patients with obsessive-compulsive disorder, the results of 2 studies in which a relationship between plasma concentration and therapeutic response was found suggested that optimal therapeutic response may be obtained in patients with plasma clomipramine concentrations ranging from 100-250 ng/mL and plasma desmethylclomipramine concentrations ranging from 230-550 ng/mL. 2,31,60
Distribution of clomipramine and its metabolites into human body tissues and fluids has not been fully characterized. However, both clomipramine and desmethylclomipramine are highly lipophilic and are widely distributed in body tissues, with moderate to high concentrations occurring in organs such as the lungs, adrenals, kidneys, heart, and brain.1,3,5,10,53 The apparent volume of distribution of clomipramine in healthy adults averages 17 L/kg (range: 9-25 L/kg).3,25,55
Both clomipramine and desmethylclomipramine cross the blood-brain barrier; the manufacturers state that desmethylclomipramine is distributed into CSF at a concentration about 2.6 times higher than in plasma.1,356 However, in one study of patients with depression or obsessive-compulsive disorder, the concentration of desmethylclomipramine in CSF was 2.6% that of the plasma concentration, corresponding to the fraction of desmethylclomipramine not bound to plasma proteins.26
Clomipramine is approximately 97-98% bound to plasma proteins, principally to albumin and possibly to α1-acid glycoprotein (α1-AGP).1,2,4,29,55,56 The extent of protein binding of clomipramine appears to be independent of plasma concentration.1 Desmethylclomipramine is approximately 97-99% bound to plasma proteins.26 Because protein binding of both clomipramine and desmethylclomipramine is extensive, the manufacturers state that, while the possibility that clomipramine interacts with other highly protein-bound drugs has not been fully evaluated, such interactions may be important.1,356 (See Drug Interactions: Protein-bound Drugs.)
Clomipramine crosses the placenta and also is distributed into human milk.1,4,22,55,60,62,71 In one case report, plasma clomipramine concentrations were measured in an infant whose mother was receiving clomipramine hydrochloride 125 mg daily during pregnancy.71 The plasma clomipramine concentration in the infant was 267 ng/mL at birth; subsequently, the plasma concentration in the infant decreased although nursing began 7 days after delivery and continued.71 After the first week postpartum, the mother's dosage of clomipramine hydrochloride was increased to 150 mg daily and the concentration of clomipramine in milk was 80-160% of the concurrent plasma clomipramine concentration at steady state.71 The infant's plasma concentration of clomipramine was at the limit of detection (9.8 ng/mL) 35 days postpartum.71 Serum concentrations of clomipramine and its metabolites (i.e., desmethylclomipramine, 8-hydroxyclomipramine, 8-hydroxydesmethylclomipramine) were not observed or were below the limit of detection in a limited number of healthy, full-term neonates and infants who were breast-fed by mothers whose only medication was clomipramine administered at a constant dosage for at least 3 weeks.62
Evidence that the steady-state plasma concentrations and AUCs of clomipramine and desmethylclomipramine may increase disproportionately with increasing oral doses of the drug suggests that the metabolism of clomipramine and desmethylclomipramine may be capacity-limited (saturable).1,8,55 The manufacturers caution that this fact should be considered when evaluating the available data concerning the pharmacokinetic parameters of clomipramine as these data often were obtained in individuals receiving 150-mg daily doses.1,356 If clomipramine and desmethylclomipramine exhibit nonlinear pharmacokinetics at dosages exceeding 150 mg daily, their elimination half-lives may be considerably prolonged at dosages near the upper limit of the recommended dosage range (i.e., 200-250 mg daily).1,8 At such dosages, clomipramine and desmethylclomipramine may accumulate, which may increase the incidence of any dose- or plasma concentration-dependent adverse effects, particularly seizures.1,8
The elimination half-life of clomipramine averages approximately 32 hours (range: 19-37 hours) and that of desmethylclomipramine averages about 69 hours (range: 54-77 hours) following a single, 150-mg oral dose of the drug.1,40
The exact metabolic fate of clomipramine has not been fully elucidated. Clomipramine appears to be extensively metabolized to desmethylclomipramine and other metabolites and their glucuronide conjugates.1,2,3,4,5,19,20,55,61,72,73 Desmethylclomipramine, the principal metabolite, is formed by N -demethylation of clomipramine.3,5,55 Other metabolites of clomipramine include 8-hydroxyclomipramine, 2-hydroxyclomipramine, and clomipramine N -oxide, which appear to be formed via 8-hydroxylation, 2-hydroxylation, and N -oxidation, respectively.19,72,73 The metabolites of desmethylclomipramine include 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which apparently are formed via 8-hydroxylation and N -demethylation, respectively.72 Although desmethylclomipramine is pharmacologically active, its efficacy in obsessive-compulsive disorder is not known.1 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine also are pharmacologically active but the clinical importance of their presence remains unknown.2,3,19,55
The hydroxylation of clomipramine and desmethylclomipramine appears to be under genetic control (similar to that of debrisoquine and sparteine).55,57,63,236 In healthy adults who were phenotyped for debrisoquine hydroxylation, extensive metabolizers were distinguishable from poor metabolizers with regard to the extent of hydroxylation of desmethylclomipramine.57 Blood concentrations of desmethylclomipramine were higher than expected in a limited number of patients who subsequently were found to be poor metabolizers.55,58,59 Limited data suggest that CYP2D6, a cytochrome P-450 isoenzyme implicated in the sparteine/debrisoquine oxidation polymorphism, is involved in the 8-hydroxylation of clomipramine and desmethylclomipramine and in the 2-hydroxylation of clomipramine.72,73 In addition, demethylation of clomipramine may involve CYP2C, which is implicated in the S -mephenytoin oxidation polymorphism73 , and CYP1A2.346
Possible differences in the metabolism of clomipramine among ethnic populations were suggested by a study in a limited number of healthy individuals that showed plasma clomipramine concentrations after a single oral dose of the drug to be higher in Asians (e.g., Indian, Pakistani) than in whites (e.g., British).10,55,75 In Japanese patients treated with clomipramine, substantial interindividual variation in demethylation and hydroxylation was observed; however, the prevalence of possibly poor demethylators and poor hydroxylators of clomipramine was estimated to be 0 and 1%, respectively.76 Further study is needed to clarify whether the pharmacokinetics of clomipramine truly differ in individuals of various ethnic backgrounds.10
Following oral administration, clomipramine and its metabolites are excreted in urine and in feces (via biliary elimination).1,4,5,11,21,29,55,73 In 2 healthy individuals, approximately 51-60 and 24-32% of an orally administered, radiolabeled, 25-mg dose of clomipramine hydrochloride were excreted in urine and feces, respectively, after 14 days.1,5 Unchanged clomipramine and desmethylclomipramine were excreted in urine in quantities that together comprised approximately 0.8-1.3% of the dose.1 In a limited number of healthy individuals who received a single oral dose of clomipramine, 8-hydroxyclomipramine glucuronide was the principal metabolite found in urine.74 Although the urinary recovery of 8-hydroxyclomipramine glucuronide in these individuals who were phenotyped for metabolism of sparteine and mephenytoin was lower in poor metabolizers of sparteine compared with extensive metabolism of sparteine, estimates of clearance via glucuronidation did not differ between phenotypes, suggesting that the capacity for glucuronidation is not contingent on the capacity for 8-hydroxylation of clomipramine.74
The effects of renal and hepatic impairment on the disposition of clomipramine have not been fully elucidated.1,60
Limited data suggest that demethylation of clomipramine may be reduced with chronic alcohol consumption.55,60,63,64 In one study, the clearance of clomipramine via demethylation was decreased substantially and the ratio of blood clomipramine to desmethylclomipramine concentrations at steady state was higher in recently detoxified alcoholic patients (abstinence periods ranged from 4-20 weeks) compared with a control group of patients with no history of alcoholism.64
Induction of drug-metabolizing enzymes (as measured by antipyrine half-life) does not appear to occur with clomipramine.1
Hemodialysis, peritoneal dialysis, forced diuresis, and/or exchange transfusion are unlikely to remove clomipramine and desmethylclomipramine substantially because of the drug s rapid distribution into body tissues.1
Clomipramine, a dibenzazepine-derivative tricyclic antidepressant, is the 3-chloro analog of imipramine.1,2,3,235 Clomipramine is commercially available as the hydrochloride salt, which occurs as a white to off-white crystalline powder. The drug is freely soluble in water, methanol, and methylene chloride, and insoluble in ethyl ether and hexane.1,2 The drug has a pKa of 9.5.2
Clomipramine hydrochloride capsules should be stored in tight containers at a temperature of 20-25°C and protected from moisture.355,356 When stored as directed, the capsules have an expiration date of 3 years following the date of manufacture.342
Additional Information
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Capsules | 25 mg* | ||
50 mg* | Anafranil® | Mallinckrodt | ||
clomiPRAMINE Hydrochloride Capsules | ||||
75 mg* | Anafranil® | Mallinckrodt | ||
clomiPRAMINE Hydrochloride Capsules |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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