CRONIL

Clomipramine, the 3-chloro analog of imipramine, is a dibenzazepine-derivative tricyclic antidepressant (TCA).

TCAs are structurally similar to phenothiazines.

They contain a tricyclic ring system with an alkyl amine substituent on the central ring.

In non-depressed individuals, clomipramine does not affect mood or arousal, but may cause sedation.

In depressed individuals, clomipramine exerts a positive effect on mood.

TCAs are potent inhibitors of serotonin and norepinephrine reuptake.

Tertiary amine

TCAs, such as clomipramine, are more potent inhibitors of serotonin reuptake than secondary amine TCAs, such as nortriptyline and desipramine.

TCAs also down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use.

The antidepressant effects of

TCAs are thought to be due to an overall increase in serotonergic neurotransmission.

TCAs also block histamine-H 1 receptors, α 1 -adrenergic receptors and muscarinic receptors, which accounts for their sedative, hypotensive and anticholinergic effects (e.g. blurred vision, dry mouth, constipation, urinary retention), respectively.

See toxicity section below for a complete listing of side effects.

Clomipramine may be used to treat obsessive-compulsive disorder and disorders with an obsessive-compulsive component (e.g. depression, schizophrenia, Tourette's disorder).

Unlabeled indications include panic disorder, chronic pain (e.g. central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy, autistic disorder, trichotillomania, onchophagia, stuttering, premature ejaculation, and premenstrual syndrome.

Clomipramine is rapidly absorbed from the gastrointestinal tract and demethylated in the liver to its primary active metabolite, desmethylclomipramine.

May be used to treat obsessive-compulsive disorder and disorders with an obsessive-compulsive component (e.g. depression, schizophrenia, Tourette's disorder).

Unlabeled indications include: depression, panic disorder, chronic pain (e.g. central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy (limited evidence), autistic disorder (limited evidence), trichotillomania (limited evidence), onchophagia (limited evidence), stuttering (limited evidence), premature ejaculation, and premenstrual syndrome.

Clomipramine, a tricyclic antidepressant, is the 3-chloro derivative of Imipramine.

It was thought that tricyclic antidepressants work exclusively by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells.

However, this response occurs immediately, yet mood does not lift for around two weeks.

It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus.

The hippocampus is part of the limbic system, a part of the brain involved in emotions.

Presynaptic receptors are affected: α 1 and β 1 receptors are sensitized, α 2 receptors are desensitized (leading to increased noradrenaline production).

Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain.

Sodium-dependent serotonin transporter

Inhibitor 5-hydroxytryptamine receptor 2A Antagonist 5-hydroxytryptamine receptor 2B Antagonist + 2 more targets.

Well absorbed from the

GI tract following oral administration.

Bioavailability is approximately 50% Oral due to extensive first-pass metabolism.

Bioavailability is not affected by food.

Peak plasma concentrations occurred 2-6 hours following oral administration of a single 50 mg dose.

The peak plasma concentration ranged from 56 ng/mL to 154 mg/mL (mean, 92 ng/mL).

There are large interindividual variations in plasma concentrations occur, partly due to genetic differences in clomipramine metabolism.

On average, steady state plasma concentrations are achieved in 1-2 weeks following multiple dose oral administration.

Smoking appears to lower the steady-state plasma concentration of clomipramine, but not its active metabolite desmethylclomipramine.

~ 17 L/kg (range: 9-25 L/kg).

Clomipramine is capable of distributing into the cerebrospinal fluid, the brain, and into breast milk.

Extensively metabolized in the liver.

The main active metabolite is desmethylclomipramine, which is formed by N -demethylation of clomipramine via CYP2C19, 3A4 and 1A2.

Other metabolites and their glucuronide conjugates are also produced.

Other metabolites of clomipramine include 8-hydroxyclomipramine formed via 8-hydroxylation, 2-hydroxyclomipramine formed via 2-hydroxylation, and clomipramine N -oxide formed by N -oxidation.

Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which are formed by 8-hydroxylation and N -demethylation, respectively. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active; however, their clinical relevance remains unknown.

Hover over products below to view reaction partners Clomipramine Desmethylclomipramine didesmethylclomipramine 2-hydroxyclomipramine 2-hydroxyclomipramine glucuronide 2-hydroxydesmethyl clomipramine 2-hydroxydesmethyl clomipramine glucuronide 8-hydroxyclomipramine 8-hydroxydesmethyl clomipramine 8-hyroxydesmethyl clomipramine glucuronide 8-hydroxyclomipramine glucuronide clomipramine N-oxide 8-OH-clomipramine 10-OH-clomipramine.

Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours).

Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism).

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Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion.

Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma.

Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity.

In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Anafranil either alone or in combination with other drugs.

One death involved a patient suspected of ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression.

Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia.

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

There has been a long­-standing concern, however, 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.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages to 24) with major depressive disorder (MDD) and other psychiatric disorders.

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.

The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.

There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.

There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.

The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications.

These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table-1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases to 24 5 additional cases Decreases Compared to Placebo to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials.

There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It 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 depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.

Although a causal link between the emergence of such symptoms 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.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers.

Such monitoring should include daily observation by families and caregivers.

Prescriptions for clomipramine hydrochloride should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Disorder – A major depressive episode may be the initial presentation of bipolar disorder.

It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.

Whether any of the symptoms described above represent such a conversion is unknown.

However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

It should be noted that clomipramine hydrochloride is not approved for use in treating bipolar depression.

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including clomipramine hydrochloride capsules, USP alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of clomipramine hydrochloride capsules, USP with MAOIs intended to treat psychiatric disorders is contraindicated.

Clomipramine hydrochloride capsules, USP should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue.

All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses.

There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking clomipramine hydrochloride capsules, USP.

Clomipramine hydrochloride capsules, USP should be discontinued before initiating treatment with the MAOI See CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION .

If concomitant use of clomipramine hydrochloride capsules, USP with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St.

John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with clomipramine hydrochloride capsules, USP and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

The pupillary dilation that occurs following use of many antidepressant drugs including clomipramine hydrochloride capsules, USP may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

During premarket evaluation, seizure was identified as the most significant risk of clomipramine hydrochloride capsules, USP use.

The observed cumulative incidence of seizures among patients exposed to clomipramine hydrochloride capsules, USP at doses up to 300 mg/day was 0.64% at 90 days, 1.12% at 180 days, and 1.45% at 365 days.

The cumulative rates correct the crude rate of 0.7% (25 of 3519 patients) for the variable duration of exposure in clinical trials.

Although dose appears to be a predictor of seizure, there is a confounding of dose and duration of exposure, making it difficult to assess independently the effect of either factor alone.

The ability to predict the occurrence of seizures in subjects exposed to doses of CMI greater than 250 mg is limited, given that the plasma concentration of CMI may be dose-dependent and may vary among subjects given the same dose.

Nevertheless, prescribers are advised to limit the daily dose to a maximum of 250 mg in adults and 3 mg/kg (or 200 mg) in children and adolescents See DOSAGE AND ADMINISTRATION.

Caution should be used in administering clomipramine hydrochloride capsules, USP to patients with a history of seizures or other predisposing factors, e.g., brain damage of varying etiology, alcoholism, and concomitant use with other drugs that lower the seizure threshold.

Rare reports of fatalities in association with seizures have been reported by foreign postmarketing surveillance, but not in U.S. clinical trials.

In some of these cases, clomipramine hydrochloride capsules, USP had been administered with other epileptogenic agents; in others, the patients involved had possibly predisposing medical conditions.

Thus a causal association between clomipramine hydrochloride capsules, USP treatment and these fatalities has not been established.

Physicians should discuss with patients the risk of taking clomipramine hydrochloride capsules, USP while engaging in activities in which sudden loss of consciousness could result in serious injury to the patient or others, e.g., the operation of complex machinery, driving, swimming, climbing.

Rare cases of drug rash with eosinophilia and systemic symptoms (DRESS) have been reported with the use of clomipramine.

In the event of severe acute reactions such as DRESS, discontinue clomipramine therapy immediately and institute appropriate treatment.

Clomipramine hydrochloride capsules, USP are contraindicated in patients with a history of hypersensitivity to clomipramine hydrochloride capsules, USP or other tricyclic antidepressants.

Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with clomipramine hydrochloride capsules, USP or within 14 days of stopping treatment with clomipramine hydrochloride capsules, USP are contraindicated because of an increased risk of serotonin syndrome.

The use of clomipramine hydrochloride capsules, USP within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated See WARNINGS and DOSAGE AND ADMINISTRATION.

Starting clomipramine hydrochloride capsules, USP in a patient who is being treated with linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome See WARNINGS and DOSAGE AND ADMINISTRATION.

Clomipramine hydrochloride capsules, USP are contraindicated during the acute recovery period after a myocardial infarction.

The treatment regimens described below are based on those used in controlled clinical trials of clomipramine hydrochloride capsules, USP in 520 adults, and 91 children and adolescents with OCD.

During initial titration, clomipramine hydrochloride capsules, USP should be given in divided doses with meals to reduce gastrointestinal side effects.

The goal of this initial titration phase is to minimize side effects by permitting tolerance to side effects to develop or allowing the patient time to adapt if tolerance does not develop.

Because both

CMI and its active metabolite, DMI, have long elimination half-lives, the prescriber should take into consideration the fact that steady-state plasma levels may not be achieved until to 3 weeks after dosage change.

Therefore, after initial titration, it may be appropriate to wait to 3 weeks between further dosage adjustments.

Treatment/Dose Adjustment (Adults) Treatment with clomipramine hydrochloride capsules, USP should be initiated at a dosage of 25 mg daily and gradually increased, as tolerated, to approximately 100 mg during the first 2 weeks.

Thereafter, the dosage may be increased gradually over the next several weeks, up to a maximum of 250 mg daily.

After titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation.

Treatment/Dose Adjustment (Children and Adolescents) As with adults, the starting dose is 25 mg daily and should be gradually increased (also given in divided doses with meals to reduce gastrointestinal side effects) during the first 2 weeks, as tolerated, up to a daily maximum of 3 mg/kg or 100 mg, whichever is smaller.

Thereafter, the dosage may be increased gradually over the next several weeks up to a daily maximum of 3 mg/kg or 200 mg, whichever is smaller.

As with adults, after titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation.

Maintenance/Continuation Treatment (Adults, Children, and Adolescents) While there are no systematic studies that answer the question of how long to continue clomipramine hydrochloride capsules, USP OCD is a chronic condition and it is reasonable to consider continuation for a responding patient.

Although the efficacy of clomipramine hydrochloride capsules, USP after 10 weeks has not been documented in controlled trials, patients have been continued in therapy under double.

• blind conditions for up to 1 year without loss of benefit.

However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment.

During maintenance, the total daily dose may be given once daily at bedtime.

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric.

Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with clomipramine hydrochloride capsules, USP.

Conversely, at least 14 days should be allowed after stopping clomipramine hydrochloride capsules, USP before starting an MAOI intended to treat psychiatric disorders See CONTRAINDICATIONS.

MAOIs, Such as Linezolid or Methylene Blue Do not start clomipramine hydrochloride capsules, USP in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome.

In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered See CONTRAINDICATIONS.

In some cases, a patient already receiving clomipramine hydrochloride capsules, USP therapy may require urgent treatment with linezolid or intravenous methylene blue.

If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, clomipramine hydrochloride capsules, USP should be stopped promptly, and linezolid or intravenous methylene blue can be administered.

The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first.

Therapy with clomipramine hydrochloride capsules, USP may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue See WARNINGS.

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with clomipramine hydrochloride capsule, USP is unclear.

The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use See WARNINGS.

Capsules, USP Capsules 25 mg – Melon Yellow OP cap / Ivory Opaque body size 3 hard gelatin capsule imprinted in black "M" on cap and "37" on body, filled with white to off white granular powder.

Bottles of 30: NDC 42571-342-30 Bottles of 90: NDC 42571-342-90 Bottles of 100: NDC 42571-342-01 Bottles of 500: NDC 42571-342-05 Capsules 50 mg – Aqua blue OP cap / Ivory Opaque body size 1 hard gelatin capsule imprinted in black "M" on cap and "38" on body, filled with white to off white granular powder.

Bottles of 30: NDC 42571-343-30 Bottles of 90: NDC 42571-343-90 Bottles of 100: NDC 42571-343-01 Capsules 75 mg – Yellow Opaque Cap / Ivory Opaque body size 1 hard gelatin capsule imprinted in black with "M" on cap and "39" on body, filled with white to off white granular powder.

Bottles of 30: NDC 42571-344-30 Bottles of 90: NDC 42571-344-90 Bottles of 100: NDC 42571-344-01 Storage – Store at 20° to 25°C (68° to 77°F) .

Dispense in well-closed, light-resistant containers with child resistant closure.

Protect from moisture.

No teratogenic effects were observed in studies performed in rats and mice at doses up to 100 mg/kg, which is 24 times the maximum recommended human daily dose (MRHD) on a mg/kg basis and 4 times (rats) and 2 times (mice) the MRHD on a mg/m 2 basis.

Slight nonspecific embryo/fetotoxic effects were seen in the offspring of treated rats given and 100 mg/kg and of treated mice given 100 mg/kg. There are no adequate or well-controlled studies in pregnant women.

Withdrawal symptoms, including jitteriness, tremor, and seizures, have been reported in neonates whose mothers had taken clomipramine hydrochloride capsules, USP until delivery.

Clomipramine hydrochloride capsules, USP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clomipramine hydrochloride capsules, USP have been found in human milk.

Because of the potential for adverse reactions, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established.

Anyone considering the use of clomipramine hydrochloride capsules, USP in a child or adolescent must balance the potential risks with the clinical need.

In a controlled clinical trial in children and adolescents (10 to 17 years of age), 46 outpatients received clomipramine hydrochloride capsules, USP for up to 8 weeks.

In addition, 150 adolescent patients have received clomipramine hydrochloride capsules, USP in open-label protocols for periods of several months to several years.

Of the 196 adolescents studied, 50 were 13 years of age or less and were 14 to 17 years of age.

The adverse reaction profile in this See ADVERSE REACTIONS is similar to that observed in adults.

The risks, if any, that may be associated with clomipramine hydrochloride capsule’s extended use in children and adolescents with OCD have not been systematically assessed.

The evidence supporting the conclusion that clomipramine hydrochloride capsules, USP is safe for use in children and adolescents is derived from relatively short term clinical studies and from extrapolation of experience gained with adult patients.

In particular, there are no studies that directly evaluate the effects of long term clomipramine hydrochloride capsules, USP use on the growth, development, and maturation of children and adolescents.

Although there is no evidence to suggest that clomipramine hydrochloride capsules, USP adversely affects growth, development or maturation, the absence of such findings is not adequate to rule out a potential for such effects in chronic use.

The safety and effectiveness in pediatric patients below the age of 10 have not been established.

Therefore, specific recommendations cannot be made for the use of clomipramine hydrochloride capsules, USP in pediatric patients under the age of 10.

Clinical studies of clomipramine hydrochloride capsules, USP did not include sufficient numbers of subjects age and over to determine whether they respond differently from younger subjects; 152 patients at least 60 years of age participating in various U.S. clinical trials received clomipramine hydrochloride capsules, USP for periods of several months to several years.

No unusual age.

• related adverse events were identified in this population.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Clomipramine hydrochloride capsules, USP has been associated with cases of clinically significant hyponatremia.

Elderly patients may be at greater risk for this adverse reaction.