Clomipramine

Generic Name: Clomipramine Hydrochloride
Dosage Form: Capsules

Rx only

Clomipramine Description

Clomipramine hydrochloride is an antiobsessional drug that belongs to the class (dibenzazepine) of pharmacologic agents known as tricyclic antidepressants.

Clomipramine hydrochloride is 3-chloro-5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine monohydrochloride, and its structural formula is:

Clomipramine hydrochloride is a white to off-white crystalline powder. It is freely soluble in water, in methanol, and in methylene chloride, and insoluble in ethyl ether and in hexane. Its molecular weight is 351.3.

Clomipramine hydrochloride capsules, USP, for oral administration, contain 25 mg, 50 mg, or 75 mg of Clomipramine hydrochloride and the following inactive ingredients: colloidal silicon dioxide, corn starch, gelatin, magnesium stearate, pharmaceutical glaze, propylene glycol, red iron oxide, silicon dioxide, sodium lauryl sulfate, synthetic black iron oxide, titanium dioxide, FD&C Red #40, D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake, FD&C Blue #2 Aluminum Lake, FD&C Red #40 Aluminum Lake. The following additional product specific coloring agents are employed:

25 mg– FD&C Blue #1, D&C Yellow #10, and D&C Red #28

50 mg– D&C Yellow #10 and D&C Red #33

75 mg– FD&C Blue #1

Clomipramine - Clinical Pharmacology

Pharmacodynamics

Clomipramine is presumed to influence obsessive and compulsive behaviors through its effects on serotonergic neuronal transmission. The actual neurochemical mechanism is unknown, but Clomipramine"s capacity to inhibit the reuptake of serotonin (5-HT) is thought to be important.

Pharmacokinetics

Absorption/Bioavailability

Clomipramine from a capsule is as bioavailable as Clomipramine from a solution. The bioavailability of Clomipramine from capsules is not significantly affected by food.

In a dose proportionality study involving multiple Clomipramine doses, steady-state plasma concentrations (CSS) and area-under-plasma-concentration-time curves (AUC) of Clomipramine and Clomipramine"s major active metabolite, desmethylClomipramine, were not proportional to dose over the ranges evaluated, i.e., between 25 to 100 mg/day and between 25 to 150 mg/day, although CSS and AUC are approximately linearly related to dose between 100 to 150 mg/day. The relationship between dose and Clomipramine/desmethylClomipramine concentrations at higher daily doses has not been systematically assessed, but if there is significant dose dependency at doses above 150 mg/day, there is the potential for dramatically higher CSS and AUC even for patients dosed within the recommended range. This may pose a potential risk to some patients (see WARNINGS and PRECAUTIONS: Drug Interactions).

After a single 50 mg oral dose, maximum plasma concentrations of Clomipramine occur within 2 to 6 hours (mean, 4.7 hr) and range from 56 ng/mL to 154 ng/mL (mean, 92 ng/mL). After multiple daily doses of 150 mg of Clomipramine hydrochloride, steady-state maximum plasma concentrations range from 94 ng/mL to 339 ng/mL (mean, 218 ng/mL) for Clomipramine and from 134 ng/mL to 532 ng/mL (mean, 274 ng/mL) for desmethylClomipramine. Additional information from a rising dose study of doses up to 250 mg suggests that desmethylClomipramine may exhibit nonlinear pharmacokinetics over the usual dosing range. At a dose of Clomipramine hydrochloride 200 mg, subjects who had a single blood sample taken approximately 9 to 22 hours, (median 16 hours), after the dose had plasma concentrations of up to 605 ng/mL for Clomipramine, 781 ng/mL for desmethylClomipramine, and 1386 ng/mL for both.

Distribution

Clomipramine distributes into cerebrospinal fluid (CSF) and brain and into breast milk. DesmethylClomipramine also distributes into CSF, with a mean CSF/plasma ratio of 2.6. The protein binding of Clomipramine is approximately 97%, principally to albumin, and is independent of Clomipramine concentration. The interaction between Clomipramine and other highly protein-bound drugs has not been fully evaluated, but may be important (see PRECAUTIONS: Drug Interactions).

Metabolism

Clomipramine is extensively biotransformed to desmethylClomipramine and other metabolites and their glucuronide conjugates. DesmethylClomipramine is pharmacologically active, but its effects on OCD behaviors are unknown. These metabolites are excreted in urine and feces, following biliary elimination. After a 25 mg radiolabeled dose of Clomipramine in two subjects, 60% and 51%, respectively, of the dose were recovered in the urine and 32% and 24%, respectively, in feces. In the same study, the combined urinary recoveries of Clomipramine and desmethylClomipramine were only about 0.8 to 1.3% of the dose administered. Clomipramine does not induce drug-metabolizing enzymes, as measured by antipyrine half-life.

Elimination

Evidence that the CSS and AUC for Clomipramine and desmethylClomipramine may increase disproportionately with increasing oral doses suggests that the metabolism of Clomipramine and desmethylClomipramine may be capacity limited. This fact must be considered in assessing the estimates of the pharmacokinetic parameters presented below, as these were obtained in individuals exposed to doses of 150 mg. If the pharmacokinetics of Clomipramine and desmethylClomipramine are nonlinear at doses above 150 mg, their elimination half-lives may be considerably lengthened at doses near the upper end of the recommended dosing range (i.e., 200 mg/day to 250 mg/day). Consequently, Clomipramine and desmethylClomipramine may accumulate, and this accumulation may increase the incidence of any dose- or plasma-concentration-dependent adverse reactions, in particular seizures (see WARNINGS).

After a 150 mg dose, the half-life of Clomipramine ranges from 19 hours to 37 hours (mean, 32 hr) and that of desmethylClomipramine ranges from 54 hours to 77 hours (mean, 69 hr). Steady-state levels after multiple dosing are typically reached within 7 to 14 days for Clomipramine. Plasma concentrations of the metabolite exceed the parent drug on multiple dosing. After multiple dosing with 150 mg/day, the accumulation factor for Clomipramine is approximately 2.5 and for desmethylClomipramine is 4.6. Importantly, it may take two weeks or longer to achieve this extent of accumulation at constant dosing because of the relatively long elimination half-lives of Clomipramine and desmethylClomipramine (see DOSAGE AND ADMINISTRATION). The effects of hepatic and renal impairment on the disposition of Clomipramine have not been determined.

Interactions

Coadministration of haloperidol with Clomipramine increases plasma concentrations of Clomipramine. Coadministration of Clomipramine with phenobarbital increases plasma concentrations of phenobarbital (see PRECAUTIONS: Drug Interactions). Younger subjects (18 to 40 years of age) tolerated Clomipramine better and had significantly lower steady-state plasma concentrations, compared with subjects over 65 years of age. Children under 15 years of age had significantly lower plasma concentration/dose ratios, compared with adults. Plasma concentrations of Clomipramine were significantly lower in smokers than in nonsmokers.

Indications and Usage for Clomipramine

Clomipramine hydrochloride capsules are indicated for the treatment of obsessions and compulsions in patients with Obsessive-Compulsive Disorder (OCD). The obsessions or compulsions must cause marked distress, be time-consuming, or significantly interfere with social or occupational functioning, in order to meet the DSM-III-R (circa 1989) diagnosis of OCD.

Obsessions are recurrent, persistent ideas, thoughts, images, or impulses that are ego-dystonic. Compulsions are repetitive, purposeful, and intentional behaviors performed in response to an obsession or in a stereotyped fashion, and are recognized by the person as excessive or unreasonable.

The effectiveness of Clomipramine for the treatment of OCD was demonstrated in multicenter, placebo-controlled, parallel-group studies, including two 10-week studies in adults and one 8-week study in children and adolescents 10 to 17 years of age. Patients in all studies had moderate-to-severe OCD (DSM-III), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS) ranging from 26 to 28 and a mean baseline rating of 10 on the NIMH Clinical Global Obsessive Compulsive Scale (NIMH-OC). Patients taking Clomipramine experienced a mean reduction of approximately 10 on the YBOCS, representing an average improvement on this scale of 35% to 42% among adults and 37% among children and adolescents. Clomipramine-treated patients experienced a 3.5 unit decrement on the NIMH-OC. Patients on placebo showed no important clinical response on either scale. The maximum dose was 250 mg/day for most adults and 3 mg/kg/day (up to 200 mg) for all children and adolescents.

The effectiveness of Clomipramine for long-term use (i.e., for more than 10 weeks) has not been systematically evaluated in placebo-controlled trials. The physician who elects to use Clomipramine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Contraindications

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

Clomipramine should not be given in combination, or within 14 days before or after treatment, with a monoamine oxidase (MAO) inhibitor. Hyperpyretic crisis, seizures, coma, and death have been reported in patients receiving such combinations.

Clomipramine is contraindicated during the acute recovery period after a myocardial infarction.

Warnings

Clinical Worsening and Suicide Risk

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. 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. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.

Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults.

All pediatric patients being treated with antidepressants for any indication should be 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. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.

Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

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 pediatric 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 health care 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. Families and caregivers of adults being treated for depression should be similarly advised.

Screening Patients for Bipolar 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.

Seizures

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

The observed cumulative incidence of seizures among patients exposed to Clomipramine hydrochloride 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 the 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 Clomipramine hydrochloride greater than 250 mg is limited, given that the plasma concentration of Clomipramine 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 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 had been administered with other epileptogenic agents; in others, the patients involved had possibly predisposing medical conditions. Thus a causal association between Clomipramine hydrochloride treatment and these fatalities has not been established.

Physicians should discuss with patients the risk of taking Clomipramine 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.

Precautions

General

Suicide

Since depression is a commonly associated feature of OCD, the risk of suicide must be considered. 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.

Cardiovascular Effects

Modest orthostatic decreases in blood pressure and modest tachycardia were each seen in approximately 20% of patients taking Clomipramine in clinical trials; but patients were frequently asymptomatic. Among approximately 1400 patients treated with Clomipramine in the premarketing experience who had ECGs, 1.5% developed abnormalities during treatment, compared with 3.1% of patients receiving active control drugs and 0.7% of patients receiving placebo. The most common ECG changes were PVCs, ST-T wave changes, and intraventricular conduction abnormalities. These changes were rarely associated with significant clinical symptoms. Nevertheless, caution is necessary in treating patients with known cardiovascular disease, and gradual dose titration is recommended.

Psychosis, Confusion, And Other Neuropsychiatric Phenomena

Patients treated with Clomipramine have been reported to show a variety of neuropsychiatric signs and symptoms including delusions, hallucinations, psychotic episodes, confusion, and paranoia. Because of the uncontrolled nature of many of the studies, it is impossible to provide a precise estimate of the extent of risk imposed by treatment with Clomipramine. As with tricyclic antidepressants to which it is closely related, Clomipramine may precipitate an acute psychotic episode in patients with unrecognized schizophrenia.

Mania/Hypomania

During premarketing testing of Clomipramine in patients with affective disorder, hypomania or mania was precipitated in several patients. Activation of mania or hypomania has also been reported in a small proportion of patients with affective disorder treated with marketed tricyclic antidepressants, which are closely related to Clomipramine.

Hepatic Changes

During premarketing testing, Clomipramine was occasionally associated with elevations in SGOT and SGPT (pooled incidence of approximately 1% and 3%, respectively) of potential clinical importance (i.e., values greater than 3 times the upper limit of normal). In the vast majority of instances these enzyme increases were not associated with other clinical findings suggestive of hepatic injury; moreover, none were jaundiced. Rare reports of more severe liver injury, some fatal, have been recorded in foreign postmarketing experience. Caution is indicated in treating patients with known liver disease, and periodic monitoring of hepatic enzyme levels is recommended in such patients.

Hematologic Changes

Although no instances of severe hematologic toxicity were seen in the premarketing experience with Clomipramine, there have been postmarketing reports of leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia in association with Clomipramine use. As is the case with tricyclic antidepressants to which Clomipramine is closely related, leukocyte and differential blood counts should be obtained in patients who develop fever and sore throat during treatment with Clomipramine.

Central Nervous System

More than 30 cases of hyperthermia have been recorded by nondomestic postmarketing surveillance systems. Most cases occurred when Clomipramine was used in combination with other drugs. When Clomipramine and a neuroleptic were used concomitantly, the cases were sometimes considered to be examples of a neuroleptic malignant syndrome.

Sexual Dysfunction

The rate of sexual dysfunction in male patients with OCD who were treated with Clomipramine in the premarketing experience was markedly increased compared with placebo controls (i.e., 42% experienced ejaculatory failure and 20% experienced impotence, compared with 2% and 2.6%, respectively, in the placebo group). Approximately 85% of males with sexual dysfunction chose to continue treatment.

Weight Changes

In controlled studies of OCD, weight gain was reported in 18% of patients receiving Clomipramine, compared with 1% of patients receiving placebo. In these studies, 28% of patients receiving Clomipramine had a weight gain of at least 7% of their initial body weight, compared with 4% of patients receiving placebo. Several patients had weight gains in excess of 25% of their initial body weight. Conversely, 5% of patients receiving Clomipramine and 1% receiving placebo had weight losses of at least 7% of their initial body weight.

Electroconvulsive Therapy

As with closely related tricyclic antidepressants, concurrent administration of Clomipramine with electroconvulsive therapy may increase the risks; such treatment should be limited to those patients for whom it is essential, since there is limited clinical experience.

Surgery

Prior to elective surgery with general anesthetics, therapy with Clomipramine hydrochloride should be discontinued for as long as is clinically feasible, and the anesthetist should be advised.

Use in Concomitant Illness

As with closely related tricyclic antidepressants, Clomipramine should be used with caution in the following:

1. Hyperthyroid patients or patients receiving thyroid medication, because of the possibility of cardiac toxicity;
2. Patients with increased intraocular pressure, a history of narrow-angle glaucoma, or urinary retention, because of the anticholinergic properties of the drug;
3. Patients with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma) in whom the drug may provoke hypertensive crises;
4. Patients with significantly impaired renal function.

Withdrawal Symptoms

A variety of withdrawal symptoms have been reported in association with abrupt discontinuation of Clomipramine, including dizziness, nausea, vomiting, headache, malaise, sleep disturbance, hyperthermia, and irritability. In addition, such patients may experience a worsening of psychiatric status. While the withdrawal effects of Clomipramine have not been systematically evaluated in controlled trials, they are well known with closely related tricyclic antidepressants, and it is recommended that the dosage be tapered gradually and the patient monitored carefully during discontinuation (see DRUG ABUSE AND DEPENDENCE).

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Clomipramine and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for Clomipramine. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Clomipramine.

Clinical Worsening and Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient"s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient"s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Physicians are advised to discuss the following issues with patients for whom they prescribe Clomipramine hydrochloride:

1. The risk of seizure (see WARNINGS);
2. The relatively high incidence of sexual dysfunction among males (see PRECAUTIONS: General: Sexual Dysfunction);
3. Since Clomipramine may impair the mental and/or physical abilities required for the performance of complex tasks, and since Clomipramine is associated with a risk of seizures, patients should be cautioned about the performance of complex and hazardous tasks (see WARNINGS);
4. Patients should be cautioned about using alcohol, barbiturates, or other CNS depressants concurrently, since Clomipramine may exaggerate their response to these drugs;
5. Patients should notify their physician if they become pregnant or intend to become pregnant during therapy;
6. Patients should notify their physician if they are breast-feeding.

Drug Interactions

The risks of using Clomipramine in combination with other drugs have not been systematically evaluated. Given the primary CNS effects of Clomipramine, caution is advised in using it concomitantly with other CNS-active drugs (see PRECAUTIONS: Information for Patients). Clomipramine should not be used with MAO inhibitors (see CONTRAINDICATIONS).

Close supervision and careful adjustment of dosage are required when Clomipramine is administered with anticholinergic or sympathomimetic drugs.

Several tricyclic antidepressants have been reported to block the pharmacologic effects of guanethidine, clonidine, or similar agents, and such an effect may be anticipated with Clomipramine because of its structural similarity to other tricyclic antidepressants.

The plasma concentration of Clomipramine has been reported to be increased by the concomitant administration of haloperidol; plasma levels of several closely related tricyclic antidepressants have been reported to be increased by the concomitant administration of methylphenidate or hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decreased by the concomitant administration of hepatic enzyme inducers (e.g., barbiturates, phenytoin), and such an effect may be anticipated with Clomipramine as well. Administration of Clomipramine has been reported to increase the plasma levels of phenobarbital, if given concomitantly (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Interactions).

Drugs Metabolized by P450 2D6

The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7 to 10% of Caucasians are so-called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, paroxetine and fluvoxamine, inhibit P450 2D6, they may vary in the extent of inhibition. Fluvoxamine has also been shown to inhibit P450 1A2, an isoform also involved in TCA metabolism. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of agents in the tricyclic antidepressant class (which includes Clomipramine) with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant agent or the other drug. Furthermore, whenever one of these drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant agent may be required. It is desirable to monitor TCA plasma levels whenever an agent of the tricyclic antidepressant class (including Clomipramine) is going to be co-administered with another drug known to be an inhibitor of P450 2D6 (and/or P450 1A2).

Because Clomipramine is highly bound to serum protein, the administration of Clomipramine to patients taking other drugs that are highly bound to protein (e.g., warfarin, digoxin) may cause an increase in plasma concentrations of these drugs, potentially resulting in adverse effects. Conversely, adverse effects may result from displacement of protein-bound Clomipramine by other highly bound drugs (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Distribution).

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenecity was found in two 2-year bioassays in rats at doses up to 100 mg/kg, which is 24 and 4 times the maximum recommended human daily dose (MRHD) on a mg/kg and mg/m2 basis, respectively, or in a 2-year bioassay in mice at doses up to 80 mg/kg, which is 20 and 1.5 times the MRHD on a mg/kg and mg/m2 basis, respectively.

In reproduction studies, no effects on fertility were found in rats given up to 24 mg/kg, which is 6 times, and approximately equal to, the MRHD on a mg/kg and mg/m2 basis, respectively.

Pregnancy

Teratogenic Effects

Pregnancy Category C

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/m2 basis. Slight nonspecific embryo/fetotoxic effects were seen in the offspring of treated rats given 50 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 until delivery. Clomipramine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Clomipramine has 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.

Pediatric Use

Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established (see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Anyone considering the use of Clomipramine 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 for up to 8 weeks. In addition, 150 adolescent patients have received Clomipramine 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 146 were 14 to 17 years of age. The adverse reaction profile in this age group (see ADVERSE REACTIONS) is similar to that observed in adults.

The risks, if any, that may be associated with Clomipramine"s extended use in children and adolescents with OCD have not been systematically assessed. The evidence supporting the conclusion that Clomipramine 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 use on the growth, development, and maturation of children and adolescents. Although there is no evidence to suggest that Clomipramine 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 in pediatric patients under the age of 10.

Geriatric Use

Clinical studies of Clomipramine did not include sufficient numbers of subjects age 65 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 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.

Adverse Reactions

Commonly Observed

The most commonly observed adverse events associated with the use of Clomipramine and not seen at an equivalent incidence among placebo-treated patients were gastrointestinal complaints, including dry mouth, constipation, nausea, dyspepsia, and anorexia; nervous system complaints, including somnolence, tremor, dizziness, nervousness, and myoclonus; genitourinary complaints, including changed libido, ejaculatory failure, impotence, and micturition disorder; and other miscellaneous complaints, including fatigue, sweating, increased appetite, weight gain, and visual changes.

Leading to Discontinuation of Treatment

Approximately 20% of 3616 patients who received Clomipramine in U.S. premarketing clinical trials discontinued treatment because of an adverse event. Approximately one-half of the patients who discontinued (9% of the total) had multiple complaints, none of which could be classified as primary. Where a primary reason for discontinuation could be identified, most patients discontinued because of nervous system complaints (5.4%), primarily somnolence. The second-most-frequent reason for discontinuation was digestive system complaints (1.3%), primarily vomiting and nausea.

There was no apparent relationship between the adverse events and elevated plasma drug concentrations.

Incidence in Controlled Clinical Trials

The following table enumerates adverse events that occurred at an incidence of 1% or greater among patients with OCD who received Clomipramine in adult or pediatric placebo-controlled clinical trials. The frequencies were obtained from pooled data of clinical trials involving either adults receiving Clomipramine (N = 322) or placebo (N = 319) or children treated with Clomipramine (N = 46) or placebo (N = 44). The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the populations studied.

Incidence of Treatment-Emergent Adverse Experience in Placebo-Controlled Clinical Trials (Percentage of Patients Reporting Event)

	Adults		Children and Adolescents
Body System/ Adverse Event*	Clomipramine hydrochloride (N=322)	Placebo (N=319)	Clomipramine hydrochloride (N=46)	Placebo (N=44)
* Events reported by at least 1% of Clomipramine patients are included.
Nervous System
Somnolence	54	16	46	11
Tremor	54	2	33	2
Dizziness	54	14	41	14
Headache	52	41	28	34
Insomnia	25	15	11	7
Libido change	21	3	-	-
Nervousness	18	2	4	2
Myoclonus	13	-	2	-
Increased appetite	11	2	-	2
Paresthesia	9	3	2	2
Memory impairment	9	1	7	2
Anxiety	9	4	2	-
Twitching	7	1	4	5
Impaired concentration	5	2	-	-
Depression	5	1	-	-
Hypertonia	4	1	2	-
Sleep disorder	4	-	9	5
Psychosomatic disorder	3	-	-	-
Yawning	3	-	-	-
Confusion	3	-	2	-
Speech disorder	3	-	-	-
Abnormal dreaming	3	-	-	2
Agitation	3	-	-	-
Migraine	3	-	-	-
Depersonalization	2	-	2	-
Irritability	2	2	2	-
Emotional lability	2	-	-	2
Panic reaction	1	-	2	-
Aggressive reaction	-	-	2	-
Paresis	-	-	2	-
Skin and Appendages
Increased sweating	29	3	9	-
Rash	8	1	4	2
Pruritus	6	-	2	2
Dermatitis	2	-	-	2
Acne	2	2	-	5
Dry skin	2	-	-	5
Urticaria	1	-	-	-
Abnormal skin odor	-	-	2	-
Digestive System
Dry mouth	84	17	63	16
Constipation	47	11	22	9
Nausea	33	14	9	11
Dyspepsia	22	10	13	2
Diarrhea	13	9	7	5
Anorexia	12	-	22	2
Abdominal pain	11	9	13	16
Vomiting	7	2	7	-
Flatulence	6	3	-	2
Tooth disorder	5	-	-	-
Gastrointestinal disorder	2	-	-	2
Dysphagia	2	-	-	-
Esophagitis	1	-	-	-
Eructation	-	-	2	2
Ulcerative stomatitis	-	-	2	-
Body as a Whole
Fatigue	39	18	35	9
Weight increase	18	1	2	-
Flushing	8	-	7	-
Hot flushes	5	-	2	-
Chest pain	4	4	7	-
Fever	4	-	2	7
Allergy	3	3	7	5
Pain	3	2	4	2
Local edema	2	4	-	-
Chills	2	1	-	-
Weight decrease	-	-	7	-
Otitis media	-	-	4	5
Asthenia	-	-	2	-
Halitosis	-	-	2	-
Cardiovascular System
Postural hypotension	6	-	4	-
Palpitation	4	2	4	-
Tachycardia	4	-	2	-
Syncope	-	-	2	-
Respiratory System
Pharyngitis	14	9	-	5
Rhinitis	12	10	7	9
Sinusitis	6	4	2	5
Coughing	6	6	4	5
Bronchospasm	2	-	7	2
Epistaxis	2	-	-	2
Dyspnea	-	-	2	-
Laryngitis	-	1	2	-
Urogenital System
Male and Female Patients Combined
Micturition disorder	14	2	4	2
Urinary tract infection	6	1	-	-
Micturition frequency	5	3	-	-
Urinary retention	2	-	7	-
Dysuria	2	2	-	-
Cystitis	2	-	-	-
Female Patients Only	(N=182)	(N=167)	(N=10)	(N=21)
Dysmenorrhea	12	14	10	10
Lactation (nonpuerperal)	4	-	-	-
Menstrual disorder	4	2	-	-
Vaginitis	2	-	-	-
Leukorrhea	2	-	-	-
Breast enlargement	2	-	-	-
Breast pain	1	-	-	-
Amenorrhea	1	-	-	-
Male Patients Only	(N=140)	(N=152)	(N=36)	(N=23)
Ejaculation failure	42	2	6	-
Impotence	20	3	-	-
Special Senses
Abnormal vision	18	4	7	2
Taste perversion	8	-	4	-
Tinnitus	6	-	4	-
Abnormal lacrimation	3	2	-	-
Mydriasis	2	-	-	-
Conjunctivitis	1	-	-	-
Anisocoria	-	-	2	-
Blepharospasm	-	-	2	-
Ocular allergy	-	-	2	-
Vestibular disorder	-	-	2	2
Musculoskeletal
Myalgia	13	9	-	-
Back pain	6	6	-	-
Arthralgia	3	5	-	-
Muscle weakness	1	-	2	-
Hemic and Lymphatic
Purpura	3	-	-	-
Anemia	-	-	2	2
Metabolic and Nutritional
Thirst	2	2	-	2

Other Events Observed During the Premarketing Evaluation of Clomipramine

During clinical testing in the U.S., multiple doses of Clomipramine were administered to approximately 3600 subjects. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, a modified World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the 3525 individuals exposed to Clomipramine who experienced an event of the type cited on at least one occasion while receiving Clomipramine. All events are included except those already listed in the previous table, those reported in terms so general as to be uninformative, and those in which an association with the drug was remote. It is important to emphasize that although the events reported occurred during treatment with Clomipramine, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in less than 1/1000 patients.

Body as a Whole: Infrequent: general edema, increased susceptibility to infection, malaise. Rare: dependent edema, withdrawal syndrome.

Cardiovascular System: Infrequent: abnormal ECG, arrhythmia, bradycardia, cardiac arrest, extrasystoles, pallor. Rare: aneurysm, atrial flutter, bundle branch block, cardiac failure, cerebral hemorrhage, heart block, myocardial infarction, myocardial ischemia, peripheral ischemia, thrombophlebitis, vasospasm, ventricular tachycardia.

Digestive System: Infrequent: abnormal hepatic function, blood in stool, colitis, duodenitis, gastric ulcer, gastritis, gastroesophageal reflux, gingivitis, glossitis, hemorrhoids, hepatitis, increased saliva, irritable bowel syndrome, peptic ulcer, rectal hemorrhage, tongue ulceration, tooth caries. Rare: cheilitis, chronic enteritis, discolored



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