Clomipramine Hydrochloride

INDICATIONS AND USAGE Clomipramine Hydrochloride capsules, USP is 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 egodystonic. 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 hydrochloride capsules, USP 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 CMI 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. CMI-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 hydrochloride capsules, USP 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 hydrochloride for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient ( see DOSAGE AND ADMINISTRATION ).

DOSAGE AND ADMINISTRATION 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 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 2 to 3 weeks after dosage change ( see CLINICAL PHARMACOLOGY ). Therefore, after initial titration, it may be appropriate to wait 2 to 3 weeks between further dosage adjustments. Initial 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. During initial titration, Clomipramine hydrochloride should be given in divided doses with meals to reduce gastrointestinal side effects. 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. Initial 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 ( see PRECAUTIONS, Pediatric Use ). 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 ). Use of Clomipramine hydrochloride capsules, USP With Other 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…

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. 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 18 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 65 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. 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 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer case 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 …

CONTRAINDICATIONS Clomipramine hydrochloride capsule, USP is contraindicated in patients with a history of hypersensitivity to Clomipramine hydrochloride or other tricyclic antidepressants. Monoamine Oxidase 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 is 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 ). Myocardial Infarction Clomipramine hydrochloride capsules, USP is contraindicated during the acute recovery period after a myocardial infarction.

Drug Interactions The risks of using Clomipramine hydrochloride capsules, USP in combination with other drugs have not been systematically evaluated. Given the primary CNS effects of Clomipramine hydrochloride capsules, USP, caution is advised in using it concomitantly with other CNS-active drugs ( see Information for Patients ). Clomipramine hydrochloride capsules, USP should not be used with MAO inhibitors ( see CONTRAINDICATIONS ). Close supervision and careful adjustment of dosage are required when Clomipramine hydrochloride capsules, USP 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 CMI because of its structural similarity to other tricyclic antidepressants. The plasma concentration of CMI 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 CMI as well. Administration of CMI has been reported to increase the plasma levels of phenobarbital, if given concomitantly ( see CLINICAL PHARMACOLOGY, 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 hydrochloride) 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 wh…

Pregnancy 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 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 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.

Nursing Mothers Clomipramine hydrochloride capsules, USP 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.

ADVERSE REACTIONS Commonly Observed The most commonly observed adverse events associated with the use of Clomipramine hydrochloride capsules, USP 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 hydrochloride capsules, USP 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 hydrochloride capsules, USP in adult or pediatric placebo-controlled clinical trials. The frequencies were obtained from pooled data of clinical trials involving either adults receiving Clomipramine hydrochloride capsules, USP (N=322) or placebo (N=319) or children treated with Clomipramine hydrochloride (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 Events reported by at least 1% of Clomipramine hydrochloride capsules, USP patients are included. Clomipramine hydrochloride (N=322) Placebo (N=319) Clomipramine hydrochloride (N=46) Placebo (N=44) 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 …