Clomipramine Hydrochloride: Package Insert and Label Information

CLOMIPRAMINE HYDROCHLORIDE- clomipramine hydrochloride capsule
Mylan Pharmaceuticals Inc.

Suicidality and Antidepressant Drugs

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of clomipramine hydrochloride or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Clomipramine hydrochloride is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD) (see WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients and Pediatric Use).

DESCRIPTION

Clomipramine hydrochloride capsules, USP are an antiobsessional drug that belong to the class (dibenzazepine) of pharmacologic agents known as tricyclic antidepressants. Clomipramine hydrochloride is available as capsules of 25, 50, and 75 mg for oral administration.

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

Clomipramine HCl Structural Formula
(click image for full-size original)

C19 H23 ClN2 • HCl MW = 351.3

Clomipramine hydrochloride, USP is a white or slightly yellow, crystalline powder. It is freely soluble in water, in methanol, and in methylene chloride, and insoluble in ethyl ether and in hexane.

Inactive ingredients. colloidal silicon dioxide, magnesium stearate, pregelatinized starch (corn) and sodium lauryl sulfate. Each of the empty gelatin capsules contains FD&C Red No. 40, gelatin, red iron oxide, sodium lauryl sulfate and titanium dioxide. The 25 mg capsules also contain FD&C Blue No. 1, D&C Yellow No. 10 and D&C Red No. 28, the 50 mg capsules also contain D&C Yellow No. 10 and D&C Red No. 33 and the 75 mg capsules also contain FD&C Blue No. 1.

In addition, the black imprinting ink for the 25 mg, 50 mg and 75 mg capsules contains D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, pharmaceutical glaze, propylene glycol and synthetic black iron oxide.

CLINICAL PHARMACOLOGY

Pharmacodynamics

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

Pharmacokinetics

Absorption/Bioavailability

CMI from clomipramine hydrochloride capsules is as bioavailable as CMI from a solution. The bioavailability of CMI from capsules is not significantly affected by food.

In a dose proportionality study involving multiple CMI doses, steady-state plasma concentrations (CSS ) and area-under-plasma-concentration-time curves (AUC) of CMI and CMI’s major active metabolite, desmethylclomipramine (DMI), 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 CMI/DMI 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 CMI 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 capsules, steady-state maximum plasma concentrations range from 94 ng/mL to 339 ng/mL (mean, 218 ng/mL) for CMI and from 134 ng/mL to 532 ng/mL (mean, 274 ng/mL) for DMI. Additional information from a rising dose study of doses up to 250 mg suggests that DMI may exhibit nonlinear pharmacokinetics over the usual dosing range. At a dose of clomipramine hydrochloride capsules 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 CMI, 781 ng/mL for DMI, and 1386 ng/mL for both.

Distribution

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

Metabolism

CMI is extensively biotransformed to DMI and other metabolites and their glucuronide conjugates. DMI 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 CMI 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 CMI and DMI were only about 0.8% to 1.3% of the dose administered. CMI does not induce drug-metabolizing enzymes, as measured by antipyrine half-life.

Elimination

Evidence that the CSS and AUC for CMI and DMI may increase disproportionately with increasing oral doses suggests that the metabolism of CMI and DMI 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 CMI and DMI 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, CMI and DMI 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 CMI ranges from 19 hours to 37 hours (mean, 32 hr) and that of DMI 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 CMI. Plasma concentrations of the metabolite exceed the parent drug on multiple dosing. After multiple dosing with 150 mg/day, the accumulation factor for CMI is approximately 2.5 and for DMI 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 CMI and DMI (see DOSAGE AND ADMINISTRATION). The effects of hepatic and renal impairment on the disposition of clomipramine hydrochloride capsules have not been determined.

Interactions

Co-administration of haloperidol with CMI increases plasma concentrations of CMI. Co-administration of CMI with phenobarbital increases plasma concentrations of phenobarbital (see PRECAUTIONS: Drug Interactions). Younger subjects (18 to 40 years of age) tolerated CMI 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 CMI were significantly lower in smokers than in nonsmokers.

INDICATIONS AND USAGE

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 hydrochloride capsules 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 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 capsules 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 hydrochloride capsules or other tricyclic antidepressants.

Monoamine Oxidase Inhibitors (MAOIs)

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

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