Professional Information — 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 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, 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 capsules, USP 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 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 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 capsules, USP 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 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 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 ).

Contraindications

Clomipramine hydrochloride capsules, USP are contraindicated in patients with a history of hypersensitivity to clomipramine hydrochloride capsules, USP 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 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 ).

Myocardial Infarction

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

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 capsules, USP (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)

*Events reported by at least 1% of clomipramine hydrochloride capsules, USP patients are included.

Other Events Observed During the Premarketing Evaluation of Clomipramine Hydrochloride Capsules, USP

During clinical testing in the U.S., multiple doses of clomipramine hydrochloride capsules, USP 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 hydrochloride capsules, USP who experienced an event of the type cited on at least one occasion while receiving clomipramine hydrochloride capsules, USP. 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 hydrochloride capsules, USP 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 feces, gastric dilatation, gingival bleeding, hiccup, intestinal obstruction, oral/pharyngeal edema, paralytic ileus, salivary gland enlargement.

Endocrine System – Infrequent- hypothyroidism. Rare -goiter, gynecomastia, hyperthyroidism.

Hemic and Lymphatic System – Infrequent -lymphadenopathy. Rare -leukemoid reaction, lymphoma-like disorder, marrow depression.

Metabolic and Nutritional Disorder – Infrequent -dehydration, diabetes mellitus, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypokalemia. Rare -fat intolerance, glycosuria.

Musculoskeletal System – Infrequent -arthrosis. Rare -dystonia, exostosis, lupus erythematosus rash, bruising, myopathy, myositis, polyarteritis nodosa, torticollis.

Nervous System – Frequent -abnormal thinking, vertigo. Infrequent -abnormal coordination, abnormal EEG, abnormal gait, apathy, ataxia, coma, convulsions, delirium, delusion, dyskinesia, dysphonia, encephalopathy, euphoria, extrapyramidal disorder, hallucinations, hostility, hyperkinesia, hypnagogic hallucinations, hypokinesia, leg cramps, manic reaction, neuralgia, paranoia, phobic disorder, psychosis, sensory disturbance, somnambulism, stimulation, suicidal ideation, suicide attempt, teeth-grinding. Rare -anticholinergic syndrome, aphasia, apraxia, catalepsy, cholinergic syndrome,    choreoathetosis,    generalized    spasm,    hemiparesis,    hyperesthesia, hyperreflexia, hypoesthesia, illusion, impaired impulse control, indecisiveness, mutism, neuropathy, nystagmus, oculogyric crisis, oculomotor nerve paralysis, schizophrenic reaction, stupor, suicide.

Respiratory System – Infrequent -bronchitis, hyperventilation, increased sputum, pneumonia. Rare -cyanosis, hemoptysis, hypoventilation, laryngismus.

Skin and Appendages – Infrequent -alopecia, cellulitis, cyst, eczema, erythematous rash, genital pruritus, maculopapular rash, photosensitivity reaction, psoriasis, pustular rash, skin discoloration. Rare -chloasma, folliculitis, hypertrichosis, piloerection, seborrhea, skin hypertrophy, skin ulceration.

Special Senses – Infrequent -abnormal accommodation, deafness, diplopia, earache, eye pain, foreign body sensation, hyperacusis, parosmia, photophobia, scleritis, taste loss. Rare -blepharitis, chromatopsia, conjunctival hemorrhage, exophthalmos, glaucoma, keratitis, labyrinth disorder, night blindness, retinal disorder, strabismus, visual field defect.

Urogenital System – Infrequent -endometriosis, epididymitis, hematuria, nocturia, oliguria, ovarian cyst, perineal pain, polyuria, prostatic disorder, renal calculus, renal pain, urethral disorder, urinary incontinence, uterine hemorrhage, vaginal hemorrhage. Rare - albuminuria, anorgasmy, breast engorgement, breast fibroadenosis, cervical dysplasia, endometrial hyperplasia, premature ejaculation, pyelonephritis, pyuria, renal cyst, uterine inflammation, vulvar disorder.

Postmarketing Experience

The following adverse drug reaction has been reported during post-approval use of clomipramine hydrochloride capsules, USP. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency.

Eye Disorders – Angle-closure glaucoma.

Immune System Disorders –Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).

Metabolism and Nutrition Disorders –Hyponatremia.

Endocrine Disorders –Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc. at 1-855-839-8195 or FDA at 1-800-FDA-1088 or ww.fda.gov/medwatch

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 notbe used with MAO inhibitors ( see CONTRAINDICATIONS ).

Close supervision and careful adjustment of dosage are required when clomipramine hydrochloride capsule 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 capsules, USP) 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 hydrochloride capsule, USP is going to be co-administered with another drug known to be an inhibitor of P450 2D6 (and/or P450 1A2).

Because clomipramine hydrochloride capsule, USP is highly bound to serum protein, the administration of clomipramine hydrochloride capsules, USP 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 hydrochloride capsules, USP by other highly bound drugs ( see CLINICAL PHARMACOLOGY , Distribution ).

Monoamine Oxidase Inhibitors (MAOIs)

( See CONTRAINDICATIONS , WARNINGS , and DOSAGE AND ADMINISTRATION .)

Serotonergic Drugs

( See CONTRAINDICATIONS , WARNINGS , and DOSAGE AND ADMINISTRATION .)

Drug Abuse and Dependence

Clomipramine hydrochloride capsules, USP have not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While a variety of withdrawal symptoms have been described in association with clomipramine hydrochloride capsules, USP discontinuation ( see PRECAUTIONS, Withdrawal Symptoms ), there is no evidence for drug-seeking behavior, except for a single report of potential clomipramine hydrochloride capsules, USP abuse by a patient with a history of dependence on codeine, benzodiazepines, and multiple psychoactive drugs. The patient received clomipramine hydrochloride capsules, USP for depression and panic attacks and appeared to become dependent after hospital discharge.

Despite the lack of evidence suggesting an abuse liability for clomipramine hydrochloride capsules, USP in foreign marketing, it is not possible to predict the extent to which clomipramine hydrochloride capsules, USP might be misused or abused once marketed in the U.S. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely.

Overdosage

Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic overdose. Therefore, hospital monitoring is required as soon as possible.

Human Experience

In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with clomipramine hydrochloride capsules, USP 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. The 10 nonfatal cases involved doses of up to 5000 mg, accompanied by plasma levels of up to 1010 ng/mL. All 10 patients completely recovered. Among reports from other countries of clomipramine hydrochloride capsules, USP overdose, the lowest dose associated with a fatality was 750 mg. Based upon postmarketing reports in the United Kingdom, CMI’s lethality in overdose is considered to be similar to that reported for closely related tricyclic compounds marketed as antidepressants.

Manifestations

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. Other CNS manifestations may include drowsiness, stupor, ataxia, restlessness, agitation, delirium, severe perspiration, hyperactive reflexes, muscle rigidity, and athetoid and choreiform movements. Cardiac abnormalities may include tachycardia, signs of congestive heart failure, and in very rare cases, cardiac arrest. Respiratory depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and oliguria or anuria may also be present.

Management

Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an  intravenous  line,  and  initiate  gastric  decontamination.  A  minimum  of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary.

If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient.

Gastrointestinal Decontamination –All patients suspected of tricyclic overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated.

Cardiovascular –A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH >7.60 or a pCO ₂<20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).

In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic poisoning.

CNS –In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center.

Psychiatric Follow-up –Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.

Pediatric Management –The principles of management of child and  adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

Description

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

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

Inactive Ingredients:magnesium stearate and pregelatinized starch (corn).

In addition, the 25 mg capsule shell contains: D&C Yellow No. 10, gelatin, iron oxide yellow and titanium dioxide. 

The 50 mg capsule shell contains: D&C Yellow No. 10, FD&C Blue No. 1, gelatin and titanium dioxide.

The 75 mg capsule shell contains: D&C Yellow No. 10, gelatin and titanium dioxide.

The black imprinting ink contains: black iron oxide and shellac.

FDA approved dissolution test specifications differ from USP

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 capsule, USP 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 C _ssand 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 C _ssand 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, USP 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 capsule, USP 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 C _ssand 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, USP 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.

How Supplied / Storage and Handling

Clomipramine Hydrochloride 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) [see USP Controlled Room Temperature].

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

Patient Counseling Information

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with clomipramine hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for clomipramine hydrochloride. 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 the 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 hydrochloride.

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 look 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 capsules, USP:

(1)  The risk of seizure (see WARNINGS );

(2)  The relatively high incidence of sexual dysfunction among males (see Sexual Dysfunction );

(3)  Since clomipramine hydrochloride capsules, USP may impair the mental and/or physical abilities required for the performance of complex tasks, and since clomipramine hydrochloride capsule 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 hydrochloride capsules, USP 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.

Patients should be advised that taking clomipramine hydrochloride capsules, USP can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre­-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.