Get your patient on Clomipramine Hydrochloride - Clomipramine Hydrochloride capsule (Clomipramine Hydrochloride)

Clomipramine hydrochloride capsules, USP 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 1,989) 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 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 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 ).

The treatment regimens described below are based on those used in controlled clinical trials of clomipramine hydrochloride 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 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, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of clomipramine hydrochloride 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. Conversely, at least 14 days should be allowed after stopping clomipramine hydrochloride 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 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 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 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 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 is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use ( see WARNINGS ).

Clomipramine hydrochloride 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 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 within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated ( see WARNINGS and DOSAGE AND ADMINISTRATION ).

Starting clomipramine hydrochloride 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 is contraindicated during the acute recovery period after a myocardial infarction.

Commonly Observed

The most commonly observed adverse events associated with the use of clomipramine hydrochloride 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 3,616 patients who received clomipramine hydrochloride 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 in adult or pediatric placebo- controlled clinical trials. The frequencies were obtained from pooled data of clinical trials involving  either adults  receiving  clomipramine hydrochloride (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.

Other Events Observed During the Premarketing Evaluation of Clomipramine Hydrochloride

During clinical testing in the U.S., multiple doses of clomipramine hydrochloride were administered to approximately 3,600 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 3,525 individuals exposed to clomipramine hydrochloride who experienced an event of the type cited on at least one occasion while receiving clomipramine hydrochloride. 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, 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 1/1,000 patients; rare events are those occurring in less than 1/1,000 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. 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).

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

Close supervision and careful adjustment of dosage are required when clomipramine hydrochloride 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 ).

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

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

Each capsule contains clomipramine hydrochloride USP, 25 mg or 50 mg or 75 mg and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate and pre-gelatinized starch. Additionally, the hard gelatin capsule shell contains:  D&C Yellow No. 10, FD&C Red No. 40 (25 mg capsules only), FD&C Blue No. 1(50 mg capsules only), gelatin, titanium dioxide and purified water. Each capsule is imprinted with black pharmaceutical ink which contains black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac and strong ammonia solution.

FDA approved dissolution specifications differ from the USP dissolution specifications.

Clomipramine hydrochloride capsules, USP for oral administration are supplied as:

25 mg: White to off-white powder filled in Size “3” hard gelatin capsule with melon yellow opaque cap imprinted with “25 mg” in black ink and ivory white opaque body imprinted with “VP” in black ink.

They are available as:

NDC 72664- 214 -30 in bottle of 30 capsules

NDC 72664- 214 -90 in bottle of 90 capsules

50 mg: White to off-white powder filled in Size “1” hard gelatin capsule with aqua blue opaque cap imprinted with “50 mg” in black ink and ivory white opaque body imprinted with “VP” in black ink.

They are available as:

NDC 72664- 215 -30 in bottle of 30 capsules

NDC 72664- 215 -90 in bottle of 90 capsules

75 mg: White to off-white powder filled in Size “1” hard gelatin capsule with yellow opaque cap imprinted with “75 mg” in black ink and ivory white opaque body imprinted with “VP” in black ink.

They are available as:

NDC 72664- 216 -30 in bottle of 30 capsules

NDC 72664- 216 -90 in bottle of 90 capsules

Storage

Store at 20º to 25ºC (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in tight, light-resistant containers with a child-resistant closure. Protect from moisture.