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 (

).

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 (

).  Therefore, after initial titration, it may be appropriate to wait 2 to 3 weeks between further dosage adjustments.

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.

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 (

). As with adults, after titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation.

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.

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 (

).

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 (

).

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 (

).

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 (

).

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.

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.

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.

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

Body System/ Adverse Event Events reported by at least 1% of clomipramine hydrochloride patients are included.	Adults		Children and Adolescents
	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	2	-	-	2
Dysphagia	2	-	-	-
Esophagitis	1	-	-	-
Eructation	-	-	2	2
Ulcerative stomatitis	-	-	2	-
Body as a Whole
Fatigue	39	18	35	9
Weight increase	18	1	2	-
Flushing	8	-	7	-
Hot flushes	5	-	2	-
Chest pain	4	4	7	-
Fever	4	-	2	7
Allergy	3	3	7	5
Pain	3	2	4	2
Local edema	2	4	-	-
Chills	2	1	-	-
Weight decrease	-	-	7	-
Otitis media	-	-	4	5
Asthenia	-	-	2	-
Halitosis	-	-	2	-
Cardiovascular System
Postural hypotension	6	-	4	-
Palpitation	4	2	4	-
Tachycardia	4	-	2	-
Syncope	-	-	2	-
Respiratory System
Pharyngitis	14	9	-	5
Rhinitis	12	10	7	9
Sinusitis	6	4	2	5
Coughing	6	6	4	5
Bronchospasm	2	-	7	2
Epistaxis	2	-	-	2
Dyspnea	-	-	2	-
Laryngitis	-	1	2	-
Urogenital System Male and Female Patients Combined
Micturition disorder	14	2	4	2
Urinary tract infection	6	1	-	-
Micturition frequency	5	3	-	-
Urinary retention	2	-	7	-
Dysuria	2	2	-	-
Cystitis	2	-	-	-
Female Patients Only	(N=182)	(N=167)	(N=10)	(N=21)
Dysmenorrhea	12	14	10	10
Lactation (nonpuerperal)	4	-	-	-
Menstrual disorder	4	2	-	-
Vaginitis	2	-	-	-
Leukorrhea	2	-	-	-
Breast enlargement	2	-	-	-
Breast pain	1	-	-	-
Amenorrhea	1	-	-	-
Male Patients Only	(N=140)	(N=152)	(N=36)	(N=23)
Ejaculation failure	42	2	6	-
Impotence	20	3	-	-
Special Senses
Abnormal vision	18	4	7	2
Taste perversion	8	-	4	-
Tinnitus	6	-	4	-
Abnormal lacrimation	3	2	-	-
Mydriasis	2	-	-	-
Conjunctivitis	1	-	-	-
Anisocoria	-	-	2	-
Blepharospasm	-	-	2	-
Ocular allergy	-	-	2	-
Vestibular disorder	-	-	2	2
Musculoskeletal
Myalgia	13	9	-	-
Back pain	6	6	-	-
Arthralgia	3	5	-	-
Muscle weakness	1	-	2	-
Hemic and Lymphatic
Purpura	3	-	-	-
Anemia	-	-	2	2
Metabolic and Nutritional
Thirst	2	2	-	2

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.

general edema, increased susceptibility to infection, malaise.

dependent edema, withdrawal syndrome.

abnormal  ECG,  arrhythmia,  bradycardia, cardiac arrest, extrasystoles, pallor.

aneurysm, atrial flutter, bundle branch block, cardiac failure, cerebral hemorrhage, heart block, myocardial infarction, myocardial ischemia, peripheral ischemia, thrombophlebitis, vasospasm, ventricular tachycardia.

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.

cheilitis, chronic enteritis, discolored feces, gastric dilatation, gingival bleeding, hiccup, intestinal obstruction, oral/pharyngeal edema, paralytic ileus, salivary gland enlargement.

- hypothyroidism.

goiter, gynecomastia, hyperthyroidism.

lymphadenopathy.

leukemoid reaction, lymphoma-like disorder, marrow depression.

dehydration, diabetes mellitus, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypokalemia.

fat intolerance, glycosuria.

arthrosis.

dystonia, exostosis, lupus erythematosus rash, bruising, myopathy, myositis, polyarteritis nodosa, torticollis.

abnormal thinking, vertigo.

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.

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.

bronchitis, hyperventilation, increased sputum, pneumonia.

cyanosis, hemoptysis, hypoventilation, laryngismus.

alopecia, cellulitis, cyst, eczema, erythematous rash, genital pruritus, maculopapular rash, photosensitivity reaction, psoriasis, pustular rash, skin discoloration.

chloasma, folliculitis, hypertrichosis, piloerection, seborrhea, skin hypertrophy, skin ulceration.

abnormal accommodation, deafness, diplopia, earache, eye pain, foreign body sensation, hyperacusis, parosmia, photophobia, scleritis, taste loss.

blepharitis, chromatopsia, conjunctival hemorrhage, exophthalmos, glaucoma, keratitis, labyrinth disorder, night blindness, retinal disorder, strabismus, visual field defect.

endometriosis, epididymitis, hematuria, nocturia, oliguria, ovarian cyst, perineal pain, polyuria, prostatic disorder, renal calculus, renal pain, urethral disorder, urinary incontinence, uterine hemorrhage, vaginal hemorrhage.

albuminuria, anorgasmy, breast engorgement, breast fibroadenosis, cervical dysplasia, endometrial hyperplasia, premature ejaculation, pyelonephritis, pyuria, renal cyst, uterine inflammation, vulvar disorder.

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.

Angle-closure glaucoma.

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)

Hyponatremia.

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 (

).Clomipramine hydrochloride should
be used with MAO inhibitors (
).

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 (

).