Clomipramine Hydrochloride

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 (

).

The treatment regimens described below are based on those used in controlled clinical trials of clomipramine hydrochloride capsules in 520 adults, and 91 children and adolescents with OCD. During initial titration, clomipramine hydrochloride capsules 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 capsules 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 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 daytimesedation.

While there are no systematic studies that answer the question of how long to continue clomipramine hydrochloride capsules, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of clomipramine hydrochloride capsules 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 capsules.  Conversely,  at  least  14 days should be allowed after stopping clomipramine hydrochloride capsules before starting an MAOI intended to treat psychiatric disorders (

).

Do not start clomipramine hydrochloride capsules 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 capsules 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 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 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 capsule 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 capsules 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 3616 patients who received clomipramine hydrochloride capsules 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 capsules 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 (N=322) or placebo (N=319) or children treated with clomipramine hydrochloride capsules (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.

	Adults				Children and Adolescents
Body System/                       Adverse Event*	Clomipramine Hydrochloride Capsules  (N=322)		Placebo (N=319)		Clomipramine Hydrochloride Capsules  (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

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

During clinical testing in the U.S., multiple doses of clomipramine hydrochloride capsules 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 who experienced an event of the type cited on at least one occasion while receiving clomipramine hydrochloride capsules. 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, 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.

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 capsules. 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 capsules in combination with other drugs have not been systematically evaluated. Given the primary CNS effects of clomipramine hydrochloride capsules, caution is advised in using it concomitantly with other CNS-active drugs (

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

Close supervision and careful adjustment of dosage are required when clomipramine hydrochloride capsules are 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 (

).

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) 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 capsules are going to be co-administered with another drug known to be an inhibitor of P450 2D6 (and/or P450 1A2).

Because clomipramine hydrochloride capsules are highly bound to serum protein, the administration of clomipramine hydrochloride capsules 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 by other highly bound drugs (

).

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