ClomiPRAMINE HYDROCHLORIDE CAPSULES USP
0956
0958
0960

Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of ClomiPRAMINE hydrochloride capsules or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. ClomiPRAMINE hydrochloride capsules are not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD). (See WARNINGS and PRECAUTIONS, Pediatric Use.)

Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.

ClomiPRAMINE hydrochloride is an antiobsessional drug that belongs to the class (dibenzazepine) of pharmacologic agents known as tricyclic antidepressants.

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

C₁₉H₂₃ClN₂≈HCl M.W. 351.3

ClomiPRAMINE hydrochloride is a white to off-white crystalline powder. It is freely soluble in water, in methanol, and in methylene chloride, and insoluble in ethyl ether and in hexane.

Each capsule, for oral administration, contains 25 mg, 50 mg, or 75 mg of ClomiPRAMINE hydrochloride. In addition, each capsule contains the following inactive ingredients: pregelatinized starch, colloidal silicon dioxide, magnesium stearate, titanium dioxide, shellac, black iron oxide, and gelatin. Each 25 mg capsule contains D&C Red No. 28, FD&C Red No. 40, D&C Yellow No. 10, FD&C Blue No. 1. Each 50 mg capsule contains FD&C Blue No. 1. Each 75 mg capsule contains red iron oxide and yellow iron oxide.

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

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 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 ClomiPRAMINE 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. ClomiPRAMINE-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 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 for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

ClomiPRAMINE hydrochloride capsules are contraindicated in patients with a history of hypersensitivity to ClomiPRAMINE or other tricyclic antidepressants.

ClomiPRAMINE should not be given in combination, or within 14 days before or after treatment, with a monoamine oxidase (MAO) inhibitor. Hyperpyretic crisis, seizures, coma, and death have been reported in patients receiving such combinations.

ClomiPRAMINE is contraindicated during the acute recovery period after a myocardial infarction.

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.

Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%.

There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults.

All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.

Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for ClomiPRAMINE hydrochloride capsules should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised.

During premarket evaluation, seizure was identified as the most significant risk of ClomiPRAMINE hydrochloride use.

The observed cumulative incidence of seizures among patients exposed to ClomiPRAMINE hydrochloride at doses up to 300 mg/day was 0.64% at 90 days, 1.12% at 180 days, and 1.45% at 365 days. The cumulative rates correct the crude rate of 0.7%, (25 of 3,519 patients) for the variable duration of exposure in clinical trials.

Although dose appears to be a predictor of seizure, there is a confounding of dose and duration of exposure, making it difficult to assess independently the effect of either factor alone. The ability to predict the occurrence of seizures in subjects exposed to doses of ClomiPRAMINE hydrochloride greater than 250 mg is limited, given that the plasma concentration of ClomiPRAMINE may be dose-dependent and may vary among subjects given the same dose. Nevertheless, prescribers are advised to limit the daily dose to a maximum of 250 mg in adults and 3 mg/kg (or 200 mg) in children and adolescents (see DOSAGE AND ADMINISTRATION).

Caution should be used in administering ClomiPRAMINE to patients with a history of seizures or other predisposing factors, e.g., brain damage of varying etiology, alcoholism, and concomitant use with other drugs that lower the seizure threshold.

Rare reports of fatalities in association with seizures have been reported by foreign postmarketing surveillance, but not in U.S. clinical trials. In some of these cases, ClomiPRAMINE had been administered with other epileptogenic agents; in others, the patients involved had possibly predisposing medical conditions. Thus a causal association between ClomiPRAMINE treatment and these fatalities has not been established.

Physicians should discuss with patients the risk of taking ClomiPRAMINE while engaging in activities in which sudden loss of consciousness could result in serious injury to the patient or others, e.g., the operation of complex machinery, driving, swimming, climbing.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with ClomiPRAMINE hydrochloride capsules and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for ClomiPRAMINE hydrochloride capsules. 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 spans. Patients should be given the opportunity to discuss the spans of the Medication Guide and to obtain answers to any questions they may have. The complete div 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 capsules.

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

Close supervision and careful adjustment of dosage are required when ClomiPRAMINE 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 ClomiPRAMINE because of its structural similarity to other tricyclic antidepressants.

The plasma concentration of ClomiPRAMINE 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 ClomiPRAMINE as well. Administration of ClomiPRAMINE has been reported to increase the plasma levels of phenobarbital, if given concomitantly (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Interactions).

No evidence of carcinogenicity was found in two 2 year bioassays in rats at doses up to 100 mg/kg, which is 24 and 4 times the maximum recommended human daily dose (MRHD) on a mg/kg and mg/m² basis, respectively, or in a 2 year bioassay in mice at doses up to 80 mg/kg, which is 20 and 1.5 times the MRHD on a mg/kg and mg/m² basis, respectively.

In reproduction studies, no effects on fertility were found in rats given up to 24 mg/kg, which is 6 times, and approximately equal to, the MRHD on a mg/kg and mg/m² basis, respectively.

ClomiPRAMINE has been found in human milk. Because of the potential for adverse reactions, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of ClomiPRAMINE hydrochloride capsules in a child or adolescent must balance the potential risks with the clinical need.

In a controlled clinical trial in children and adolescents (10 to 17 years of age), 46 outpatients received ClomiPRAMINE for up to 8 weeks. In addition, 150 adolescent patients have received ClomiPRAMINE in open-label protocols for periods of several months to several years. Of the 196 adolescents studied, 50 were 13 years of age or less and 146 were 14 to 17 years of age. The adverse reaction profile in this age group (see ADVERSE REACTIONS) is similar to that observed in adults.

The risks, if any, that may be associated with ClomiPRAMINE’s extended use in children and adolescents with OCD have not been systematically assessed. The evidence supporting the conclusion that ClomiPRAMINE is safe for use in children and adolescents is derived from relatively short term clinical studies and from extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long term ClomiPRAMINE use on the growth, development, and maturation of children and adolescents. Although there is no evidence to suggest that ClomiPRAMINE adversely affects growth, development or maturation, the absence of such findings is not adequate to rule out a potential for such effects in chronic use.

The safety and effectiveness in pediatric patients below the age of 10 have not been established. Therefore, specific recommendations cannot be made for the use of ClomiPRAMINE in pediatric patients under the age of 10.

Clinical studies of ClomiPRAMINE hydrochloride did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects; 152 patients at least 60 years of age participating in various U.S. clinical trials received ClomiPRAMINE hydrochloride for periods of several months to several years. No unusual age-related adverse events were identified in this population. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

The most commonly observed adverse events associated with the use of ClomiPRAMINE 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 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 in adult or pediatric placebo-controlled clinical trials. The frequencies were obtained from pooled data of clinical trials involving either adults receiving ClomiPRAMINE (N = 322) or placebo (N = 319) or children treated with ClomiPRAMINE (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 non-drug factors to the incidence of side effects in the populations studied.

During clinical testing in the U.S., multiple doses of ClomiPRAMINE 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 who experienced an event of the type cited on at least one occasion while receiving ClomiPRAMINE. All events are included except those already uled 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, they were not necessarily caused by it.

Events are further categorized by body system and uled 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.

ClomiPRAMINE has 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 discontinuation (see PRECAUTIONS, General, Withdrawal Symptoms), there is no evidence for drug-seeking behavior, except for a single report of potential ClomiPRAMINE abuse by a patient with a history of dependence on codeine, benzodiazepines, and multiple psychoactive drugs. The patient received ClomiPRAMINE for depression and panic attacks and appeared to become dependent after hospital discharge.

Despite the lack of evidence suggesting an abuse liability for ClomiPRAMINE in foreign marketing, it is not possible to predict the extent to which ClomiPRAMINE 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.

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.

In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with ClomiPRAMINE either alone or in combination with other drugs. One death involved a patient suspected of ingesting a dose of 7,000 mg. The second death involved a patient suspected of ingesting a dose of 5,750 mg. The 10 nonfatal cases involved doses of up to 5,000 mg, accompanied by plasma levels of up to 1,010 ng/mL. All 10 patients completely recovered. Among reports from other countries of ClomiPRAMINE overdose, the lowest dose associated with a fatality was 750 mg. Based upon postmarketing reports in the United Kingdom, ClomiPRAMINE’s lethality in overdose is considered to be similar to that reported for closely related tricyclic compounds marketed as antidepressants.

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.

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.

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 Pco₂< 20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1 A and 1 C 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.

The treatment regimens described below are based on those used in controlled clinical trials of ClomiPRAMINE in 520 adults, and 91 children and adolescents with OCD. During initial titration, ClomiPRAMINE 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 ClomiPRAMINE and its active metabolite, desmethylclomipramine, 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.

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 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 (see PRECAUTIONS, Pediatric Use). 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, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of ClomiPRAMINE 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.

ClomiPRAMINE hydrochloride capsules USP are available as follows:

ClomiPRAMINE hydrochloride capsules USP, 25 mg: No. 2 capsule with a white body and a medium orange cap, imprinted “93”“956” on both the body and the cap, available in bottles of 100.

ClomiPRAMINE hydrochloride capsules USP, 50 mg: No. 1 capsule with a white body and light blue cap, imprinted “93”“958” on both the body and the cap, available in bottles of 100.

ClomiPRAMINE hydrochloride capsules USP, 75 mg: No. 0 capsule with a white body and caramel cap, imprinted “93”“960” on both the body and the cap, available in bottles of 100.

Store at 20^o to 25^oC (68^o to 77^oF) [See USP Controlled Room Temperature].

Protect from moisture.

Dispense spans in a tight container as defined in the USP, with a child-resistant closure (as required).

Phospholipidosis and testicular changes, commonly associated with tricyclic compounds, have been observed with ClomiPRAMINE. In chronic rat studies, changes related to ClomiPRAMINE consisted of systemic phospholipidosis, alterations in the testes (atrophy, mineralization) and secondary changes in other tissues. In addition, cardiac thrombosis and dermatitis/keratitis were observed in rats treated for 2 years at doses which were 24 and 10 times the maximum recommended human daily dose (MRHD), respectively, on a mg/kg basis, and 4 and 1.5 times the MRHD, respectively, on a mg/m2 basis.

What is the most important information I should know if my child is being prescribed an antidepressant?

Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant:

• There is a risk of suicidal thoughts or actions
• How to try to prevent suicidal thoughts or actions in your child
• You should watch for certain signs if your child is taking an antidepressant
• There are benefits and risks when using antidepressants

1. There is a Risk of Suicidal Thoughts or Actions

Children and teenagers sometimes think about suicide, and many report trying to kill themselves.

Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal.

A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal.

For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with

• Bipolar illness (sometimes called manic-depressive illness)
• A family history of bipolar illness
• A personal or family history of attempting suicide

If any of these are present, make sure you tell your healthcare provider before your child takes an antidepressant.

2. How to Try to Prevent Suicidal Thoughts and Actions

To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child's life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are uled in Section 3, on what to watch for.

Whenever an antidepressant is started or its dose is changed, pay close attention to your child.

After starting an antidepressant, your child should generally see his or her healthcare provider:

• Once a week for the first 4 weeks
• Every 2 weeks for the next 4 weeks
• After taking the antidepressant for 12 weeks
• After 12 weeks, follow your healthcare provider's advice about how often to come back
• More often if problems or questions arise (see Section 3)

You should call your child's healthcare provider between visits if needed.

3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant

Contact your child's healthcare provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child's teacher:

• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Difficulty sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking
• Other unusual changes in behavior or mood

Never let your child stop taking an antidepressant without first talking to his or her healthcare provider. Stopping an antidepressant suddenly can cause other symptoms.

4. There are Benefits and Risks When Using Antidepressants

Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your healthcare provider, not just the use of antidepressants.

Other side effects can occur with antidepressants (see section below).

Of all the antidepressants, only fluoxetine (Prozac^®)^* has been FDA approved to treat pediatric depression.

For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (Prozac^®)^*, sertraline (Zoloft^®)^*, fluvoxamine, and clomipramine (Anafranil^®)^*.

Your healthcare provider may suggest other antidepressants based on the past experience of your child or other family members.

Is this all I need to know if my child is being prescribed an antidepressant?

No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare provider or pharmacist where to find more information.

This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. M 3/2006