clomipramine hydrochloride 40 MG Oral Tablet

INDICATIONS AND USAGE Clomipramine hydrochloride capsules, USP is indicated for the treatment of obsessions and compulsions in patients with Obsessive-Compulsive Disorder (OCD). The obsessions or compulsions must cause marked distress, be time-consuming, or significantly interfere with social or occupational functioning, in order to meet the DSM-III-R (circa 1989) diagnosis of OCD. Obsessions are recurrent, persistent ideas, thoughts, images, or impulses that are ego­-dystonic. Compulsions are repetitive, purposeful, and intentional behaviors performed in response to an obsession or in a stereotyped fashion, and are recognized by the person as excessive or unreasonable. The effectiveness of clomipramine hydrochloride capsules, USP for the treatment of OCD was demonstrated in multicenter, placebo-controlled, parallel-group studies, including two 10-week studies in adults and one 8-week study in children and adolescents 10 to 17 years of age. Patients in all studies had moderate-to-severe OCD (DSM-III), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS) ranging from 26 to 28 and a mean baseline rating of 10 on the NIMH Clinical Global Obsessive Compulsive Scale (NIMH-OC). Patients taking CMI experienced a mean reduction of approximately 10 on the YBOCS, representing an average improvement on this scale of 35% to 42% among adults and 37% among children and adolescents. CMI-treated patients experienced a 3.5 unit decrement on the NIMH-OC. Patients on placebo showed no important clinical response on either scale. The maximum dose was 250 mg/day for most adults and 3 mg/kg/day (up to 200 mg) for all children and adolescents. The effectiveness of clomipramine hydrochloride capsules, USP for long-term use (i.e., for more than 10 weeks) has not been systematically evaluated in placebo-controlled trials. The physician who elects to use clomipramine hydrochloride capsules, USP for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient ( see DOSAGE AND ADMINISTRATION ).

DOSAGE AND ADMINISTRATION The treatment regimens described below are based on those used in controlled clinical trials of clomipramine hydrochloride capsules, USP in 520 adults, and 91 children and adolescents with OCD. During initial titration, clomipramine hydrochloride capsules, USP should be given in divided doses with meals to reduce gastrointestinal side effects. The goal of this initial titration phase is to minimize side effects by permitting tolerance to side effects to develop or allowing the patient time to adapt if tolerance does not develop. Because both CMI and its active metabolite, DMI, have long elimination half-lives, the prescriber should take into consideration the fact that steady-state plasma levels may not be achieved until 2 to 3 weeks after dosage change ( see CLINICAL PHARMACOLOGY ). Therefore, after initial titration, it may be appropriate to wait 2 to 3 weeks between further dosage adjustments. Initial Treatment/Dose Adjustment (Adults) Treatment with clomipramine hydrochloride capsules, USP should be initiated at a dosage of 25 mg daily and gradually increased, as tolerated, to approximately 100 mg during the first 2 weeks. During initial titration, clomipramine hydrochloride capsules, USP should be given in divided doses with meals to reduce gastrointestinal side effects. Thereafter, the dosage may be increased gradually over the next several weeks, up to a maximum of 250 mg daily. After titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation. Initial Treatment/Dose Adjustment (Children and Adolescents) As with adults, the starting dose is 25 mg daily and should be gradually increased (also given in divided doses with meals to reduce gastrointestinal side effects) during the first 2 weeks, as tolerated, up to a daily maximum of 3 mg/kg or 100 mg, whichever is smaller. Thereafter, the dosage may be increased gradually over the next several weeks up to a daily maximum of 3 mg/kg or 200 mg, whichever is smaller ( see PRECAUTIONS, Pediatric Use ). As with adults, after titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation. Maintenance/Continuation Treatment (Adults, Children, and Adolescents) While there are no systematic studies that answer the question of how long to continue clomipramine hydrochloride capsules, USP OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of clomipramine hydrochloride capsules, USP after 10 weeks has not been documented in controlled trials, patients have been continued in therapy under double- blind conditions for up to 1 year without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment. During maintenance, the total daily dose may be given once daily at bedtime. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with clomipramine hydrochloride capsules, USP. Conversely, at least 14 days should be allowed after stopping clomipramine hydrochloride capsules, USP before starting an MAOI intended to treat psychiatric disorders ( see CONTRAINDICATIONS ). Use of Clomipramine Hydrochloride With Other MAOIs, Such as Linezolid or Methylene Blue Do not start clomipramine hydrochloride capsules, USP in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered ( see CONTRAINDICATIONS ). In some cases, a patient already receiving clomipramine hydrochloride capsules, USP therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, clomipramine hydrochloride capsules, USP should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with clomipramine hydrochloride capsules, USP may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue ( see WARNINGS ). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with clomipramine hydrochloride capsule, USP is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use ( see WARNINGS ).

WARNINGS Clinical Worsening and Suicide Risk 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. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long­-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table-1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and 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. 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 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 healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for clomipramine hydrochloride should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder – A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that clomipramine hydrochloride is not approved for use in treating bipolar depression. Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including clomipramine hydrochloride capsules, USP alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of clomipramine hydrochloride capsules, USP with MAOIs intended to treat psychiatric disorders is contraindicated. Clomipramine hydrochloride capsules, USP should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking clomipramine hydrochloride capsules, USP. Clomipramine hydrochloride capsules, USP should be discontinued before initiating treatment with the MAOI ( see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION ) . If concomitant use of clomipramine hydrochloride capsules, USP with other serotoner

CONTRAINDICATIONS Clomipramine hydrochloride capsules, USP are contraindicated in patients with a history of hypersensitivity to clomipramine hydrochloride capsules, USP or other tricyclic antidepressants. Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with clomipramine hydrochloride capsules, USP or within 14 days of stopping treatment with clomipramine hydrochloride capsules, USP are contraindicated because of an increased risk of serotonin syndrome. The use of clomipramine hydrochloride capsules, USP within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated ( see WARNINGS and DOSAGE AND ADMINISTRATION ). Starting clomipramine hydrochloride capsules, USP in a patient who is being treated with linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome ( see WARNINGS and DOSAGE AND ADMINISTRATION ). Myocardial Infarction Clomipramine hydrochloride capsules, USP are contraindicated during the acute recovery period after a myocardial infarction.

CLINICAL PHARMACOLOGY Pharmacodynamics Clomipramine (CMI) is presumed to influence obsessive and compulsive behaviors through its effects on serotonergic neuronal transmission. The actual neurochemical mechanism is unknown, but CMI’s capacity to inhibit the reuptake of serotonin (5-HT) is thought to be important. Pharmacokinetics Absorption/Bioavailability – CMI from clomipramine hydrochloride capsule, USP is as bioavailable as CMI from a solution. The bioavailability of CMI from capsules is not significantly affected by food. In a dose proportionality study involving multiple CMI doses, steady-state plasma concentrations (Css) and area-under-plasma-concentration-time curves (AUC) of CMI and CMI’s major active metabolite, desmethylclomipramine (DMI), were not proportional to dose over the ranges evaluated, i.e., between 25 to 100 mg/day and between 25 to 150 mg/day, although C ss and AUC are approximately linearly related to dose between 100 to 150 mg/day. The relationship between dose and CMI/DMI concentrations at higher daily doses has not been systematically assessed, but if there is significant dose dependency at doses above 150 mg/day, there is the potential for dramatically higher C ss and AUC even for patients dosed within the recommended range. This may pose a potential risk to some patients ( see WARNINGS and PRECAUTIONS , Drug Interactions ). After a single 50 mg oral dose, maximum plasma concentrations of CMI occur within 2 to 6 hours (mean, 4.7 hr) and range from 56 ng/mL to 154 ng/mL (mean, 92 ng/mL). After multiple daily doses of 150 mg of clomipramine hydrochloride capsules, USP steady-state maximum plasma concentrations range from 94 ng/mL to 339 ng/mL (mean, 218 ng/mL) for CMI and from 134 ng/mL to 532 ng/mL (mean, 274 ng/mL) for DMI. Additional information from a rising dose study of doses up to 250 mg suggests that DMI may exhibit nonlinear pharmacokinetics over the usual dosing range. At a dose of clomipramine hydrochloride capsule, USP 200 mg, subjects who had a single blood sample taken approximately 9 to 22 hours, (median 16 hours), after the dose had plasma concentrations of up to 605 ng/mL for CMI, 781 ng/mL for DMI, and 1386 ng/mL for both. Distribution – CMI distributes into cerebrospinal fluid (CSF) and brain and into breast milk. DMI also distributes into CSF, with a mean CSF/plasma ratio of 2.6. The protein binding of CMI is approximately 97%, principally to albumin, and is independent of CMI concentration. The interaction between CMI and other highly protein-bound drugs has not been fully evaluated, but may be important ( see PRECAUTIONS , Drug Interactions ). Metabolism – CMI is extensively biotransformed to DMI and other metabolites and their glucuronide conjugates. DMI is pharmacologically active, but its effects on OCD behaviors are unknown. These metabolites are excreted in urine and feces, following biliary elimination. After a 25 mg radiolabeled dose of CMI in two subjects, 60% and 51%, respectively, of the dose were recovered in the urine and 32% and 24%, respectively, in feces. In the same study, the combined urinary recoveries of CMI and DMI were only about 0.8% to 1.3% of the dose administered. CMI does not induce drug- metabolizing enzymes, as measured by antipyrine half-life. Elimination – Evidence that the C ss and AUC for CMI and DMI may increase disproportionately with increasing oral doses suggests that the metabolism of CMI and DMI may be capacity limited. This fact must be considered in assessing the estimates of the pharmacokinetic parameters presented below, as these were obtained in individuals exposed to doses of 150 mg. If the pharmacokinetics of CMI and DMI are nonlinear at doses above 150 mg, their elimination half-lives may be considerably lengthened at doses near the upper end of the recommended dosing range (i.e., 200 mg/day to 250 mg/day). Consequently, CMI and DMI may accumulate, and this accumulation may increase the incidence of any dose- or plasma-concentration-dependent adverse reactions, in particular seizures ( see WARNINGS ). After a 150 mg dose, the half-life of CMI ranges from 19 hours to 37 hours (mean, 32 hr) and that of DMI ranges from 54 hours to 77 hours (mean, 69 hr). Steady-state levels after multiple dosing are typically reached within 7 to 14 days for CMI. Plasma concentrations of the metabolite exceed the parent drug on multiple dosing. After multiple dosing with 150 mg/day, the accumulation factor for CMI is approximately 2.5 and for DMI is 4.6. Importantly, it may take two weeks or longer to achieve this extent of accumulation at constant dosing because of the relatively long elimination half-lives of CMI and DMI ( see DOSAGE AND ADMINISTRATION ). The effects of hepatic and renal impairment on the disposition of clomipramine hydrochloride capsules, USP have not been determined. Interactions – Co-administration of haloperidol with CMI increases plasma concentrations of CMI. Co-administration of CMI with phenobarbital increases plasma concentrations of phenobarbital ( see PRECAUTIONS , Drug Interactions ). Younger subjects (18 to 40 years of age) tolerated CMI better and had significantly lower steady-state plasma concentrations, compared with subjects over 65 years of age. Children under 15 years of age had significantly lower plasma concentration/dose ratios, compared with adults. Plasma concentrations of CMI were significantly lower in smokers than in nonsmokers.