Clomipramine Hydrochloride

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of clomipramine hydrochloride or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and 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 is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD) ( see WARNINGS, Clinical Worsening and Suicide Risk; PRECAUTIONS, Information for Patients; and PRECAUTIONS, Pediatric Use).

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 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 ( see DOSAGE AND ADMINISTRATION).

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

Clomipramine Hydrochloride Capsules USP

Capsules 25 mg – the body is opaque ivory with "T" and the cap is opaque orange with "280" imprinted on it

Bottles of 100…………………………………...NDC 52817-280-10

Capsules 50 mg – the body is opaque ivory with "T" and the cap is opaque light blue with "281" imprinted on it

Bottles of 100…………………………………..NDC 52817-281-10

Capsules 75 mg – the body is opaque ivory with "T" and the cap is opaque yellow with "282" imprinted on it

Bottles of 100…………………………………..NDC 52817-282-10

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

Monoamine Oxidase Inhibitors (MAOIs)

The use of MAOIs intended to treat psychiatric disorders with clomipramine hydrochloride capsules or within 14 days of stopping treatment with clomipramine hydrochloride capsules is contraindicated because of an increased risk of serotonin syndrome.  The use of clomipramine hydrochloride capsules 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 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 are contraindicated during the acute recovery period after a myocardial infarction.

Clomipramine hydrochloride capsules USP is an antiobsessional drug that belongs to the class (dibenzazepine) of pharmacologic agents known as tricyclic antidepressants. Clomipramine hydrochloride capsules are available as capsules of 25, 50, and 75 mg for oral administration.

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

Clomipramine hydrochloride USP 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.

Inactive Ingredients. colloidal silicon dioxide, D&C Yellow No. 10, FD&C Blue No. 1 (25 mg and 50 mg strengths only), FD&C Red No. 3 (25 mg and 50 mg strengths only), FD&C Red No. 40 (50 mg strength only), FD&C Yellow No. 6 (25 mg and 75 mg strength only), gelatin , magnesium stearate, pregelatinized starch, and titanium dioxide.

In addition, the black imprinting ink for the 25 mg, 50 mg and 75 mg capsules contains black iron oxide, propylene glycol, shellac, strong ammonia solution.

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 them concomitantly with other CNS-active drugs ( see Information for Patients). Clomipramine hydrochloride capsules should not be used with MAO inhibitors ( see CONTRAINDICATIONS).

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 ( see CLINICAL PHARMACOLOGY, Interactions).

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with clomipramine hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for clomipramine hydrochloride. 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 contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text 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.

Clomipramine hydrochloride 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 hydrochloride capsules  for up to 8 weeks. In addition, 150 adolescent patients have received clomipramine hydrochloride capsules 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 hydrochloride capsules' extended use in children and adolescents with OCD have not been systematically assessed. The evidence supporting the conclusion that clomipramine hydrochloride capsules are 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 hydrochloride capsules use on the growth, development, and maturation of children and adolescents. Although there is no evidence to suggest that clomipramine hydrochloride capsules adversely affect 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 hydrochloride capsules in pediatric patients under the age of 10.

Clinical studies of clomipramine hydrochloride capsules 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 capsules 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.

Clomipramine hydrochloride capsules has been associated with cases of clinically significant hyponatremia. Elderly patients may be at greater risk for this adverse reaction ( see PRECAUTIONS, Hyponatremia).

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/m ² 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/m ² 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/m ² basis, respectively.

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.

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.

Phospholipidosis and testicular changes, commonly associated with tricyclic compounds, have been observed with clomipramine hydrochloride capsules. In chronic rat studies, changes related to clomipramine hydrochloride capsules 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/m ² basis.

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

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

No teratogenic effects were observed in studies performed in rats and mice at doses up to 100 mg/kg, which is 24 times the maximum recommended human daily dose (MRHD) on a mg/kg basis and 4 times (rats) and 2 times (mice) the MRHD on a mg/m ² basis. Slight nonspecific embryo/fetotoxic effects were seen in the offspring of treated rats given 50 and 100 mg/kg and of treated mice given 100 mg/kg.

There are no adequate or well-controlled studies in pregnant women. Withdrawal symptoms, including jitteriness, tremor, and seizures, have been reported in neonates whose mothers had taken clomipramine hydrochloride capsules until delivery. Clomipramine hydrochloride capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

Read the Medication Guide that comes with you or your family member's antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's, healthcare provider about:

• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?

• Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
• Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
• How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
  
  
  
  
  • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
  • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
  • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

Low Salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:

• headache
• weakness or feeling unsteady
• confusion, problems concentrating or thinking or memory problems

Visual problems

• eye pain
• changes in vision
• swelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

Who should not take clomipramine hydrochloride capsules?

Do not take clomipramine hydrochloride capsules if you:

• Take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
  • Do not take an MAOI within 2 weeks of stopping clomipramine hydrochloride capsules unless directed to do so by your physician.
  • Do not start clomipramine hydrochloride capsules if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.

What else do I need to know about antidepressant medicines?

• Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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

Manufactured by

Tulex Pharmaceuticals Inc.

5 Cedarbrook Drive,

Cranbury, NJ 08512

Distributed By:

TruPharma, LLC

Tampa, FL33609



PI2801000300 Rev 04/2020

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

Dispense in well-closed containers with a child-resistant closure. Protect from moisture.

NDC 52817-280-10



100 Capsules







clomiPRAMINE Hydrochloride Capsules, USP



25 mg Rx only







Pharmacist: Please dispense with attached medication guide



TULEX Pharmaceuticals

LA2801000300 04/2020

Lot:



Exp:

USUAL DOSAGE: See package insert .



STORAGE: Store at 20 °C to 25 °C (68 °F to 77 °F) [see USP Controlled Room Temperature].



Dispense in well-closed containers with a child-resistant closure. Protect from moisture.



Do not accept if seal over bottle opening is broken or missing.

Each capsule contains:



Clomipramine Hydrochloride USP ... 25 mg

Manufactured by

Tulex Pharmaceuticals Inc.

Cranbury, NJ 08512

Distributed By:

TruPharma, LLC

Tampa, FL33609

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of clomipramine hydrochloride or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and 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 is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD) ( see WARNINGS, Clinical Worsening and Suicide Risk; PRECAUTIONS, Information for Patients; and PRECAUTIONS, Pediatric Use).

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 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 ( see DOSAGE AND ADMINISTRATION).

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

Clomipramine Hydrochloride Capsules USP

Capsules 25 mg – the body is opaque ivory with "T" and the cap is opaque orange with "280" imprinted on it

Bottles of 100…………………………………...NDC 52817-280-10

Capsules 50 mg – the body is opaque ivory with "T" and the cap is opaque light blue with "281" imprinted on it

Bottles of 100…………………………………..NDC 52817-281-10

Capsules 75 mg – the body is opaque ivory with "T" and the cap is opaque yellow with "282" imprinted on it

Bottles of 100…………………………………..NDC 52817-282-10

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

Monoamine Oxidase Inhibitors (MAOIs)

The use of MAOIs intended to treat psychiatric disorders with clomipramine hydrochloride capsules or within 14 days of stopping treatment with clomipramine hydrochloride capsules is contraindicated because of an increased risk of serotonin syndrome.  The use of clomipramine hydrochloride capsules 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 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 are contraindicated during the acute recovery period after a myocardial infarction.

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 them concomitantly with other CNS-active drugs ( see Information for Patients). Clomipramine hydrochloride capsules should not be used with MAO inhibitors ( see CONTRAINDICATIONS).

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 ( see CLINICAL PHARMACOLOGY, Interactions).

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with clomipramine hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for clomipramine hydrochloride. 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 contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text 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.

Clomipramine hydrochloride 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 hydrochloride capsules  for up to 8 weeks. In addition, 150 adolescent patients have received clomipramine hydrochloride capsules 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 hydrochloride capsules' extended use in children and adolescents with OCD have not been systematically assessed. The evidence supporting the conclusion that clomipramine hydrochloride capsules are 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 hydrochloride capsules use on the growth, development, and maturation of children and adolescents. Although there is no evidence to suggest that clomipramine hydrochloride capsules adversely affect 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 hydrochloride capsules in pediatric patients under the age of 10.

Clinical studies of clomipramine hydrochloride capsules 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 capsules 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.

Clomipramine hydrochloride capsules has been associated with cases of clinically significant hyponatremia. Elderly patients may be at greater risk for this adverse reaction ( see PRECAUTIONS, Hyponatremia).

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/m ² 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/m ² 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/m ² basis, respectively.

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.

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.

Clomipramine hydrochloride capsules USP is an antiobsessional drug that belongs to the class (dibenzazepine) of pharmacologic agents known as tricyclic antidepressants. Clomipramine hydrochloride capsules are available as capsules of 25, 50, and 75 mg for oral administration.

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

Clomipramine hydrochloride USP 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.

Inactive Ingredients. colloidal silicon dioxide, D&C Yellow No. 10, FD&C Blue No. 1 (25 mg and 50 mg strengths only), FD&C Red No. 3 (25 mg and 50 mg strengths only), FD&C Red No. 40 (50 mg strength only), FD&C Yellow No. 6 (25 mg and 75 mg strength only), gelatin , magnesium stearate, pregelatinized starch, and titanium dioxide.

In addition, the black imprinting ink for the 25 mg, 50 mg and 75 mg capsules contains black iron oxide, propylene glycol, shellac, strong ammonia solution.

Phospholipidosis and testicular changes, commonly associated with tricyclic compounds, have been observed with clomipramine hydrochloride capsules. In chronic rat studies, changes related to clomipramine hydrochloride capsules 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/m ² basis.

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

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

No teratogenic effects were observed in studies performed in rats and mice at doses up to 100 mg/kg, which is 24 times the maximum recommended human daily dose (MRHD) on a mg/kg basis and 4 times (rats) and 2 times (mice) the MRHD on a mg/m ² basis. Slight nonspecific embryo/fetotoxic effects were seen in the offspring of treated rats given 50 and 100 mg/kg and of treated mice given 100 mg/kg.

There are no adequate or well-controlled studies in pregnant women. Withdrawal symptoms, including jitteriness, tremor, and seizures, have been reported in neonates whose mothers had taken clomipramine hydrochloride capsules until delivery. Clomipramine hydrochloride capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

Read the Medication Guide that comes with you or your family member's antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's, healthcare provider about:

• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?

• Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
• Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
• How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
  
  
  
  
  • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
  • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
  • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

Low Salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:

• headache
• weakness or feeling unsteady
• confusion, problems concentrating or thinking or memory problems

Visual problems

• eye pain
• changes in vision
• swelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

Who should not take clomipramine hydrochloride capsules?

Do not take clomipramine hydrochloride capsules if you:

• Take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
  • Do not take an MAOI within 2 weeks of stopping clomipramine hydrochloride capsules unless directed to do so by your physician.
  • Do not start clomipramine hydrochloride capsules if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.

What else do I need to know about antidepressant medicines?

• Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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

Manufactured by

Tulex Pharmaceuticals Inc.

5 Cedarbrook Drive,

Cranbury, NJ 08512

Distributed By:

TruPharma, LLC

Tampa, FL33609



PI2801000300 Rev 04/2020

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

Dispense in well-closed containers with a child-resistant closure. Protect from moisture.

NDC 52817-280-10



100 Capsules







clomiPRAMINE Hydrochloride Capsules, USP



25 mg Rx only







Pharmacist: Please dispense with attached medication guide



TULEX Pharmaceuticals

LA2801000300 04/2020

Lot:



Exp:

USUAL DOSAGE: See package insert .



STORAGE: Store at 20 °C to 25 °C (68 °F to 77 °F) [see USP Controlled Room Temperature].



Dispense in well-closed containers with a child-resistant closure. Protect from moisture.



Do not accept if seal over bottle opening is broken or missing.

Each capsule contains:



Clomipramine Hydrochloride USP ... 25 mg

Manufactured by

Tulex Pharmaceuticals Inc.

Cranbury, NJ 08512

Distributed By:

TruPharma, LLC

Tampa, FL33609