클로미프라민

Pharmaceuticals -> Tricyclic Antidepressants (TCAs)

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Used in Switzerland

log Kow = 5.19

4.5

5.19

Breast Feeding; Lactation; Milk, Human; Antidepressive Agents; Antidepressive Agents, Tricyclic

Pharmaceuticals

Medicines for obsessive compulsive disorders

160-170 °C at 3.00E-01 mm Hg

160-170 °C at 0.3 mm Hg

191.5-192

189.5 °C

9.38

9.38

9.1

174.5 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: APCI+; Dataset: TOXCAST; Source Identifier: DTXSID3042633]

174.3 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

174.4 Ų [M+H]+ [CCS Type: DT; Method: single field calibrated]

160.44 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Crystals from acetone-ether/methanol-ether. MW 351.31. MP 189-190 °C ...; also reported as crystals from acetone; mp 191-5-192 °C... Freely soluble in water, methanol, methylene chloride; practically insoluble in ethyl ether, benzene /Clomipramine hydrochloride/

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 42 reports by companies from 2 notifications to the ECHA C&L Inventory.

REACH registered substance: Clomipramine (EC: 206-144-2)

5H-Dibenzb,fazepine-5-propanamine, 3-chloro-10,11-dihydro-N,N-dimethyl-: Does not have an individual approval but may be used under an appropriate group standard

Clomipramine tablets. ... Indications for use /in dogs/. For use as part of a comprehensive behavioral management program to treat separation anxiety in dogs greater than 6 months of age. ... Limitations: Federal law restricts this drug to use by or on the order of a licensed veterinarian.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl clomipramine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Clomipramine hydrochloride/

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Clomipramine hydrochloride is included on this list. /Clomipramine hydrochloride/

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

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. (L1712)

Limited data suggest that demethylation of clomipramine may be reduced with chronic alcohol consumption. In one study, the clearance of clomipramine via demethylation was decreased substantially and the ratio of blood clomipramine to desmethylclomipramine concentrations at steady state was higher in recently detoxified alcoholic patients (abstinence periods ranged from 4-20 weeks) compared with a control group of patients with no history of alcoholism.

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 (eg, cimetidine, fluoxetine) and decreased by the concomitant administration of hepatic enzyme inducers (eg, 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.

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.

Close supervision and careful adjustment of dosage are required when clomipramine is administered with anticholinergic or sympathomimetic drugs.

For more Interactions (Complete) data for Clomipramine (11 total), please visit the HSDB record page.

Liver test abnormalities have been reported to occur in up to 16% of patients being treated with tricyclic antidepressants, but elevations are uncommonly above 3 times the upper limit of normal. Serum aminotransferase elevations during clomipramine therapy are reported in 1% to 3% of patients and the abnormalities were usually mild, asymptomatic and transient, reversing even with continuation of medication. As with many tricyclic antidepressants, rare instances of clinically apparent acute liver injury have been reported in patients taking clomipramine. The clinical features of cases of drug induced liver disease from clomipramine have not been well defined. The acute liver injury caused by tricyclic antidepressants typically arises within 1 to 4 weeks of starting the medication and presents with fatigue followed by dark urine and jaundice. Both hepatocellular and cholestatic patterns of injury have been described. The injury is usually mild-to-moderate in severity and recovery is rapid when the tricyclic is discontinued. Immunoallergic features such as rash, fever and eosinophilia are not common and autoantibodies are generally not detected. Fatal cases are extremely rare.

The adverse effects of clomipramine include nausea, weight gain, increased appetite, sedation, dry mouth, constipation, urinary retention, blurred vision, headache, dizziness, fatigue, hypotension, anxiety, restlessness, sweating, blue-green urine, and sexual dysfunction. Life-threatening adverse effects include arrhythmia, tachycardia, QTc prolongation, orthostasis, seizures, paralytic ileus, hyperthermia, hepatic failure, increased intraocular pressure, mania induction, and activation of suicidality.

Well absorbed from the GI tract following oral administration. Bioavailability is approximately 50% orally due to extensive first-pass metabolism. Bioavailability is not affected by food. Peak plasma concentrations occurred 2-6 hours following oral administration of a single 50 mg dose. The peak plasma concentration ranged from 56 ng/mL to 154 mg/mL (mean, 92 ng/mL). There are large interindividual variations in plasma concentrations occur, partly due to genetic differences in clomipramine metabolism. On average, steady state plasma concentrations are achieved in 1-2 weeks following multiple dose oral administration. Smoking appears to lower the steady-state plasma concentration of clomipramine, but not its active metabolite desmethylclomipramine.

... Four clomipramine-treated breastfeeding mother-infant pairs were assessed for serum concentrations of clomipramine, N-desmethylclomipramine, and corresponding 8-hydroxymetabolites. Although the mothers exhibited a wide range of serum concentrations, the parent drug and metabolites were either nondetectable or below the quantifiable limit in the sera of all infants. ...

Signs and Symptoms of Overdose

Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α₁-receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type.

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. In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Anafranil either alone or in combination with other drugs. One death involved a patient suspected of ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg.

/HUMAN EXPOSURE STUDIES/ ... Four clomipramine-treated breastfeeding mother-infant pairs were assessed for serum concentrations of clomipramine, N-desmethylclomipramine, and corresponding 8-hydroxymetabolites. Although the mothers exhibited a wide range of serum concentrations, the parent drug and metabolites were either nondetectable or below the quantifiable limit in the sera of all infants. No adverse clinical effects were observed. ...

/SIGNS AND SYMPTOMS/ 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, 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.

/SIGNS AND SYMPTOMS/ Abrupt or gradual discontinuation of tricyclic antidepressants may precipitate withdrawal symptoms. The most common of these are general somatic or gastrointestinal distress, anxiety and agitation, sleep disturbance, akathisia, parkinsonism, paradoxical behavioral activation and mania. There are very few reports of withdrawal reactions following discontinuation of clomipramine ...

/CASE REPORTS/ 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 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg. The 10 nonfatal cases involved doses of up to 5000 mg, accompanied by plasma levels of up to 1010 ng/mL. All 10 patients completely recovered.

For more Human Toxicity Excerpts (Complete) data for Clomipramine (25 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

clomipramine

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Acute Exposure/ To determine the effects of clomipramine hydrochloride on heart rate and rhythm in 17 healthy Beagles. In experiment 1, 8 dogs received placebo or clomipramine (20 mg/kg of body weight, q 24 hr, po) for 7 days in a 2-way crossover design. In experiment 2, 9 dogs were evaluated for 48 hours before and 24 hours after oral administration of clomipramine (4 or 12 mg/kg) in a 2-way crossover design. Electrocardiogram and heart rate were monitored continuously by use of telemetry. A significant diurnal rhythm in heart rate was detected; minimum values were recorded at night. Administration of 20 mg of clomipramine/kg induced a significant reduction in heart rate, with peak effect achieved approximately 12 hours after dosing. Administration of 4 or 12 mg of clomipramine/kg did not result in significant changes in heart rate. Sinoatrial and second-degree atrioventricular block and ventricular escape beats were observed during periods of slow heart rate in more dogs that received clomipramine (3 to 4 of 8 dogs), compared with dogs that received placebo (1 to 2 of 8 dogs), but this difference was not significant. Short-term administration of clomipramine induced benign cardiovascular effects in dogs rather than the potentially dangerous arrhythmias or tachycardia reported following administration of tricyclic antidepressants to humans.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The authors studied the effect of daily administration of a single dose of either clomipramine or desipramine, two monoamine-reuptake-inhibitors with preferential serotonergic and noradrenergic profiles, respectively, during 15 days, on the visuo-spatial memory of adults rats measured through their performance in an eight-arm radial maze. Rats receiving 10 mg/kg i.p. daily of clomipramine or desipramine, 30 min before testing, committed a significantly greater number of errors than saline-treated control rats throughout the duration of the test (5 sessions, 15 days), excepting for session one (after 3 days of testing) where there were no differences between the 3 groups of rats. Results indicated that both serotonergic and noradrenergic antidepressants could impair long-term visuo-spatial memory in the rat, whereas inducing no changes in working memory, effects that are likely related to changes in brain monoamine metabolism ...

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ No evidence of carcinogenecity 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/sq m 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/sq m basis, respectively.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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/sq m 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.

For more Non-Human Toxicity Excerpts (Complete) data for Clomipramine (7 total), please visit the HSDB record page.

Clomipramine tablets. ... Indications for use /in dogs/. For use as part of a comprehensive behavioral management program to treat separation anxiety in dogs greater than 6 months of age. ... Limitations: Federal law restricts this drug to use by or on the order of a licensed veterinarian.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl clomipramine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Clomipramine hydrochloride/

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Clomipramine hydrochloride is included on this list. /Clomipramine hydrochloride/

N06AA04

N - Nervous system

QN - Nervous system

N06AA04

Clomipramine, a tricyclic antidepressant, is the 3-chloro derivative of Imipramine. It was thought that tricyclic antidepressants work exclusively by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: α₁ and β₁ receptors are sensitized, α₂ receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain.

Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α₁-receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type.

The pharmacology of clomipramine is complex and in many ways resembles that of other antidepressants, particularly those agents (eg, selective serotonin-reuptake inhibitors, trazodone) that predominantly potentiate the pharmacologic effects of serotonin (5-HT). Although clomipramine's principal pharmacologic effect in vitro is the selective inhibition of serotonin reuptake, in vivo the drug's pharmacologic activity is not so selective because of the action of its demethylated metabolite, desmethylclomipramine, as an inhibitor of norepinephrine reuptake. As a result of this and other effects, clomipramine also shares the pharmacologic profile of other tricyclic antidepressants.

The precise mechanism of action that is responsible for the efficacy of clomipramine in the treatment of obsessive-compulsive disorder is unclear. However, because of its pronounced potency in blocking serotonin reuptake at the presynaptic neuronal membrane and its efficacy in the treatment of obsessive-compulsive disorder, a serotonin hypothesis has been developed to explain the pathogenesis of the condition. The hypothesis postulates that a dysregulation of serotonin is responsible for obsessive-compulsive disorder and that clomipramine is effective because it corrects this imbalance.

Clomipramine and its principal metabolite, desmethylclomipramine, have been shown to block the reuptake of serotonin and norepinephrine, respectively, at the presynaptic neuronal membrane. The effects of serotonin and norepinephrine may thus be potentiated. However, it has been suggested that postsynaptic receptor modification is mainly responsible for the antidepressant action observed during long-term administration of antidepressant agents. During long-term therapy with most antidepressants (eg, tricyclic antidepressants, monoamine oxidase [MAO] inhibitors), these adaptive changes generally consist of subsensitivity of the noradrenergic adenylate cyclase system in association with a decrease in the number of beta-adrenergic receptors; such effects on noradrenergic receptor function commonly are referred to as "down-regulation." In addition, some antidepressants reportedly decrease the number of 5-HT binding sites following chronic administration.

Clomipramine's principal metabolite, desmethylclomipramine, is an inhibitor of norepinephrine reuptake. Clomipramine decreases the concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG), a metabolite of norepinephrine, in CSF in patients with obsessive-compulsive disorder. Patients with depressive affective (mood) disorders (e.g., major depressive episode) also exhibit decreases in concentrations of 5-HIAA and MHPG in CSF during treatment with clomipramine. The decrease in the concentration of 5-HIAA in CSF was correlated with inhibition of the in vitro uptake of 3H-serotonin in plasma. The change in concentration of MHPG in CSF during clomipramine therapy was correlated with amelioration of depression.

For more Mechanism of Action (Complete) data for Clomipramine (10 total), please visit the HSDB record page.

Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours). Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism).

The elimination half-life of clomipramine averages approximately 32 hours (range: 19-37 hours) and that of desmethylclomipramine averages about 69 hours (range: 54-77 hours) following a single, 150-mg oral dose of the drug.

To determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs after IV or oral administration of a single dose. 6 male and 6 female Beagles. Clomipramine was administered IV (2 mg/kg), PO (4 mg/kg) after food was withheld for 15 hours, and PO (4 mg/kg) within 25 minutes after dogs were fed. ... For clomipramine, after IV administration, elimination half-life was 5 hours ...

/The objective of this study was/ to determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs following single-dose and repeated-dose oral administration at various dosages. ... Clomipramine was administered orally at a dose of 1, 2, or 4 mg/kg to 3 male and 3 female dogs, first as a single dose and then, after an interval of 14 days, twice daily for 10 days. ... Terminal half-life increased slightly (1.6-fold for clomipramine and 1.2-fold for desmethylclomipramine) with repeated-dose administration but remained short in all groups (< or = 4 hours).

Extensively metabolized in the liver. The main active metabolite is desmethylclomipramine, which is formed by <i>N</i>-demethylation of clomipramine via CYP2C19, 3A4 and 1A2. Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine formed via 8-hydroxylation, 2-hydroxyclomipramine formed via 2-hydroxylation, and clomipramine <i>N</i>-oxide formed by <i>N</i>-oxidation. Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which are formed by 8-hydroxylation and <i>N</i>-demethylation, respectively. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active; however, their clinical relevance remains unknown.

The exact metabolic fate of clomipramine has not been fully elucidated. Clomipramine appears to be extensively metabolized to desmethylclomipramine and other metabolites and their glucuronide conjugates. Desmethylclomipramine, the principal metabolite, is formed by N-demethylation of clomipramine. Other metabolites of clomipramine include 8-hydroxyclomipramine, 2-hydroxyclomipramine, and clomipramine N-oxide, which appear to be formed via 8-hydroxylation, 2-hydroxylation, and N-oxidation, respectively. The metabolites of desmethylclomipramine include 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which apparently are formed via 8-hydroxylation and N-demethylation, respectively. Although desmethylclomipramine is pharmacologically active, its efficacy in obsessive-compulsive disorder is not known. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine also are pharmacologically active but the clinical importance of their presence remains unknown.

The hydroxylation of clomipramine and desmethylclomipramine appears to be under genetic control (similar to that of debrisoquine and sparteine). In healthy adults who were phenotyped for debrisoquine hydroxylation, extensive metabolizers were distinguishable from poor metabolizers with regard to the extent of hydroxylation of desmethylclomipramine. Blood concentrations of desmethylclomipramine were higher than expected in a limited number of patients who subsequently were found to be poor metabolizers. Limited data suggest that CYP2D6, a cytochrome P-450 isoenzyme implicated in the sparteine/debrisoquine oxidation polymorphism, is involved in the 8-hydroxylation of clomipramine and desmethylclomipramine and in the 2-hydroxylation of clomipramine. In addition, demethylation of clomipramine may involve CYP2C, which is implicated in the S-mephenytoin oxidation polymorphism, and CYP1A2.

The fate of clomipramine (CMI) and its main demethylated metabolite demethylclomipramine (DCMI) was studied in two strains of Swiss mice (NMRI and CD1) after intraperitoneal injection. A study of its distribution among various tissues showed that fixation was most marked in lungs, perirenal fat and kidneys, and only moderate in the brain. The pharmacokinetic parameters of both molecules were determined in brain tissue and plasma. Absorption was rapid (tmax CMI = 14 min), metabolism prompt (tmax DCMI = 17 or 18 min according to the breed) and elimination rapid from both plasma and brain tissue. The first two stages were similar in the two strains, but elimination of CMI from both plasma and brain was faster in the NMRI mice (plasma t1/2 = 53 min against 165 min in the CD1 mice). Both values were well below that reported for man (mean plasma t1/2 = 24 hr). ...

Clomipramine has known human metabolites that include 10-hydroxy-clomipramine, N-Desmethylclomipramine, 8-hydroxy-clomipramine, and 2-hydroxy-clomipramine.

Extensively metabolized in the liver. The main active metabolite is desmethylclomipramine, which is formed by <i>N</i>-demethylation of clomipramine via CYP2C19, 3A4 and 1A2. Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine formed via 8-hydroxylation, 2-hydroxyclomipramine formed via 2-hydroxylation, and clomipramine <i>N</i>-oxide formed by <i>N</i>-oxidation. Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which are formed by 8-hydroxylation and <i>N</i>-demethylation, respectively. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active; however, their clinical contribution remains unknown. Route of Elimination: Urine (51-60%) and feces via biliary elimination (24-32%) Half Life: Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours). Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism).

NUV44L116D

CLOMIPRAMINE

Established Pharmacologic Class [EPC] - Tricyclic Antidepressant

Clomipramine is a Tricyclic Antidepressant.

Substances that contain a fused three-ring moiety and are used in the treatment of depression. These drugs block the uptake of norepinephrine and serotonin into axon terminals and may block some subtypes of serotonin, adrenergic, and histamine receptors. However, the mechanism of their antidepressant effects is not clear because the therapeutic effects usually take weeks to develop and may reflect compensatory changes in the central nervous system.

Compounds that specifically inhibit the reuptake of serotonin in the brain.

Well absorbed from the GI tract following oral administration. Bioavailability is approximately 50% orally due to extensive first-pass metabolism. Bioavailability is not affected by food. Peak plasma concentrations occurred 2-6 hours following oral administration of a single 50 mg dose. The peak plasma concentration ranged from 56 ng/mL to 154 mg/mL (mean, 92 ng/mL). There are large interindividual variations in plasma concentrations occur, partly due to genetic differences in clomipramine metabolism. On average, steady state plasma concentrations are achieved in 1-2 weeks following multiple dose oral administration. Smoking appears to lower the steady-state plasma concentration of clomipramine, but not its active metabolite desmethylclomipramine.

Urine (51-60%) and feces via biliary elimination (24-32%)

~ 17 L/kg (range: 9-25 L/kg). Clomipramine is capable of distributing into the cerebrospinal fluid, the brain, and into breast milk.

Clomipramine hydrochloride appears to be well absorbed from the GI tract following oral administration. However, extensive first-pass metabolism decreases its oral bioavailability to about 50%. The oral capsules and solution of clomipramine hydrochloride reportedly are bioequivalent. Food does not appear to substantially affect the bioavailability of clomipramine from the capsules.

In one case report, plasma clomipramine concentrations were measured in an infant whose mother was receiving clomipramine hydrochloride 125 mg daily during pregnancy. ... After the first week postpartum, the mother's dosage of clomipramine hydrochloride was increased to 150 mg daily and the concentration of clomipramine in milk was 80-160% of the concurrent plasma clomipramine concentration at steady state. ...

Peak plasma clomipramine concentrations of approximately 56-154 ng/mL (mean: 92 ng/mL) usually occur within 2-6 hours (mean: 4.7 hours) following oral administration of a single 50-mg dose of clomipramine hydrochloride. Like other tricyclic antidepressants, clomipramine exhibits considerable interindividual variation in plasma concentrations achieved with a given dose due, at least in part, to genetic differences in the metabolism of the drug.

Antidepressant

THERAP CAT: Antidepressant, antiobsessional agent

THERAP CAT (VET): In treatment of canine separation anxiety

Use (kg; approx.) in Germany (2009): >1000

May be used to treat obsessive-compulsive disorder and disorders with an obsessive-compulsive component (e.g. depression, schizophrenia, Tourette's disorder). Unlabeled indications include: depression, panic disorder, chronic pain (e.g. central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy (limited evidence), autistic disorder (limited evidence), trichotillomania (limited evidence), onchophagia (limited evidence), stuttering (limited evidence), premature ejaculation, and premenstrual syndrome.

N-[3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-t-yl)propyl]-N,N',N'-trimethylpropane-1,3-diamine

3-(3-chloro-5H-dibenzo[b,f]azepin-5-yl]-N,N-dimethylpropan-1-amine

3-(3,7-dichloro-10,11-dihydro-5H-dibenzol[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine

3-chloro-5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine

For more Impurities (Complete) data for Clomipramine (11 total), please visit the HSDB record page.