Clomipramine Hydrochloride

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

EMA approved medicines: Veterinary medicine

FDA approved animal drugs -> Active ingredient

Warning

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

P203, P261, P264, P264+P265, P270, P271, P273, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P317, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P391, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 61 reports by companies from 11 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Hazard Traits - Bioaccumulation; Environmental Persistence

REACH registered substance: Clomipramine hydrochloride (EC: 241-344-3)

Clomipramine hydrochloride: Does not have an individual approval but may be used under an appropriate group standard

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)

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.

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.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Clomipramine hydrochloride

vMost-DILI-concern

8

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

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).

CLOMIPRAMINE HYDROCHLORIDE

Tricyclic Antidepressant [EPC]

CLOMIPRAMINE HYDROCHLORIDE CAPSULES

Tricyclic Antidepressant [EPC]

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.

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.