Lofepramine

Easily oxidized by air and other oxidizing agents to desipramine and p-chlorbenzoic acid

MW: 455.43; crystals from butanone; mp: 152-154 °C; sol in methanol, ethanol, chloroform; practically insol in water. /Hydrochloride/

Hydroxyl radical reaction rate constant = 3.0X10-10 cu cm/molec-sec @ 25 °C /Estimated/

Danger

H336 (100%): May cause drowsiness or dizziness [Warning Specific target organ toxicity, single exposure; Narcotic effects]

P260, P261, P264, P270, P271, P304+P340, P308+P316, P319, P321, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 2 reports by companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Lofepramine may potentiate alcohol sedation.

Seizures or arrhythmias may be precipitated /SRP: by flumazenil/ in patients with a serious cyclic antidepressant overdose. /Flumazenil/

/SIGNS AND SYMPTOMS/ Lofepramine overdose in humans may be associated with tachycardia, hypertension, dry mouth, dilated pupils, ileus, blurred vision, dizziness, flushing, hypersalivation, muscle weakness, and vomiting. Only 1 of 55 cases studied had deep coma requiring ventilation. Hypotension, convulsion, and cardiac arrhythmias were not reported.

/SIGNS AND SYMPTOMS/ Twenty-one patients ingested between 0.14 and 4.9 g of lofepramine. Seven were asymptomatic (mean dose 1.85 g) and 14 patients had mild symptoms. One had a deep coma, suffered from respiration depression, and required ventilation for 36 hours. Five had mild hypertension, 5 had tachycardia, and several had anticholinergic symptoms. Hypotension, convulsion, and cardiac arrhythmias were not reported. When lofepramine was ingested with other drugs, hypotension, arrhythmias, and coma were observed.

N - Nervous system

QN - Nervous system

Lofepramine is a tricyclic antidepressant that is structurally similar to imipramine and is extensively metabolised to desipramine. In the absence of other major pharmacological effects it appears that its antidepressant activity stems from the facilitation of noradrenergic neurotransmission by uptake inhibition, and possibly by the additional facilitation of serotoninergic neurotransmission.

The in vitro metabolism of lofepramine was studied in comparison with imipramine. Both compounds were hydroxylated and demethylated by a NADPH-generating system in rat and human liver microsomes. Three metabolites were in common for the two drugs, namely desipramine (DMI), 2-hydroxydesipramine (2-OH-DMI) and didesmethylimipramine (DDMI). Lofepramine was also metabolized to three unique tricyclic metabolites. Comparisons with authentic reference compounds suggested that two of these metabolites were 2-hydroxylofepramine and desmethyllofepramine. The ratio between the concentrations of DDMI and DMI was higher for lofepramine than imipramine. This is probably due to DDMI formation via two parallel metabolic pathways of lofepramine, i.e. DMI and desmethyllofepramine, respectively. It is speculated that the different metabolic pattern of lofepramine as compared with desipramine and imipramine is of importance for the therapeutic profile of the drug.

Lofepramine is partially metabolized to desipramine by a cytochrome p450 dependent enzyme system on first pass through the liver. It is metabolized by N-dealkylation, hydroxylation, and glucuronidation. The plasma clearance of lofepramine is 686 L/hr. Its main urinary metabolites are desipramine, 2-hydroxydesipramine, and its glucuronide (2-hydroxyimodibenzyl), and the glycine conjugate of p-chlorobenzoic acid.