Lofepramine

419.0 g/mol

418.96

245-396-8

OCA4JT7PAW

DTXSID2023220

Crystals from methanol or acetone

N - Nervous system

23.6 Ų

log Kow = 7.3 /Estimated/

104-406 °C

In water, 1.4X10-2 mg/L @ 25 °C /Estimated/

1.5X10-9 mm Hg @ 25 °C /Estimated/

Henry's Law constant = 2.0X10-11 atm-cu m/mol @ 25 °C /Estimated/

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/

Lancaster SG, Gonzalez JP; Lofepramine: A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy in Depressive Illness; Drugs 37: 123-140 (1989)

|Danger|H336 (100%): May cause drowsiness or dizziness [Warning Specific target organ toxicity, single exposure; Narcotic effects]|P260, P261, P264, P270, P271, P304+P340, P307+P311, P312, P314, P321, P403+P233, P405, and P501|Aggregated GHS information provided by 2 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/

LD50 Mouse oral >2500 mg/kg /Lofepramine hydrochloride/|LD50 Mouse ip 920 mg/kg /Lofepramine hydrochloride/|LD50 Mouse sc >1000 mg/kg /Lofepramine hydrochloride/|LD50 Rat oral >1000 mg/kg /Lofepramine hydrochloride/|For more Non-Human Toxicity Values (Complete) data for LOFEPRAMINE (6 total), please visit the HSDB record page.

Lofepramine is a tricyclic antidepressant related to imipramine. Meta-analyses were carried out with respect to efficacy and tolerability by combining outcome and adverse reaction from over 20 controlled trials comparing lofepramine with other tricyclic antidepressants. Lofepramine was at least as effective as the comparators with fewer adverse effects. In particular, the risk/benefit ratio seemed superior to the comparators amitriptyline, imipramine, clomipramine, maprotiline and desipramine.|The results of double blind trial in which 139 patients with primary depression were randomly assigned to either lofepramine (46), imipramine (48), or placebo (45) are discussed. After treatment with either active drug, lofepramine or imipramine, the clinical outcome was significantly greater than with placebo. No significant differences were found in clinical responses between lofepramine and imipramine. With regard to reported side effects, however, a statistically significant lower number of severe and/or moderate side effects were reported for the lofepramine group than for the imipramine group.|EXPTL Therapy: In a randomized, placebo-controlled double-blind trial a combination of lofepramine, phenylalanine and vitamin B(12) was found to be effective in relieving the symptoms of multiple sclerosis (MS). The effect occurred within 2-4 weeks, and improved all types of symptoms in all types of MS. The combination was also effective in relieving symptoms in patients with chronic pain and chronic fatigue.|EXPTL Therapy: A double-blind randomised controlled trial of the effect of low dose lofepramine (70 mg once daily) against placebo was carried out on depressed elderly inpatients on general medical wards for the elderly, comparing measures of depression and side-effects between the randomised groups. Patients were identified for the study using the Geriatric Depression Scale (GDS) and the Brief Assessment Schedule Depression Cards (BASDEC). Sixty-three subjects were randomised: 46 patients completed the entire trial of 28 days treatment. BASDEC and GDS were administered on day 8 post-admission, and depressed patients were randomised double-blind to either low dose lofepramine (70 mg daily) (n = 23) or placebo (n = 23). Assessment of changes in depressive states were made using the Montgomery Asberg Depression Rating Scale (MADRS) on days 8, 18 and 36 post-admission. Both groups improved by a similar amount during the trial. Lofepramine tended to be more effective than placebo in those patients who were more depressed (GDS > or = 18). On the other hand, subjects who were less depressed (i.e. GDS < 18) improved more on placebo than lofepramine. Low dose lofepramine may prove useful in moderately or severely depressed patients treated for only 4 weeks. However, low dose lofepramine is not indicated for mild (GDS 15-18) depression.

Dry mouth is the most common side effect. Constipation, dizziness, sweating, nausea/vomiting, tremor palpitation, blurred vision, drowsiness, fatigue, headache, and insomnia were also observed during clinical studies. There does not appear to be a correlation between plasma lofepramine levels and adverse effects.|Lofepramine is a tricyclic antidepressant that is structurally similar to imipramine ... . Dry mouth is the most commonly reported side effect of usual therapeutic doses of lofepramine, but the incidence of this and other anticholinergic side effects is less among patients treated with lofepramine than with imipramine. Lofepramine has not been associated with adverse effects on cardiac function even in cases of attempted suicide by overdose.|Physostigmine should not be used as an antidote for cyclic antidepressant overdose because it may worsen cardiac conduction disturbances, cause bradyarrhythmias or asystole, and aggravate or precipitate seizures. /Physostigmine/

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. (See all compounds classified as Antidepressive Agents, Tricyclic.)

Following oral administration of a single dose of 210 mg to healthy subjects, lofepramine is rapidly absorbed, with peak plasma concentrations of 140 ng/ml(lofepramine) and 5 ng/ml (desipramine) achieved within 1 and 4 hours, respectively.

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.

The mean elimination half-lives are 1.7 hours for a 70 mg dose and 2.5 hours for a 140 mg dose. Lofepramine has a half-life in the beta phase of about 5 hours (compared with 24 hours for other TCAs).

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.

Measures such as hemodialysis and hemoperfusion are not likely to be of value in view of the high degree of protein binding and the extensive volume of distribution.|Treatment of lofepramine overdose is largely symptomatic and supportive. Intubation and ventilation should be provided where indicated.|Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/|Physostigmine should not be used as an antidote for cyclic antidepressant overdose because it may worsen cardiac conduction disturbances, cause bradyarrhythmias or asystole, and aggravate or precipitate seizures. /Physostigmine/

/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.

Deftan

Lofepramine hydrochloride is available in the United Kingdom as Gamanil tablets, which are scored and contain lofepramine 70 mg (as the hydrochloride).|Trade Names: ... Deftan, Deprimil, Emdalen, Gamanil, Gamonil (E. Merck, Germany), Tymelyt (Leo, Sweden). /Lofepramine Hydrochloride/

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