Nomifensine

238.32752

238.33

DTXSID0023377

N - Nervous system

2933499090

29.3

2.4 (est)

1.1±0.1 g/cm3

180 °C

378.4±42.0 °C at 760 mmHg

164.0±23.0 °C

1.623

In water, 280 mg/L at 25 deg C (est)

7.61X10-7 mm Hg at 25 deg C (est)

TDLo orl-wmn: 7 mg/kg/7D-I:BLD BMJOAE 288,830,84

Henry's Law constant = 4.09X10-11 atm-cu m/mol at 25 °C (est)

Hydroxyl radical reaction rate constant = 2.89X10-10 cu cm/molec-sec at 25 °C (est)

III

6.1(b)

3249

3

22-36/37/38

26-36

NX4912800

Xn

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.

Drug products withdrawn or removed from the market for reasons of safety or effectiveness. The following drug product was withdrawn or removed from the market because such drug product or component of such drug product was found to be unsafe or not effective. The following drug product may not be compounded under the exemptions provided by section 503A(a) of the Federal Food, Drug, and Cosmetic Act: normifensine maleate. /Nomifensine maleate/

A likely cause of nomifensine toxicity is the aromatic amine group, as compounds containing this chemical substructure are notorious for producing toxic metabolites.

Six epileptic patients (aged 21-28 yr) on either phenytoin and phenobarbital (phenobarbitone) or phenytoin and carbamazepine, and 6 controls (aged 21-25 yr), were given single oral doses of 30 mg mianserin and 100 mg of nomifensine, at least one month apart, to determine if treatment with anticonvulsants would influence the pharmacokinetics of mianserin and nomifensine. The results showed that plasma levels of mianserin and nomifensine were significantly reduced in epileptic patients treated with anticonvulsants.

LD50 rat intravenous 72 mg/kg|LD50 mouse oral 260 mg/kg|LD50 mouse intravenous 90 mg/kg|LD50 guinea pig intravenous 264 mg/kg

Nomifensine, formerly marketed as Merital capsules, was associated with an increased incidence of hemolytic anemia. The approved application holder removed Merital capsules from the market on January 23, 1986. FDA published a notice of its determination that Merital capsules were removed from the market for safety reasons (see the Federal Register of June 17, 1986 (51 FR 21981)). Approval of the NDA for Merital capsules was withdrawn on March 20, 1992 (see the Federal Register of March 20, 1992 (57 FR 9729)). Also withdrawn from the Canadian and UK markets.|Nomifensine, introduced in 1985, is a tetrahydroisoquinoline antidepressant. /No longer approved for use in the US/

Nomifensine, formerly marketed as Merital capsules, was associated with an increased incidence of hemolytic anemia. The approved application holder removed Merital capsules from the market on January 23, 1986. FDA published a notice of its determination that Merital capsules were removed from the market for safety reasons (see the Federal Register of June 17, 1986 (51 FR 21981)). Approval of the NDA for Merital capsules was withdrawn on March 20, 1992 (see the Federal Register of March 20, 1992 (57 FR 9729)). Also withdrawn from the Canadian and UK markets.|The development of sudden fever in 6 women and one man (mean age, 64 yr) during oral nomifensine therapy at usual doses is reported. During original therapy, fever occurred within 2 wk (range, a few hr to 30 days) and sooner during a second treatment (one to 3 days). In 6 cases, the recurrence of the fever closely following the rechallenge is suggestive of a causal relationship and implies a hypersensitivity reaction.|In humans, nomifensine has been found to mildly elevate heart rate but not to affect orthostatic blood pressure, QRS width, QT interval, or the His-bundle electrocardiogram at doses up to 200 mg/day for three weeks.|... Potent dopaminergic activity may induce, or bring out, dyskinetic movements in susceptible individuals as has been described in at least one case.|For more Drug Warnings (Complete) data for NOMIFENSINE (6 total), please visit the HSDB record page.

Nomifensine is a dopamine reuptake inhibitor test-marketed in the United States by Hoechst AG (now Novartis) that increases the amount of synaptic dopamine available to receptors by blocking dopamine's re-uptake transporter. Nomifensine is now mainly used in scientific research, particularly in studies involving dopamine release in response to addiction.

Drugs that block the transport of DOPAMINE into axon terminals or into storage vesicles within terminals. Most of the ADRENERGIC UPTAKE INHIBITORS also inhibit dopamine uptake. (See all compounds classified as Dopamine Uptake Inhibitors.)

The pharmacokinetics of nomifensine were studied in 6 subjects aged 23-41 yr, after single oral administration of two 50 mg capsules of nomifensine maleate (Nomival) and 100 mg intravenous injection, and after 2 wk of oral daily administration of 150 mg in capsule form. The determination of free and total nomifensine in plasma and urine was performed by HPLC. Nomifensine was rapidly absorbed from the gastrointestinal tract and peak concentration of free nomifensine was reached at 1.13 hr. The elimination half life after single dose was about 4 hr regardless of the route of administration. Nomifensine was extensively distributed in body fluids and tissues, with an apparent volume of distribution of 8.69 L/kg. The AUC of free nomifensine after oral dosing was only 26.5% of that after intravenous infusion. Absorption from the gastrointestinal tract was complete, and the AUCs of total nomifensine were equal after all treatments. The AUC of free nomifensine decreased substantially and the elimination half life was shortened after a 2-wk dosing period. It was concluded that the main reason for limited bioavailability seems to be extensive first-pass metabolism during the absorption process and that a marked induction of the metabolizing enzymes is suggested; therefore, an increase in nomifensine dosage may be needed in some patients to maintain a full therapeutic effect. /Nomifensine maleate/|The pharmacokinetics of nomifensine were assessed in 12 healthy men and women following single 100 mg oral doses of nomifensine maleate (Merital). Mean plasma half-life of unconjugated nomifensine was 1.9 hr and for total nomifensine was 4.1 hr. The mean peak plasma concentration of unconjugated nomifensine was 130 + or - 36.5 ug/L for men and 38 + or - 9.7 ug/L for women, a significant difference. No differences between males and females were observed for peak total nomifensine plasma concentrations. ... Oral clearance was higher in women than men as were the respective volumes of distribution.|The disposition of radioactivity from (14)C-nomifensine has been compared in pregnant and non-pregnant female rats by examining plasma profiles, the qualitative tissue distribution (whole body autoradiography) and the quantitative tissue distribution of radioactivity. The clearance of radioactivity of (14)C-nomifensine from the plasma of pregnant and non-pregnant rats was similar and was complex with secondary peaks and plateaux after both oral and intravenous dosing. Maximum plasma levels (mean +/- S.D., 0.20 +/- 0.05 and 0.22 +/- 0.02 ug equivalents nomifensine/mL plasma for pregnant and non-pregnant rats respectively) occurred at 30 to 45 min after oral dosing. The biological half-life of radioactivity in plasma was between 4 and 5 hr for both routes of administration, although there was an additional rapid initial phase (half life approx. 20 min) after intravenous dosing. Whole body autoradiography also showed a very similar tissue distribution pattern of radioactivity between pregnant and non-pregnant rats with extensive distribution from blood into tissue. Only traces of radioactivity from (14)C-nomifensine were seen to cross the placenta into the fetuses of 15-day pregnant rats and these rapidly cleared with time. Slightly higher amounts were seen to cross the fetuses of 18-day pregnant rats and radioactivity was seen in the fetal brain, heart, liver and lung. Quantitative tissue distribution studies confirmed these qualitative findings. The biological half-life of radioactivity in both adult and fetal tissues was approximately 5 hr, except for adult livers where a longer half-life of radioactivity of approximately 10 hr was found.|Nomifensine (1 and 5 mg/kg) was administered to dogs orally and intravenously. The pharmacokinetics of the drug was evaluated. Nomifensine was rapidly absorbed from the gastro-intestinal tract reaching maximum concentration at 0.5-1 hr. The peak levels were directly proportional to the doses administered. The elimination half-life was 6 hr and only very small amounts were found in blood at 24 hr after administration. The apparent volume of distribution (Vd) was 120-149 1, suggesting an extensive distribution of the drug throughout body fluids and tissues. The area under the serum concentration-time curve (AUC) obtained after oral administration was significantly smaller than that after intravenous administration indicating incomplete bioavailability of the drug in oral form. The conjugation of nomifensine after the two different administration routes was also studied: the conjugation reaction was in equilibrium at 15 min after oral administration, while after intravenous administration, equilibrium was not reached until 1-1.5 hr. The metabolism of nomifensine occurred in the gastrointestinal membranes and or in the liver during the absorption process; the first-pass effect was marked.|Nomifensine is rapidly absorbed and is widely distributed. After oral administration, peak levels are obtained within one to two hours. It has a rapid elimination half life of two hours and is primarily excreted in the urine, 60% to 65% unchanged, the remainder as metabolites. Nomifensine is excreted in breast milk. Despite the short half life, electroencephalographic studies in humans reveal that maximal central nervous system effects are sustained up to eight hours after the oral administration of 75 or 150 mg of nomifensine. Thus, central effects persist long after the plasma levels of the drug have diminished.

The metabolism of nomifensine maleate was studied in 6 healthy subjects aged 22-41 yr, after single oral administration of two 50 mg capsules and 100 mg intravenous injection, and after 2 wk of oral daily administration of 150 mg in capsule form. The determination of the 3 main metabolites of nomifensine maleate in plasma and urine was performed by HPLC. The 3 principal metabolites reached maximum plasma concentrations rapidly (1-1.5 hr), less than 10% as a free, unconjugated form and were eliminated rapidly (elimination half life between 6.8 and 9.0 hr). Only very low concentrations of free metabolites were found in plasma after 24 hr. Two wk of dosing had no significant influence on the elimination of half life or AUC values of the metabolites, indicating no change in the hydroxylation and methylation reactions and there were no changes in the conjugation reactions. Nomifensine had a very short half life and no tendency for accumulation after repeated doses. It was concluded that the clinical pharmacokinetic profile of nomifensine maleate is not significantly changed by the kinetic behavior of its 3 main metabolites after the usual maintenance doses. /Nomifensine maleate/|Nomifensine is an antidepressant agent that was removed from use because of a high incidence of hemolytic anemia. It contains an N-methyl-8-aminotetrahydroisoquinoline ring which has the potential to be oxidized to quaternary dihydroisoquinolinium and isoquinolinium ions, albeit such a transformation had not been previously observed. In this report, ... the conversion of nomifensine to a dihydroisoquinolinium ion metabolite by several human enzymes /is demonstrated/. Human liver microsomes supplemented with NADPH generated the dihydroisoquinolinium ion metabolite along with other hydroxylated metabolites, whereas when supplemented with t-butyl peroxide, only the dihydroisoquinolinium ion metabolite was observed. Monoamine oxidase A, but not monoamine oxidase B, catalyzed this reaction, as well as human hemoglobin supplemented with H2O2. Human myeloperoxidase catalyzed this reaction in the presence of H2O2, and activation of the reaction was observed when incubations were conducted in the presence of acetaminophen at concentrations relevant to those measured in humans. The reaction was also observed in human whole blood. The equilibrium between the dihydroisoquinolinium ion and carbinolamine was shown to have a pK of about 11.7.

The pharmacokinetics of nomifensine were studied in 6 subjects aged 23-41 yr, after single oral administration of two 50 mg capsules of nomifensine maleate (Nomival) and 100 mg intravenous injection, and after 2 wk of oral daily administration of 150 mg in capsule form. ... The elimination half life after single dose was about 4 hr regardless of the route of administration. ... /Nomifensine maleate/|The pharmacokinetics of nomifensine were assessed in 12 healthy men and women following single 100 mg oral doses of nomifensine maleate (Merital). Mean plasma half-life of unconjugated nomifensine was 1.9 hr and for total nomifensine was 4.1 hr.|The disposition of radioactivity from (14)C-nomifensine has been compared in pregnant and non-pregnant female rats ... . The biological half-life of radioactivity in plasma was between 4 and 5 hr for both routes of administration /oral and intravenous/, although there was an additional rapid initial phase (half life approx. 20 min) after intravenous dosing. ... The biological half-life of radioactivity in both adult and fetal tissues was approximately 5 hr, except for adult livers where a longer half-life of radioactivity of approximately 10 hr was found.|Nomifensine (1 and 5 mg/kg) was administered to dogs orally and intravenously. ... The elimination half-life was 6 hr and only very small amounts were found in blood at 24 hr after administration. ...

Nomifensine ... while it resembles the imipramine type agents in many of the pharmacologic tests used in screening potential antidepressive activity, nomifensine is distinct in its potent inhibitory effects on the neuronal reuptake of dopamine. ... Nomifensine's dopaminergic profile is essentially restricted to reuptake blockade. It has no presynaptic effects on dopamine release as would amphetamine and no post synaptic effects on adenylate-cyclase linked dopamine (D-1) receptors as would apomorphine (a dopamine agonist).|In addition to its potent dopaminergic effects, nomifensine has important effects on the noradrenergic system. Nomifensine is more than 20 times as potent as imipramine, and equipotent to desipramine, in inhibiting the neuronal reuptake of norepinephrine. In electrophysiologic studies nomifensine is four times as active, within the locus coeruleus (a major noradrenergic brain nucleus), as desipramine, and nomifensine is 20 times as potent as imipramine with this test system. In accord with such activity, chronic treatment with nomifensine leads to a reduction in the sensitivity of postsynaptic beta-noradrenergic receptors.|Nomifensine has relatively weak alpha-adrenergic blocking effect. In vitro binding studies suggest that nomifensine is six times less potent than imipramine at antagonism of the alpha-1 receptor, but twice as potent at the alpha-2. In this regard, nomifensine has less alpha-blocking activity than trazodone. Based upon these characteristics, both sedation and adverse cardiovascular (eg, hypotensive) effects should not be prominent with nomifensine.|Effects on the serotonergic system are varied. Nomifensine is a weak inhibitor of serotonin reuptake into rat brain synaptosomes, and is 1/300 times as potent as imipramine, and equipotent to desipramine, in this regard. This is confirmed in electrophysiologic studies where nomifensine has extremely weak, although not absent, activity within the dorsal raphe. However, while nomifensine appears to be inactive in serotonergic systems it has some binding affinity for serotonergic receptors; it is as avid as imipramine for the 5-HT 1 receptor, but is less than 1/100 as avid as imipramine for the 5-HT 2 receptor.|For more Mechanism of Action (Complete) data for NOMIFENSINE (6 total), please visit the HSDB record page.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). 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 0.9% saline (NS) 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 ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ In two large series of cases (193 total) of nomifensine overdose (63 with nomifensine alone) reported to regional poison centers the most common symptoms noted included drowsiness, sinus tachycardia, and tremor. Once case each of coma and ventricular ectopy have been reported. Central nervous system toxicity (excitement, coma, and other) has been observed when nomifensine is ingested with other substances such as benzodiazepines and /or alcohol. There have been no cases of seizures and no deaths associated with nomifensine overdosage alone.|/CASE REPORTS/ Nomifensine was introduced as an effective antidepressant drug with few side effects. However, among our patients we have seen 2 typical cases of drug fever due to nomifensine. 2-4 weeks after start of nomifensine treatment, 75-150 mg/day, for recurrent endogenous depressions the patients developed shiverings and fever. Nomifensine was withdrawn and both became afebrile within 1 day. A provocation test with 50 mg nomifensine p.o. again resulted in shiverings and fever within 6-8 hr 1 of the patients was allergic to other drugs and suffered from asthma. During the acute episode of illness the serum concentration of alanine aminotransferase was elevated and it normalized after stopping the treatment. A liver biopsy at that time showed liver cell necrosis, and a moderate grade of steatosis and fibrosis was also present. The results indicate that nomifensine may cause drug fever. It is possible that patients with allergy and/or liver diseases in particular may be susceptible to drug fever due to nomifensine.|/CASE REPORTS/ Two cases of immune hemolytic anaemia and acute renal failure induced by nomifensine are reported. The two female patients had been under continuous nomifensine therapy because of reactive depressions. In both cases nomifensine had been discontinued and the clinical reactions--immune hemolytic anaemia and acute renal failure--started immediately after they had taken again a capsule of nomifensine. In one case the patient's serum contained a potent antibody which agglutinated her red blood cells in presence of nomifensine in the antiglobulin test.|/CASE REPORTS/ A case of acute renal failure after an overdose of nomifensine is reported in a man who had evidence of chronic intravascular hemolysis on presentation, but not of acute hemolysis. Acute renal failure after nomifensine overdose is therefore not always due to acute intravascular hemolysis.|For more Human Toxicity Excerpts (Complete) data for NOMIFENSINE (14 total), please visit the HSDB record page.

Hoe 984

Nomifensine, formerly marketed as Merital capsules, was associated with an increased incidence of hemolytic anemia. The approved application holder removed Merital capsules from the market on January 23, 1986. FDA published a notice of its determination that Merital capsules were removed from the market for safety reasons (see the Federal Register of June 17, 1986 (51 FR 21981)). Approval of the NDA for Merital capsules was withdrawn on March 20, 1992 (see the Federal Register of March 20, 1992 (57 FR 9729)). Also withdrawn from the Canadian and UK markets.

Analyte: nomifensine; matrix: solutions; procedure: high-performance liquid chromatography with electrochemical oxidation detection|Analyte: nomifensine; matrix: bulk sample; procedure: high-performance liquid chromatography with ultraviolet detection at 254 nm; limit of quantitation: 25 ng

Analyte: nomifensine; matrix: blood (plasma, whole); procedure: high-performance liquid chromatography with diode array detection and ultraviolet detection at 240 nm; limit of detection: <120 ng/mL

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