Phenelzine ( Nardil )

Phenelzine ( Nardil )

Phenelzine sulfate
Phenelzine sulfate is a potent inhibitor of monoamine oxidase (MAO). Phenelzine sulfate is a hydrazine derivative. It has a molecular weight of 234.27 and is chemically described as C8H12N2.H2SO4.Each phenelzine sulfate tablet contains phenelzine sulfate equivalent to 15 mg phenelzine base. Inactive ingredients include maize starch, sunset yellow FCF, gelatin, povidone, sucrose.Pharmacology
MAO is a complex flavin-containing enzyme system that is widely distributed throughout the body. MAO inhibitors exert their effects mainly on organ systems influenced by sympathomimetic amines and 5-hydroxytryptamine and inhibit not only MAO but also other enzymes as well, interfering with the hepatic metabolism of many drugs. It is unknown whether all the clinical effects produced by this class of drug result from MAO inhibition, other pharmacological actions, or an interaction of both. Therefore the physician should become familiar with all the effects produced by drugs of this class.Phenelzine sulfate is oxidised by MAO to form reactive intermediates which then irreversibly inactivate the flavin prosthetic group of MAO. In the clinical setting, maximal inhibition of MAO is usually achieved within a few days (5 to 10 days in biopsy samples), although the antidepressant effect may be delayed for 2 to 3 weeks. Evaluation of MAO activity in human subjects indicates that favourable clinical responses are likely to occur when platelet MAO is inhibited by 85%.Up to 2 weeks may be required to restore amine metabolism to normal following withdrawal of MAO inhibitors, presumably because of the necessity for the re-synthesis of MAO. This is the reason why a period of 10 to 14 days is necessary after discontinuing MAO therapy before commencing a normal diet (see Precautions).Pharmacokinetics
There is little information available on the pharmacokinetics of phenelzine sulfate. Orally administered phenelzine sulfate is rapidly absorbed from the gastro-intestinal tract and has a short half life reported to be 1.2 hours in humans. The decay in the action-time curve for MAO inhibitors is not dependent on the pharmacokinetic parameters but on the rate of protein synthesis which restores the functional levels of MAO in the tissue compartments where it has been irreversibly inactivated. Although the biological activity of phenelzine sulfate is prolonged due to the characteristics of their interaction with the enzyme, its clinical efficacy appears to be reduced when given less frequently than once daily. Phenelzine sulfate is metabolised primarily by acetylation. The rate of metabolism is dependent upon the kinetic profile of the patient who may be a "slow" or "rapid" acetylator. There has been no consistent correlation noted between acetylator status and adverse effects of the drug. The major metabolites of phenelzine sulfate are phenylacetic acid and parahydroxyphenyl acetic acid. These metabolites constitute up to 79% of a single administered phenelzine dose excreted in the urine within 96 hours. It is not known whether these metabolites have clinical activity.Indications
Depressive illness, especially when phobic symptoms are present or when other anti-depressant therapy has failed.Contraindications
Phenelzine sulfate should not be used in patients who are hypersensitive to the drug, with phaeochromocytoma, congestive heart failure, a history of liver disease, or with abnormal liver function tests.MAO inhibitors including phenelzine sulfate are contraindicated in patients receiving guanethidine.Patients taking phenelzine sulfate should not undergo elective surgery requiring general anaesthesia. Also, they should not be given cocaine or local anaesthesia containing sympathomimetic vasoconstrictors. The possible combined hypotensive effects of phenelzine sulfate and spinal anaesthesia should be kept in mind. Phenelzine sulfate should be discontinued at least 10 days prior to elective surgery.Precautions
In depressed patients, the possibility of suicide should always be considered and adequate precautions taken. It is recommended that careful observations of patients undergoing phenelzine sulfate treatment be maintained until control of depression is achieved. If necessary, additional measures (ECT, hospitalisation, etc.) should be instituted.All patients undergoing treatment with phenelzine sulfate should be closely followed for symptoms of postural hypotension. Hypotensive side effects have occurred in hypertensive as well as normotensive and hypotensive patients. Blood pressure usually returns to pre-treatment levels rapidly when the drug is discontinued or the dosage is reduced.Because the effect of phenelzine sulfate on the convulsive threshold may be variable, adequate precautions should be taken when treating epileptic patients.Phenelzine sulfate may cause excessive stimulation in schizophrenic patients; in manic-depressive states it may result in a swing from a depressive to a manic phase.Phenelzine sulfate should be used with caution in combination with anti-hypertensive drugs, including thiazide diuretics and ß-blockers, since exaggerated hypotensive effects may result.There is conflicting evidence as to whether or not MAO inhibitors affect glucose metabolism or potentiate hypoglycaemic agents. This should be kept in mind if phenelzine sulfate is administered to diabetics.Carcinogenicity, Mutagenicity and Impairment of Fertility
Carcinogenicity has been observed in mouse studies but not in the rat. This is consistent with tumour and mutagenicity data reported for the MAO inhibitor, isoniazid.A group of 50 male and 50 female random-bred Swiss mice, 6 weeks of age, were given 0.015% phenelzine sulfate in the drinking water for their lifetime. An untreated group of 200 mice served as controls. Of the treated group, pulmonary tumours developed as follows: 38% adenomas, 7% adenomas and adenocarcinomas, and 1% adenocarcinomas). This compared to the pulmonary tumour incidence in the untreated group of 14% adenomas, 3% adenomas and adenocarcinomas, and 5% adenocarcinomas. Of the mice in the treated group 26% developed vascular tumours compared to 5% in the untreated group.An 87 week study of 26 male Sprague-Dawley rats, fed diets of phenelzine to evaluate carcinogenesis reported no significant difference in the incidence of both colonic and small intestinal adenocarcinomas between the phenelzine treated group (n=13) and matched controls (n=13).In the Salmonella typhimurium DNA reversion (Ames) test, phenelzine sulfate was a weak inducer of base-pair mutations in the absence of metabolic activation by rat liver homogenate. Results obtained in the pol A+/A- DNA reversion test in Escherichia coli report phenelzine sulfate as reactive against DNA. Similarly, phenelzine sulfate has been reported to inactivate Bacilus subtilis plasmid DNA.There is insufficient evidence to assess the carcinogenicity of phenelzine sulfate in humans.Impairment of fertility
25 female white mice were given 25 mg/kg per day phenelzine sulfate by s.c. injection on days 1-6 of pregnancy. The first day of pregnancy was dated from the finding of the vaginal plug. 9 out of 25 (36%) mice had surviving litters at autopsy on day 14, the remaining sixteen showed no signs of implantation. Within the control group, 67% of mice with vaginal plugs became pregnant. This result was statistically significant (p < 0.001). It was concluded that, during the first 6 days of gestation, implantation was partially suppressed.Use in Pregnancy
Pregnancy category B3. The safe use of phenelzine sulfate during pregnancy has not been established. There are insufficient adequate and well-controlled studies in pregnant women. Therefore, phenelzine should be used in pregnant women only if clearly needed and if the potential benefits justify the potential risk to the foetus.Use in Lactation
The safe use of phenelzine sulfate during lactation has not been established. There are insufficient adequate and well-controlled studies in lactating women. Therefore, phenelzine sulfate should be used in lactating women only if clearly needed. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants to phenelzine sulfate, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother, or to discontinue nursing.Paediatric Usage
Phenelzine sulfate is not recommended for patients under 16 years of age since there are no controlled studies of safety in this age group.Warning to the Patient
All patients should be warned that the following foods, beverages, and medications must be avoided while taking phenelzine sulfate, and for two weeks after discontinuing use.Foods and Beverages to Avoid:
Meat and fish: pickled herring, liver, dry sausage (including Genoa salami, hard salami, pepperoni, and Lebanon bologna)Vegetables: broad bean pods (fava bean pods) and sauerkrautDairy Products: cheese, yoghurt (cottage cheese and cream cheese are allowed)Beverages: beer, wine, alcohol-free and reduced alcohol beer and wine productsMiscellaneous: yeast extract (including brewer's yeast in large quantities), meat extract, excessive amounts of caffeine and chocolate, any spoiled or improperly refrigerated, handled or stored protein-rich foods such as meats, fish, and dairy products, including foods that may have undergone protein changes by aging, pickling, fermentation, or smoking to improve flavour.Medications to Avoid:
Cold and cough preparations (including those containing dextromethorphan)Nasal decongestants (tablets, drops or spray)Hay-fever medicationsSinus medicationsAsthma inhalant medicationsAnti-appetite medicinesWeight-reducing preparations"Pep" pillsTryptophan-containing preparationsCertain prescription drugs should be avoided. Therefore, patients under the care of another physician or dentist, should inform him/her that they are taking phenelzine sulfate.Patients should be warned that the use of the above foods, beverages, or medications may cause a reaction characterised by headache and other serious symptoms due to a rise in blood pressure, with the exception of dextromethorphan which may cause reactions similar to those seen with pethidine.Patients should be instructed to report promptly the occurrence of headache or other unusual symptoms.Interactions
The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see Adverse Reactions). Therefore, patients being treated with phenelzine sulfate should not take sympathomimetic drugs (including amphetamines, cocaine, methylphenidate hydrochloride, dopamine, adrenaline, noradrenaline and ephedrine) or related compounds (including methyldopa, levodopa, tryptophan, L-tyrosine and phenylalanine). Hypertensive crises during phenelzine sulfate therapy may also be caused by the ingestion of foods with a high concentration of tyramine or dopamine. Therefore, patients being treated with phenelzine sulfate should avoid high protein food that has undergone protein breakdown by aging, fermentation, pickling, smoking, or bacterial contamination. Patients should avoid cheeses (especially aged varieties), pickled herring, beer, wine, liver, yeast extract (including brewer's yeast in large quantities), dry sausage (including Genoa salami, hard salami, pepperoni, and Lebanon bologna), pods of broad beans (Fava beans) and yoghurt. Excessive amounts of caffeine, and chocolate may also cause hypertensive reactions.Phenelzine sulfate should not be used in combination with dextromethorphan or with CNS depressants such as alcohol and certain narcotics (including pethidine and propoxyphene). Excitation seizures, delirium, hyperpyrexia, circulatory collapse, coma, and death have been reported in patients receiving MAO inhibitor therapy who have been given a single dose of pethidine. Phenelzine sulfate should not be administered together with or in rapid succession to other MAO inhibitors, or dibenzazepine derivative drugs because hypertensive crises and convulsive seizures, fever, marked sweating, excitation, delirium, tremor, coma, and circulatory collapse may occur. Dibenzazepine derivative drugs include nortriptyline hydrochloride amitriptyline hydrochloride, perphenazine, clomipramine hydrochloride, desipramine hydrochloride, imipramine hydrochloride, doxepin hydrochloride, carbamazepine, cyclobenzaprine hydrochloride, amoxapine hydrochloride, maprotiline hydrochloride, trimipramine maleate, protriptyline hydrochloride.At least 10 days should elapse between the discontinuation of another MAO inhibitor and the institution of phenelzine sulfate.MAO inhibitors, including phenelzine sulfate, potentiate hexobarbital hypnosis in animals. Therefore, barbiturates should be given at a reduced dose with phenelzine sulfate.MAO inhibitors inhibit the destruction of serotonin and noradrenaline, which are believed to be released from tissue stores by rauwolfia alkaloids. Accordingly, caution should be exercised when rauwolfia is used concomitantly with an MAO inhibitor, including phenelzine sulfate. Phenelzine sulfate should not be used in combination with buspirone hydrochloride, since several cases of elevated blood pressure have been reported in patients taking MAO inhibitors who were then given buspirone hydrochloride.At least 10 days should elapse between the discontinuation of phenelzine sulfate and the institution of another antidepressant or buspirone hydrochloride.There have been reports of serious reactions (including hyperthermia, rigidity, myoclonic movements and death) when serotonin re-uptake inhibitors or venlafaxine hydrochloride has been combined with an MAO inhibitor. Therefore, phenelzine sulfate should not be used in combination with venlafaxine hydrochloride, or serotonin re-uptake inhibitors.Before initiating phenelzine sulfate after using other serotonin re-uptake inhibitors, a sufficient amount of time must be allowed for clearance of the serotonin re-uptake inhibitor and its active metabolites. Allow at least five weeks between discontinuation of fluoxetine and initiation of phenelzine sulfate and at least 10 days between discontinuation of phenelzine sulfate and initiation of fluoxetine, or other serotonin re-uptake inhibitors.The combination of MAO inhibitors and tryptophan has been reported to cause behavioural and neurological symptoms including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperflexia, shivering, ocular oscillations and Babinski signs.Adverse Reactions
Phenelzine sulfate is a potent inhibitor of monoamine oxidase. Because this enzyme is widely distributed throughout the body, diverse pharmacological effects can be expected to occur. When they occur, such adverse effects can be mild, moderate or severe (see below), and can be minimised by adjusting dosage.Common side effects include:Nervous System - Dizziness, headache, drowsiness, sleep disturbances (including insomnia and hypersomnia), fatigue, weakness, tremors, twitching, myoclonic movements, hyperreflexia.Gastrointestinal - Constipation, dry mouth, gastrointestinal disturbances, elevated serum transaminases (without accompanying signs and symptoms).Metabolic - Weight gain.Cardiovascular - Postural hypotension, oedema.Genitourinary - Sexual disturbances, i.e., anorgasmia and ejaculatory disturbances.Less common mild to moderate side effects (some of which have been reported in a single patient or by a single physician) include:Nervous System - Jitteriness, palilalia, euphoria, nystagmus, paraesthesias.Genitourinary - Urinary retention.Metabolic - Hypernatraemia.Dermatological - Pruritus, skin rash, sweating.Special Senses - Blurred vision, glaucoma.Of the more severe side effects that have been reported with any consistency, hypomania has been the most common. This reaction has been largely limited to patients in whom disorders characterised by hyperkinetic symptoms coexist with, but are obscured by, depressive affect; hypomania usually appeared as depression improved. If agitation is present, it may be increased with phenelzine sulfate. Hypomania and agitation also have been reported at higher than recommended doses, or following long-term therapy.Although reported less frequently, and sometimes only once, additional severe side effects include:Nervous System - Ataxia, shock-like coma, toxic delirium, manic reaction, delusional parasitosis, convulsions, acute anxiety reaction, precipitation of schizophrenia, acute dystonic reaction, sensorimotor peripheral neuropathy, speech blockade, transient respiratory and cardiovascular depression following ECT.Gastrointestinal - To date, fatal progressive necrotising hepatocellular damage has been reported infrequently. Reversible jaundice.Haematological - Leucopoenia.Immunological - Lupus-like illnessMetabolic - Inappropriate ADH secretion, Hypermetabolic syndrome (which may include, but is not limited to, hyperpyrexia, tachycardia, tachypnoea, muscular rigidity, elevated CK levels, metabolic acidosis, hypoxia, coma and may resemble an overdose).Respiratory - Oedema of the glottis.General - Fever associated with increased muscle tone.The most serious reactions to phenelzine sulfate involve changes in blood pressure.Hypertensive Crises
The most important reaction associated with phenelzine sulfate administration is the occurrence of hypertensive crises, which have sometimes been fatal.These crises are characterised by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea, vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), dilated pupils, and photophobia. Either tachycardia or bradycardia may be present and can be associated with constricting chest pain.NOTE: Intracranial bleeding has been reported in association with the increase in blood pressure.Blood pressure should be observed frequently to detect evidence of any pressor response in all patients receiving phenelzine sulfate. Therapy should be discontinued immediately upon the occurrence of palpitation or frequent headaches during therapy.Recommended treatment in hypertensive crisis
If a hypertensive crisis occurs, phenelzine sulfate should be discontinued immediately and therapy to lower blood pressure should be instituted immediately. On the basis of present evidence, phentolamine is recommended. (The dosage reported for phentolamine is 5 mg intravenously.) Care should be taken to administer this drug slowly in order to avoid producing an excessive hypotensive effect. Fever should be managed by means of external cooling.Withdrawal may be associated with nausea, vomiting, and malaise.An uncommon withdrawal syndrome following abrupt withdrawal of phenelzine sulfate has been infrequently reported. Signs and symptoms of this syndrome generally commence 24 to 72 hours after drug discontinuation and may range from vivid nightmares with agitation to frank psychosis and convulsions. This syndrome generally responds to reinstitution of low-dose phenelzine sulfate therapy followed by cautious downward titration and discontinuation.Dosage and Administration
Initial dose: The usual starting dose of Nardil is 15 mg three times a day.Early phase treatment: Dosage should be increased to at least 60 mg a day at a fairly rapid pace consistent with patient tolerance. It may be necessary to increase dosage to 90 mg a day to obtain sufficient MAO inhibition. Many patients do not show a clinical response until treatment at 60 mg a day has been continued for at least four weeks.Maintenance dose: After maximum benefit from Nardil is achieved, usually within two to six weeks, the dosage should be reduced slowly over several weeks. Maintenance doses may be as low as one tablet (usual dose) a day or every other day, and should be continued for as long as is required.While most patients will be adequately controlled on the recommended dose, some may not. As Nardil is metabolised by acetylation, patients who have a "fast acetylation" phenotype may require a higher dose. The above recommended doses should be adjusted by the physician in accordance with clinical observation.Children
Nardil is not recommended for use in children.The Elderly
Nardil should not be administered to patients over 60 years of age.Overdosage
Note - For management of HYPERTENSIVE CRISES see Adverse Reactions. Accidental or intentional overdosage may be more common in patients who are depressed. It should be remembered that multiple drugs and/or alcohol may have been ingested.Depending on the amount of overdosage with phenelzine sulfate, a varying and mixed clinical picture may develop, including signs and symptoms of central nervous system and cardiovascular stimulation and/or depression. Signs and symptoms may be absent or minimal during the initial 12-hour period following ingestion and may develop slowly thereafter, reaching a maximum in 24-48 hours. Death has been reported following overdosage. Therefore, immediate hospitalisation with continuous patient observation and monitoring throughout this period, is essential.Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonus, rigidity, convulsions and coma, rapid and irregular pulse, hypertension, hypotension and vascular collapse, precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin.Treatment
Intensive symptomatic and supportive treatment may be required. Induction of emesis or gastric lavage with instillation of charcoal slurry may be helpful in early poisoning, provided the airway has been protected against aspiration. Signs and symptoms of central nervous system stimulation, including convulsions, should be treated with diazepam, given slowly intravenously. Phenothiazine derivatives and central nervous system stimulants should be avoided. Hypotension and vascular collapse should be treated with intravenous fluids and, if necessary, blood pressure titration with an intravenous infusion of dilute pressor agent. It should be noted that adrenergic agents may produce a markedly increased pressor response.Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance as required. Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential.There are no data on the lethal dose in man. The pathophysiological effects of massive overdosage may persist for several days, since the drug acts by inhibiting physiological enzyme systems. With symptomatic and supportive measures, recovery from mild overdosage may be expected within 3 to 4 days. Haemodialysis, peritoneal dialysis, and charcoal haemoperfusion may be of value in massive overdosage, but sufficient data are not available to recommend their routine use in these cases.Toxic blood levels of phenelzine have not been established, and assay methods are not practical for clinical or toxicological use.Presentation
Tablets: Phenelzine as sulphate 15mg; orange, biconvex, sugar-coatedPharmaceutical Precautions
Store below 25ºCMedicine Classification
Prescription medicine.Packaging Quantities
Tablet, 15 mg; 50's.


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