Parnate 10 mg
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Pharmacology
Tranylcypromine is a nonhydrazine monoamine oxidase (MAO) inhibitor with a rapid onset of activity. It increases the concentration of epinephrine, norepinephrine and serotonin in storage sites in the nervous system. In theory, the increased concentration of monoamines in the brain stem is the basis for its antidepressant activity.
Tranylcypromine differs from other MAO inhibitors in being a reversible inhibitor. When tranylcypromine is withdrawn, monoamine oxidase activity is generally restored within a week, although the drug is excreted in 24 hours.
Indications
Tranylcypromine has been used successfully to treat psychotic depressive states such as: depressive phase of manic-depressive psychosis, involutional melancholia, reactive depression and psychoneurotic depression of moderate to severe intensity.
In the psychiatric treatment of severe endogenous depression, it is impossible to predict, with presently known data, which patients will respond best to tranylcypromine and which to electroconvulsive therapy (ECT). The drug may be indicated in some reactive depressions in which ECT is not indicated.
Tranylcypromine is not recommended for use in mild depressive states resulting from temporary situational difficulties.
Note: Because tranylcypromine is a potent agent with the capability of producing serious side effects (e.g., hypertensive crises, sometimes complicated by fatal intracranial bleeding), its use should be reserved for patients who can be closely supervised.
Before prescribing tranylcypromine, the physician should be thoroughly familiar with information on its dosage, side effects and contraindications, as well as the principles of MAO inhibitor therapy and the side effects of this class of drugs as reported in the literature. The physician should also be familiar with the symptomatology of mental depression and alternative methods of treatment, to aid in the careful selection of patients for tranylcypromine therapy.
Selecting the Patient:
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Tranylcypromine should be used for the symptomatic treatment of moderate to severe depression. It is not recommended for those mild depressive reactions where more conservative therapy is indicated.
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Tranylcypromine should be reserved for those patients who can be followed closely. Blood pressure should be recorded periodically to detect evidence of pressor response to tranylcypromine therapy.
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Tranylcypromine should not be used in patients with cerebrovascular or cardiovascular disorders (e.g., arteriosclerosis, hypertension) (see Contraindications).
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Tranylcypromine should not be used in patients receiving any other antidepressant medication (see Contraindications).
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Tranylcypromine is not recommended for patients with a history of recurring or frequent headaches, especially the tension and vascular types.
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Tranylcypromine should not be used alone in patients with marked psychomotor agitation, since it is recognized that antidepressant drugs can aggravate some coexisting symptoms such as agitation or anxiety.
Tranylcypromine Combined With Trifluoperazine: Tranylcypromine has been combined with trifluoperazine in the treatment of coexisting anxiety and depression. Such combined therapy has been found particularly valuable when used to treat depressed patients in whom a persistent disorder of mood is associated with anxiety, moderate agitation, inappropriate mental symptoms (such as unnatural fears or suspicions and phobias) or improper response to single-agent therapy.
Combined tranylcypromine-trifluoperazine therapy has been used successfully in the treatment of psychiatric conditions such as psychoneurotic depression, agitated depression, schizo-affective disorders and pseudoneurotic schizophrenia. If the patient appears to have a pure depression, tranylcypromine should be used alone and, similarly, if the symptoms appear to indicate a pure anxiety state, trifluoperazine should be used first. The combined therapy has frequently displayed striking effectiveness in patients who obtained little benefit from treatment with a succession of single drugs.
For comprehensive prescribing information on trifluoperazine, refer to Prescribing Information on that product.
Precautions
Drug Interactions
(see also Contraindications): In general, the physician should bear in mind the possibility of a lowered margin of safety when tranylcypromine is administered in combination with potent drugs and should adjust dosage carefully.
A marked potentiating effect has been reported on some CNS depressants such as morphine, meperidine, barbiturates and alcohol. For this reason, narcotics and barbiturates should be used conservatively with tranylcypromine, and patients should be warned that the drug may potentiate the effects of alcoholic beverages.
Caution should be exercised when giving tranylcypromine with hypotensive agents: guanethidine, as its action may be antagonized; reserpine, as hyperactivity may occur; alpha-methyldopa, since the combination may give rise to central excitation.
When tranylcypromine is combined with those phenothiazine derivatives or other compounds known to affect blood pressure, patients should be observed more closely because of the possibility of additive hypotensive effects.
Caution should also be exercised when giving tranylcypromine with antiparkinson agents, as the combination may result in potentiation, with profuse sweating, tremulousness and a rise in body temperature.
Drugs which lower the seizure threshold, including MAO inhibitors, should not be used with Amipaque. As with other MAOIs, tranylcypromine should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours after the procedure.
Caution should be exercised when giving tranylcypromine with clomipramine hydrochloride, as this drug, in combination with a MAOI, has been reported to result in hyperpyrexia, diffuse intravascular coagulation, and status epilepticus; and pethidine, as this drug in combination with a MAOI may lead to an increase of serotonin associated effects which could cause serotonin toxicity.
Tranylcypromine should be administered with caution to patients receiving disulfiram. In a single study, rats given high intraperitoneal doses of d- or l-isomers of tranylcypromine sulfate plus disulfiram experienced severe toxicity including convulsions and death. Additional studies in rats given high oral doses of racemic tranylcypromine sulfate and disulfiram produced no adverse interaction.
Occupational Hazards
Tranylcypromine may affect ability to drive or operate machinery.
In Angina: MAOIs may have the capacity to suppress anginal pain that would otherwise serve as a warning of myocardial ischemia.
In Depression: Tranylcypromine may aggravate coexisting symptoms in depression, such as anxiety and agitation. In depressed patients, the possibility of suicide should always be considered and adequate precautions taken. Exclusive reliance on drug therapy to prevent suicidal attempts is unwarranted, as there may be a delay in the onset of therapeutic effect or an increase in anxiety and agitation. Also, some patients fail to respond to drug therapy or may respond only temporarily.
In Diabetes: Some MAOIs have contributed to hypoglycemic episodes in diabetic patients receiving insulin or oral hypoglycemic agents. Therefore, tranylcypromine should be used with caution in diabetics under treatment with these drugs.
In Epilepsy: Because the influence of tranylcypromine on the convulsive threshold is variable in animal experiments, suitable precautions should be taken if epileptic patients are treated.
In Hyperthyroidism: Use tranylcypromine with caution in hyperthyroid patients, because of their increased sensitivity to pressor amines.
In Renal Dysfunction: The usual precautions should be observed in patients with impaired renal function, since there is a possibility of cumulative effects in such patients.
Pregnancy and Lactation
Tranylcypromine has been shown to pass through the placental barrier to the fetus of the rat and into the milk of the lactating dog. Nevertheless, as with any potent drug, the physician must assess the definite medical need when prescribing for the pregnant patient. Adequate human data on use during pregnancy or lactation and adequate animal reproduction studies are not available.
In Surgery: It is suggested that tranylcypromine be discontinued at least 7 days before elective surgery, to allow time for recovery of monoamine oxidase activity before anesthetic agents are given.
Drug Dependency: There have been reports of drug dependency in patients using doses of tranylcypromine significantly in excess of the therapeutic range. Some of these patients had a history of previous substance abuse.
Tranylcypromine tablets contain sodium benzoate.
Supplied
Each biconvex, rose-red, film-coated tablet, with PARNATE and SB monogram printed in black on one side, contains: tranylcypromine 10 mg. Nonmedicinal ingredients: carnauba wax, citric acid, croscarmellose sodium, D&C Red No. 7, edible black printing ink, FD&C Blue No. 2, FD&C Yellow No. 6, gelatin, hydroxypropylmethyl cellulose, lactose, magnesium stearate, microcrystalline cellulose, talc, propylene glycol 400, purified water and titanium dioxide. Bottles of 100. Store at 15-30°C.
Contraindications
In patients with a previous history of hypersensitivity to tranylcypromine or excipients.
In patients with cerebrovascular or cardiovascular disorders or a history of recurrent or frequent headaches. Tranylcypromine should not be administered to patients with confirmed or suspected cerebrovascular defect, hypertension or cardiovascular disease.
The drug should be used with caution in individuals beyond the age of 60, because of the possibility of existing cerebral sclerosis with damaged vessels.
In patients with liver damage or blood dyscrasias. Extensive clinical use and laboratory tests have revealed no evidence of liver toxicity or blood dyscrasias due to tranylcypromine therapy. Because rare cases of hepatitis have been reported, it is recommended that patients with known liver damage or blood dyscrasias should not be treated with tranylcypromine.
In pheochromocytoma. Tranylcypromine should not be used in the presence of known or suspected pheochromocytoma, as such tumours secrete pressor substances.
In combination with certain drugs. Because the effect of many antidepressant drugs may persist for 10 to 20 days, do not commence tranylcypromine therapy within less than a week of discontinuing treatment with such drugs; then, use half the normal dosage for the first week. Similarly, allow 1 week to elapse between the discontinuance of tranylcypromine and the administration of any other drug that is contraindicated with tranylcypromine such as:
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Other monoamine oxidase inhibitors (MAOIs) such as isocarboxazid and phenelzine sulfate.
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Dibenzazepine derivatives such as amitriptyline, nortriptyline, protriptyline, desipramine, imipramine, doxepin, perphenazine, carbamazepine, cyclobenzaprine, amoxapine, maprotiline and trimipramine, as combination with these drugs may induce hypertensive crises or severe convulsive seizures.
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Sympathomimetics including amphetamines, ephedrine and over-the-counter preparations for colds, hay fever and weight reduction that contain vasoconstrictors (e.g., phenylephrine, phenylpropanolamine) as well as with methyldopa, dopamine, levodopa and tryptophan, as such combinations may precipitate hypertension, severe headache, hyperpyrexia and rarely even cerebral (subarachnoid) hemorrhage. The combination of MAOIs and tryptophan has been reported to cause behavior and neurologic syndromes including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperreflexia, shivering, ocular oscillations and Babinski signs.
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SSRIs or SNRIs (eg. venlafaxine): There have been reports of serious, sometimes fatal reactions when MAOIs are given before, with, or shortly after discontinuation with some SSRIs or SNRIs. It is recommended that MAOIs are not used in combination with SSRIs or SNRIs. If SSRIs or SNRIs are used consecutively, a suitable washout period should be observed. The following is a guide, but prescribing information for individual products should be consulted:
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MAOI followed by SSRI or SNRI (eg. venlafaxine)—2 weeks
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Fluoxetine followed by MAOI—5 weeks
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Other SSRI followed by MAOI—2 weeks
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SNRI (eg. venlafaxine) followed by MAOI—1 week
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Other drugs: dextromethorphan, buspirone HCl.
In combination with cheese or other foods with a high tyramine content: Hypertensive crises have sometimes occurred during tranylcypromine therapy after ingestion of foods with a high tyramine content. Tyramine is normally metabolized by monoamine oxidase in the intestinal and hepatic cells. When monoamine oxidase is inhibited, tyramine absorbed from the gastrointestinal tract passes freely into the circulation. It releases norepinephrine from adrenergic neurones, causing exaggerated hypertensive and other effects.
In general, the patient should avoid protein foods in which aging or protein breakdown is used to increase flavor. In particular, patients should be instructed not to take foods such as cheese (exceptions: cream cheese and cottage cheese), sour cream, pickled herring, liver, meat prepared with tenderizers, Bovril, yeast extracts like Marmite, soy beans, pods of broad beans (fava beans), canned figs, raisins, bananas (peel) or avocados (especially if overripe), chocolate and caviar.
Alcoholic beverages have been known to precipitate a severe reaction. Therefore, the patient should avoid alcoholic drinks, especially red wines (such as Chianti), sherry, beer (including nonalcoholic beer), etc.
Patients on tranylcypromine therapy should also be advised not to consume excessive amounts of caffeine in any form (coffee, tea, cola drinks, etc.) because of possible enhanced effects of caffeine on the CNS.
Warnings
Mania and bipolar disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone can increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. As with all antidepressants, tranylcypromine should be used with caution in patients with a history of mania.
Hypertensive Crisis
The most important adverse reaction associated with tranylcypromine is hypertensive crisis, which has sometimes been fatal. This response is not usually dose-related. It is associated with a distinctive reaction characterized by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea or vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin) with early pallor followed later by flushing, and photophobia. Either tachycardia or bradycardia may be present, sometimes associated with constricting chest pain. Mydriasis may occur.
The occipital headache, together with pain and stiffness in the cervical muscles, may mimic subarachnoid hemorrhage, but can equally be associated with actual intracranial bleeding, as in other conditions where a sudden rise in blood pressure occurs. Cases of such bleeding have been reported, some of which have been fatal.
Blood pressure should be followed closely in patients taking tranylcypromine to detect evidence of any pressor response. It is emphasized that full reliance should not be placed on blood pressure readings, but that the patient should also be observed frequently.
Therapy should be discontinued immediately upon the occurrence of palpitation or frequent headache during tranylcypromine therapy. These signs may be prodromal of a hypertensive reaction. Patients should be instructed to report promptly the occurrence of headache or other symptoms.
If a hypertensive reaction occurs, tranylcypromine should be discontinued and therapy to lower blood pressure should be given immediate consideration. Headache tends to abate as blood pressure decreases. On the basis of present evidence, phentolamine is recommended for use in acute cases (the dosage reported for phentolamine is 5 mg i.v. administered slowly). Do not use parenteral reserpine or rauwolfia alkaloids for the treatment of a hypertensive crisis, as they may, by releasing catecholamines, exacerbate the condition. Care should be taken to administer these drugs in such a way as to avoid producing an excessive hypotensive effect. Fever should be managed by means of external cooling. Other symptomatic and supportive measures may be desirable in particular cases. Acute distress generally subsides in 24 hours or less. For milder reactions, the more moderate adrenolytic action of injectable chlorpromazine (available as Largactil) may be more appropriate.
Hypotension, which may be postural, has been observed during tranylcypromine therapy, particularly at doses above 30 mg daily. It is seen most commonly (but not exclusively) in patients with pre-existing hypertension. In most instances, it affects the systolic readings. Rare instances of syncope have been seen. Dosage increases should be made more gradually in patients showing a tendency toward hypotension at the starting dose. Postural hypotension can usually be relieved by having the patient lie down until blood pressure returns to normal. This side effect is usually temporary, but if it persists, tranylcypromine should be discontinued. Blood pressure usually returns rapidly to pretreatment levels upon discontinuation of tranylcypromine.
Also, when tranylcypromine is combined with those phenothiazine derivatives or other compounds known to cause hypotension, the possibility of additive hypotensive effects should be considered.
Children and adolescents (less than 18 years of age)
Treatment with antidepressants is associated with an increased risk of suicidal thinking and behaviour in children and adolescents with major depressive disorder and other psychiatric disorders.
Clinical worsening and suicide risk in adults with psychiatric disorders
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications. This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases. It is general clinical experience with all antidepressant therapies that the risk of suicide may increase in the early stages of recovery.
Patients with a history of suicidal behaviour or thoughts, and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. It should be recognised that the onset of some neuropsychiatric symptoms could be related either to the underlying disease state or the drug therapy (see Mania and bipolar disorder below).
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Adverse Effects
The most frequently seen side effect is insomnia, which can usually be overcome by giving the last dose of the day not later than 3 p.m., by reducing the dose, or by prescribing a mild hypnotic.
Some of the following unwanted reactions have been reported in the literature; others are possible. They are classified according to their seriousness and probable cause—an arrangement intended to help the physician view them in proper perspective.
Pharmacologic Reactions of a Serious Nature:
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Hypertensive Crisis: see Warnings.
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Hypotension: see Warnings.
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Overstimulation: Overstimulation, which may include increased anxiety, agitation and manic symptoms, is usually evidence of excessive therapeutic action. Dosage should be reduced, or a phenothiazine tranquilizer should be administered concomitantly.
Pharmacologic Reactions of a Less Serious Nature: Patients may experience restlessness, insomnia, drowsiness, dizziness, weakness, dry mouth, nausea, abdominal pain, anorexia, diarrhea or constipation. Tachycardia, palpitation, blurred vision, headache without blood pressure elevation, chills, sweating, urinary retention, edema and impotence have each been reported in at least 1 patient.
Hematologic or Allergic Reactions: Blood dyscrasias, including anemia, leukopenia, agranulocytosis and thrombocytopenia have been reported. Rare instances of hepatitis (e.g., one case of mild jaundice, not of the serious type associated with hydrazine MAOIs) and skin rash have been reported.
Other Reactions: Micturition difficulty has been reported. Tinnitus, muscle spasm and tremors, paresthesia and habituation have been reported so rarely that the role of tranylcypromine cannot be established. Alopecia has been reported very rarely.
Drug Dependency: There have been reports of drug dependency in patients using tranylcypromine tablets (see Precautions). Symptoms reported after stopping tranylcypromine include: sleep disturbances, depression, confusion, delirium, tremor, agitation, convulsion, anxiety, hallucinations, fatigue, headache.
Overdose
Symptoms
The characteristic symptoms that may arise as a result of tranylcypromine overdosage are usually those which have already been described under Warnings and Adverse Effects. However, an intensification of these symptoms and sometimes severe additional manifestations may be seen, depending on the degree of overdosage and on individual susceptibility.
Some patients exhibit insomnia, restlessness and anxiety, progressing in severe cases to agitation, mental confusion and incoherence. Hypotension, dizziness, weakness and drowsiness may occur, progressing in severe cases to extreme dizziness and shock. A few patients have displayed hypertension with severe headache and other symptoms. Rare instances have been reported in which hypertension was accompanied by twitching or myoclonic fibrillation of skeletal muscles with hyperpyrexia, sometimes progressing to generalized rigidity and coma.
Treatment
Treatment normally consists of general supportive measures, close observation of vital signs and steps to counteract specific symptoms as they occur. The management of hypertensive reactions is described under Warnings. Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
External cooling is recommended if hyperpyrexia occurs. Barbiturates have been reported to help myoclonic reactions, but frequency of administration should be controlled carefully because tranylcypromine may prolong barbiturate activity.
When hypotension requires treatment, the standard measures for managing circulatory shock should be initiated. If pressor agents are required, norepinephrine is the most suitable. The rate of infusion should be regulated by careful observation of the patient. MAOIs may sometimes increase the pressor response, as has been demonstrated with norepinephrine. Mephentermine may be required if marked refractory hypotension occurs.
Although tranylcypromine is rapidly excreted, its MAO inhibiting action may persist for approximately 1 week.
Dosage
Dosage should be adjusted to the requirements of the individual patient. If the patient responds to therapy, the response is usually seen within 48 hours to 3 weeks after starting medication.
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Recommended starting dosage is 20 mg/day (10 mg in the morning and 10 mg in the afternoon).
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Continue this dosage for 2 to 3 weeks.
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If no signs of a response appear, increase dosage to 30 mg daily (20 mg upon arising and 10 mg in the afternoon).
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Continue this dosage for at least 1 week. If no improvement occurs, continued administration is unlikely to be beneficial. Although dosages above 30 mg/day have been used, it should be borne in mind that the incidence and severity of side effects may increase as dosage is raised. Dosage increases should be made in increments of 10 mg/day, and ordinarily at intervals of 1 to 3 weeks.
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When a satisfactory response is obtained, dosage may be reduced to a maintenance level.
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Some patients will be maintained on 20 mg/day; many will need only 10 mg daily.
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Reduction from peak to maintenance dosage may be desirable before withdrawal. If withdrawn prematurely, original symptoms will recur. No tendency to produce rebound depressions of greater intensity has been seen, although this is a theoretical possibility in patients treated at high doses. Experimental work indicates that tranylcypromine is rapidly excreted. Inhibition of MAO activity may, however, persist for up to 1 week.
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Combined tranylcypromine-trifluoperazine therapy: For those physicians wishing to combine tranylcypromine with trifluoperazine, the usual dosage is tranylcypromine 10 mg plus trifluoperazine 1 mg or 2 mg twice daily (morning and afternoon) depending on the individual patient requirements. After a satisfactory response is secured, medication can often be reduced to one dose daily, usually administered in the morning. Patients displaying marked mental disturbance, especially psychotic manifestations or severe agitation, will usually require larger initial doses of trifluoperazine.
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Children and adolescents (less than 18 years of age): PARNATE is not indicated for use in children or adolescents aged less than 18 years (see Warnings and Precautions).
Note: When ECT is being administered concurrently with PARNATE, 10 mg b.i.d. can usually be given during the series, then reduced to 10 mg daily for maintenance therapy.
